Cardiovascular Inflammation Reduction Trial (CIRT)

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ClinicalTrials.gov Identifier: NCT01594333

Recruitment Status : Completed

First Posted : May 9, 2012

Results First Posted : July 24, 2020

Last Update Posted : July 24, 2020

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Sponsor:

Collaborator:

National Heart, Lung, and Blood Institute (NHLBI)

Information provided by (Responsible Party):

Paul Ridker, Brigham and Women's Hospital

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition	Cardiovascular Disease
Interventions	Drug: Methotrexate Drug: Placebo
Enrollment	4786

Participant Flow

Recruitment Details	9321 subjects were screened and 4786 subjects were randomized starting from April, 2013 through March 2018 in 417 clinical sites in Canada and the United States
Pre-assignment Details	9321 subjects were screened, 2987 were found to be ineligible and 176 were discontinued due to premature trial closure prior to entering the open label run-in. 6158 started the run-in. Of those, 1171 were ineligible, 201 were discontinued due to premature trial closure and 4786 subjects were randomly assigned to either Methotrexate or Placebo


Arm/Group Title	Methotrexate	Placebo
Arm/Group Description	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Period Title: Overall Study
Started	2391	2395
Completed	2230	2244
Not Completed	161	151
Reason Not Completed
Death	96	83
Lost to Follow-up	5	5
Withdrawal by Subject	60	63

Baseline Characteristics

Arm/Group Title		Methotrexate	Placebo	Total
Arm/Group Description		Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...	Total of all reporting groups
Arm/Group Description		Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week	Total of all reporting groups
Overall Number of Baseline Participants		2391	2395	4786
Baseline Analysis Population Description		...
Baseline Analysis Population Description		All randomized participants
Age, Continuous ^[1] Median (Inter-Quartile Range) Unit of measure: Years
	Number Analyzed	2391 participants	2395 participants	4786 participants
		65.6 (59.7 to 71.8)	66.0 (59.8 to 71.7)	65.8 (59.7 to 71.7)
		[1] Measure Description: Age at randomization
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2395 participants	4786 participants
	Female	461 19.3%	437 18.2%	898 18.8%
	Male	1930 80.7%	1958 81.8%	3888 81.2%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants
Hispanic/Latino	Number Analyzed	2391 participants	2395 participants	4786 participants
Hispanic/Latino		206 8.6%	177 7.4%	383 8.0%
White/Non-hispanic or Latino	Number Analyzed	2391 participants	2395 participants	4786 participants
White/Non-hispanic or Latino		1801 75.3%	1837 76.7%	3638 76.0%
Asian	Number Analyzed	2391 participants	2395 participants	4786 participants
Asian		89 3.7%	92 3.8%	181 3.8%
Black or African American	Number Analyzed	2391 participants	2395 participants	4786 participants
Black or African American		186 7.8%	152 6.3%	338 7.1%
American Indian or Alaska Native	Number Analyzed	2391 participants	2395 participants	4786 participants
American Indian or Alaska Native		6 0.3%	6 0.3%	12 0.3%
Native Hawaiian or other Pacific Islander	Number Analyzed	2391 participants	2395 participants	4786 participants
Native Hawaiian or other Pacific Islander		3 0.1%	6 0.3%	9 0.2%
Multiracial	Number Analyzed	2391 participants	2395 participants	4786 participants
Multiracial		13 0.5%	7 0.3%	20 0.4%
Other	Number Analyzed	2391 participants	2395 participants	4786 participants
Other		42 1.8%	45 1.9%	87 1.8%
White, Unknown Ethnicity	Number Analyzed	2391 participants	2395 participants	4786 participants
White, Unknown Ethnicity		45 1.9%	73 3.0%	118 2.5%
Region of Enrollment Measure Type: Number Unit of measure: Participants
Canada	Number Analyzed	2391 participants	2395 participants	4786 participants
Canada		407	404	811
Puerto Rico	Number Analyzed	2391 participants	2395 participants	4786 participants
Puerto Rico		19	17	36
United States	Number Analyzed	2391 participants	2395 participants	4786 participants
United States		1965	1974	3939
Smoking status Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2395 participants	4786 participants
	Current smoker	267 11.2%	270 11.3%	537 11.2%
	Past smoker	1173 49.1%	1215 50.7%	2388 49.9%
	Never smoked cigarettes	951 39.8%	910 38.0%	1861 38.9%
Alcohol use Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2395 participants	4786 participants
	Rarely/Never	1487 62.2%	1473 61.5%	2960 61.8%
	<=1 drink/week	514 21.5%	520 21.7%	1034 21.6%
	>1 drink/week	390 16.3%	402 16.8%	792 16.5%
Body Mass Index Median (Inter-Quartile Range) Unit of measure: Kilograms per meter squared
	Number Analyzed	2391 participants	2395 participants	4786 participants
		31.6 (28.2 to 35.5)	31.3 (28.1 to 35.6)	31.5 (28.2 to 35.6)
History of diagnosed hypertension ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2394 participants	4785 participants
	Yes	2153 90.0%	2169 90.6%	4322 90.3%
	No	238 10.0%	225 9.4%	463 9.7%
		[1] Measure Analysis Population Description: One subject is missing this information
Qualifying event Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2395 participants	4786 participants
	Myocardial infarction	1451 60.7%	1458 60.9%	2909 60.8%
	Multivessel coronary disease	940 39.3%	937 39.1%	1877 39.2%
Qualifying coexisting condition Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2395 participants	4786 participants
	Diabetes only	788 33.0%	823 34.4%	1611 33.7%
	Metabolic syndrome only	771 32.2%	780 32.6%	1551 32.4%
	Diabests and metabolic syndrome	832 34.8%	792 33.1%	1624 33.9%
History of congestive heart failure ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2394 participants	4785 participants
	Yes	288 12.0%	332 13.9%	620 13.0%
	No	2103 88.0%	2062 86.1%	4165 87.0%
		[1] Measure Analysis Population Description: One subject is missing this information
History of percutaneous coronary intervention ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2394 participants	4785 participants
	Yes	1396 58.4%	1420 59.3%	2816 58.9%
	No	995 41.6%	974 40.7%	1969 41.1%
		[1] Measure Analysis Population Description: One subject is missing this information
History of coronary-artery bypass grafting ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2394 participants	4785 participants
	Yes	1010 42.2%	1032 43.1%	2042 42.7%
	No	1381 57.8%	1362 56.9%	2743 57.3%
		[1] Measure Analysis Population Description: One subject is missing this information
Family history of premature myocardial infarction ^[1] [2] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2118 participants	2116 participants	4234 participants
	Yes	550 26.0%	536 25.3%	1086 25.6%
	No	1568 74.0%	1580 74.7%	3148 74.4%
		[1] Measure Description: A family history of premature myocardial infarction was considered to be an event occurring in the mother before the age of 65 or in the father before the age of 55. [2] Measure Analysis Population Description: 552 subjects are missing this information
Family history of premature stroke ^[1] [2] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2144 participants	2160 participants	4304 participants
	Yes	142 6.6%	136 6.3%	278 6.5%
	No	2002 93.4%	2024 93.7%	4026 93.5%
		[1] Measure Description: A family history of premature stroke infarction was considered to be an event occurring in the mother before the age of 65 or in the father before the age of 55. [2] Measure Analysis Population Description: 482 subjects are missing this information
Use of ACE inhibitor or ARB ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2395 participants	4786 participants
	Yes	1736 72.6%	1724 72.0%	3460 72.3%
	No	655 27.4%	671 28.0%	1326 27.7%
		[1] Measure Description: ACE denotes angiotensin-converting enzyme and ARB denotes angiotensin-receptor blocker
Use of a statin Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2395 participants	4786 participants
	Yes	2058 86.1%	2052 85.7%	4110 85.9%
	No	333 13.9%	343 14.3%	676 14.1%
Use of a beta-blocker Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2395 participants	4786 participants
	Yes	1870 78.2%	1905 79.5%	3775 78.9%
	No	521 21.8%	490 20.5%	1011 21.1%
Use of antiplatelet or antithrombotic agent Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	2391 participants	2395 participants	4786 participants
	Yes	2082 87.1%	2054 85.8%	4136 86.4%
	No	309 12.9%	341 14.2%	650 13.6%
Total cholesterol ^[1] [2] Median (Inter-Quartile Range) Unit of measure: mg/dL
	Number Analyzed	2369 participants	2372 participants	4741 participants
		141.0 (122.0 to 168.0)	140.9 (122.0 to 164.0)	141.0 (122.0 to 166.0)
		[1] Measure Description: Values are from enrollment, before the active-treatment run-in phase [2] Measure Analysis Population Description: 45 subjects are missing this information
Low density lipoprotein cholesterol ^[1] [2] Median (Inter-Quartile Range) Unit of measure: mg/dL
	Number Analyzed	2288 participants	2306 participants	4594 participants
		68.0 (54.0 to 87.0)	68.0 (53.3 to 86.0)	68.0 (53.7 to 87.0)
		[1] Measure Description: Values are from enrollment, before the active-treatment run-in phase [2] Measure Analysis Population Description: 192 subjects are missing this information
High density lipoprotein cholesterol ^[1] [2] Median (Inter-Quartile Range) Unit of measure: mg/dL
	Number Analyzed	2369 participants	2372 participants	4741 participants
		41.0 (34.7 to 49.0)	41.0 (35.0 to 48.0)	41.0 (35.0 to 48.0)
		[1] Measure Description: Values are from enrollment, before the active-treatment run-in phase [2] Measure Analysis Population Description: 45 subjects are missing this information
Triglycerides ^[1] [2] Median (Inter-Quartile Range) Unit of measure: mg/dL
	Number Analyzed	2369 participants	2372 participants	4741 participants
		135.4 (98.0 to 191.2)	136.0 (98.2 to 191.6)	135.4 (98.0 to 191.2)
		[1] Measure Description: Values are from enrollment, before the active-treatment run-in phase [2] Measure Analysis Population Description: 45 subjects are missing this information
High-sensitivity C-reactive protein level ^[1] [2] Median (Inter-Quartile Range) Unit of measure: Mg/liter
	Number Analyzed	2343 participants	2348 participants	4691 participants
		1.53 (0.78 to 3.59)	1.50 (0.70 to 3.29)	1.51 (0.74 to 3.44)
		[1] Measure Description: Values are from enrollment, before the active-treatment run-in phase [2] Measure Analysis Population Description: 95 subjects are missing this information
Glycated hemoglobin level ^[1] [2] Median (Inter-Quartile Range) Unit of measure: %
	Number Analyzed	2372 participants	2378 participants	4750 participants
		6.6 (6.0 to 7.5)	6.5 (5.9 to 7.5)	6.5 (6.0 to 7.5)
		[1] Measure Description: Values are from enrollment, before the active-treatment run-in phase [2] Measure Analysis Population Description: 36 subjects are missing this information

Outcome Measures

1.Primary Outcome


Title	Number of Subjects With Major Adverse Cardiovascular Events
Description	The first occurrence of Major Adverse Cardiovascular Event which is de...
Description	The first occurrence of Major Adverse Cardiovascular Event which is defined as the occurrence of one or more of the following: Cardiovascular Death, Non-Fatal Myocardial Infarction or Non-Fatal Stroke.
Time Frame	From randomization to trial end (April 2, 2018) up to a maximum of 5 years

Outcome Measure Data

Analysis Population Description

All randomized subjects


Arm/Group Title	Methotrexate	Placebo
Arm/Group Description:	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description:	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Overall Number of Participants Analyzed	2391	2395
Measure Type: Number Unit of Measure: participants
	170	167

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.91
	Comments	2-sided unadjusted p-value
	Method	Log Rank
	Comments	Stratified according to type of qualifying event, time of qualifying event and risk status(diabetes or metabolic syndrome alone)

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95% 0.82 to 1.25
	Estimation Comments	Confidence intervals have not been adjusted for multiplicity, and therefore inferences drawn from these intervals may not be reproducible.

2.Primary Outcome


Title	Number of Subjects With Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina That Led to Urgent Coronary Revascularization
Description	The first occurrence of Major Adverse Cardiovascular Event or Hospital...
Description	The first occurrence of Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina that led to Urgent Coronary Revascularization.
Time Frame	From randomization to trial end (April 2, 2018) - up to a maximum of 5 years

Outcome Measure Data

Analysis Population Description

All randomized participants


Arm/Group Title	Methotrexate	Placebo
Arm/Group Description:	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description:	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Overall Number of Participants Analyzed	2391	2395
Measure Type: Number Unit of Measure: participants
	201	207

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.67
	Comments	2-sided unadjusted p-value
	Method	Log Rank
	Comments	Stratified according to type of qualifying event, time of qualifying event and risk status(metabolic syndrome alone or diabetes at enrollment).

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95% 0.79 to 1.16
	Estimation Comments	Confidence intervals have not been adjusted for multiplicity, and therefore inferences drawn from these intervals may not be reproducible.

3.Secondary Outcome


Title	Number of Subjects With All-cause Mortality
Description	Subjects who died from any cause.
Description	Subjects who died from any cause.
Time Frame	From randomization to the trial end (April 2, 2018) up to a maximum of 5 years

Outcome Measure Data

Analysis Population Description

All Randomized Participants


Arm/Group Title	Methotrexate	Placebo
Arm/Group Description:	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description:	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Overall Number of Participants Analyzed	2391	2395
Measure Type: Number Unit of Measure: participants
	96	83

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.32
	Comments	2-sided unadjusted p-value
	Method	Log Rank
	Comments	Stratified according to type of qualifying event, time of qualifying event and risk status (metabolic syndrome alone or diabetes at enrollment).

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95% 0.87 to 1.56
	Estimation Comments	Confidence intervals have not been adjusted for multiplicity, and therefore inferences drawn from these intervals may not be reproducible.

4.Secondary Outcome


Title	Number of Subjects With Major Adverse Cardiovascular Event or Any Coronary Revascularization
Description	The first occurrence of Major Adverse Cardiovascular Event or Any Coro...
Description	The first occurrence of Major Adverse Cardiovascular Event or Any Coronary Revascularization.
Time Frame	From randomization to the trial end (April 2, 2018) - up to a maximum of 5 years

Outcome Measure Data

Analysis Population Description

All randomized participants


Arm/Group Title	Methotrexate	Placebo
Arm/Group Description:	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description:	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Overall Number of Participants Analyzed	2391	2395
Measure Type: Number Unit of Measure: participants
	278	288

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.57
	Comments	2-sided unadjusted p-value
	Method	Log Rank
	Comments	Stratified according to type of qualifying event, time of qualifying event and risk status (metabolic syndrome alone or diabetes) at enrollment.

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95% 0.81 to 1.12
	Estimation Comments	Confidence intervals have not been adjusted for multiplicity, and therefore inferences drawn from these intervals may not be reproducible.

5.Secondary Outcome


Title	Number of Subjects With Hospitalization for Congestive Heart Failure
Description	The first occurrence of Hospitalization for Congestive Heart Failure
Description	The first occurrence of Hospitalization for Congestive Heart Failure
Time Frame	From randomization to trial end (April 2, 2018) up to a maximum of 5 years

Outcome Measure Data

Analysis Population Description

All randomized participants


Arm/Group Title	Methotrexate	Placebo
Arm/Group Description:	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description:	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Overall Number of Participants Analyzed	2391	2395
Measure Type: Number Unit of Measure: participants
	48	53

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.54
	Comments	2-sided unadjusted p-value
	Method	Log Rank
	Comments	Stratified according to type of qualifying event, type of qualifying event and risk status (diabetes or metabolic syndrome alone) at enrollment

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95% 0.60 to 1.31
	Estimation Comments	Confidence intervals have not been adjusted for multiplicity, and therefore inferences drawn from these intervals may not be reproducible.

6.Secondary Outcome


Title	Number of Subjects With Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality
Description	The first occurrence of Major Adverse Cardiovascular Event, Coronary R...
Description	The first occurrence of Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality.
Time Frame	From randomization to trial end (April 2, 2018) up to a maximum of 5 years

Outcome Measure Data

Analysis Population Description

All randomized participants


Arm/Group Title	Methotrexate	Placebo
Arm/Group Description:	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description:	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Overall Number of Participants Analyzed	2391	2395
Measure Type: Number Unit of Measure: participants
	344	345

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.80
	Comments	2-sided unadjusted p-value
	Method	Log Rank
	Comments	Stratified according to type of qualifying event, time since qualifying event and risk status (diabetes or metabolic syndrome alone) at enrollment.

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95% 0.84 to 1.14
	Estimation Comments	Confidence intervals have not been adjusted for multiplicity, and therefore inferences drawn from these intervals may not be reproducible.

7.Secondary Outcome


Title	Number of Subjects With New Onset Type 2 Diabetes
Description	New onset type 2 diabetes among those without diabetes at baseline. Ba...
Description	New onset type 2 diabetes among those without diabetes at baseline. Baseline diabetes is defined as any of the following prior to randomization: clinician report of diabetes, use of antidiabetic medication, hbA1c >=6.5 or fasting plasma glucose >=126.
Time Frame	From randomization to the trial end (April 2, 2018) - up to 5 years

Outcome Measure Data

Analysis Population Description

Randomized participants without pre-randomization diabetes


Arm/Group Title	Methotrexate	Placebo
Arm/Group Description:	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description:	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Overall Number of Participants Analyzed	605	620
Measure Type: Count of Participants Unit of Measure: Participants
	4 0.7%	6 1.0%

8.Other Pre-specified Outcome


Title	Number of Subjects With Hospitalization for Unstable Angina That Led to Unplanned Coronary Revascularization
Description	The first occurrence of hospitalization for unstable angina that led t...
Description	The first occurrence of hospitalization for unstable angina that led to unplanned coronary revascularization
Time Frame	From randomization to the trial end (April 2, 2018) up to 5 years

Outcome Measure Data

Analysis Population Description

All randomized participants


Arm/Group Title	Methotrexate	Placebo
Arm/Group Description:	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description:	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Overall Number of Participants Analyzed	2391	2395
Measure Type: Number Unit of Measure: participants
	41	50

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.31
	Comments	2-sided unadjusted p-value
	Method	Log Rank
	Comments	Stratified according to type of qualifying event, time of qualifying event and risk status (diabetes or metabolic syndrome alone) at enrollment.

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95% 0.53 to 1.22
	Estimation Comments	Confidence intervals have not been adjusted for multiplicity, and therefore inferences drawn from these intervals may not be reproducible.

9.Other Pre-specified Outcome


Title	Number of Subjects With Coronary Revascularization
Description	The first occurrence of coronary revascularization
Description	The first occurrence of coronary revascularization
Time Frame	From randomization to trial end (April 2, 2018) up to 5 years

Outcome Measure Data

Analysis Population Description

All randomized participants


Arm/Group Title	Methotrexate	Placebo
Arm/Group Description:	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description:	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Overall Number of Participants Analyzed	2391	2395
Measure Type: Number Unit of Measure: participants
	190	205

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.38
	Comments	2-sided unadjusted p-value
	Method	Log Rank
	Comments	Stratified according to type of qualifying event, time of qualifying event and risk status (diabetes or metabolic syndrome alone) at enrollment

Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95% 0.75 to 1.12
	Estimation Comments	Confidence intervals have not been adjusted for multiplicity, and therefore inferences drawn from these intervals may not be reproducible.

10.Other Pre-specified Outcome


Title	Number of Subjects With Peripheral Artery Disease
Description	The first occurrence of new or worsening of peripheral artery disease
Description	The first occurrence of new or worsening of peripheral artery disease
Time Frame	From randomization to the trial end (April 2, 2018) - up to 5 years

Outcome Measure Data Not Reported

11.Other Pre-specified Outcome


Title	Number of Subjects With Deep Vein Thrombosis or Pulmonary Embolism
Description	The first occurrence of symptomatic deep vein thrombosis or pulmonary ...
Description	The first occurrence of symptomatic deep vein thrombosis or pulmonary embolism
Time Frame	From randomization to the trial end (April 2, 2018) - up to 5 years

Outcome Measure Data

Analysis Population Description

The trial was ended prematurely. There were not sufficient outcome measures for analysis


Arm/Group Title	Methotrexate	Placebo
Arm/Group Description:	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description:	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

12.Other Pre-specified Outcome


Title	Number of Subjects With Aortic Stenosis
Description	The first occurrence of clinically significant aortic stenosis
Description	The first occurrence of clinically significant aortic stenosis
Time Frame	From randomization to the trial end (April 2, 2018) - up to 5 years

Outcome Measure Data

Analysis Population Description

The trial ended prematurely. There were not sufficient outcome measures for analysis.


Arm/Group Title	Methotrexate	Placebo
Arm/Group Description:	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description:	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

13.Other Pre-specified Outcome


Title	Number of Subjects With Atrial Fibrillation
Description	The first occurrence of new or worsening of atrial fibrillation
Description	The first occurrence of new or worsening of atrial fibrillation
Time Frame	From randomization to the trial end (April 2, 2018) - up to 5 years

Outcome Measure Data Not Reported

Adverse Events

Time Frame	From randomization to the trial end (April 2, 2018) - up to 5 years.
Adverse Event Reporting Description	Pre-specified adverse events were collected via questions on the case report forms (CRFs) at each visit. Sites queried participants about any other adverse events and recorded them using a standard adverse event form that included the seriousness, relatedness, severity and outcomes. Those adverse events were MedDRA coded.

Arm/Group Title	Methotrexate	Placebo
Arm/Group Description	Methotrexate: Tablet, Oral, Target ...	Placebo: Tablet, Oral, weekly plus ...
Arm/Group Description	Methotrexate: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week	Placebo: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
All-Cause Mortality
	Methotrexate	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	96/2391 (4.02%)	83/2395 (3.47%)
Serious Adverse Events Serious Adverse Events
	Methotrexate	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	569/2391 (23.80%)	549/2395 (22.92%)
Blood and lymphatic system disorders
Anaemia ^† 1	7/2391 (0.29%)	9/2395 (0.38%)
Febrile neutropenia ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Leukopenia ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Leukopenia (AE & Lab Combined) ^† 1 [1]	2/2391 (0.08%)	0/2395 (0.00%)
Thrombocytopenia ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Thrombocytopenia (AE & Lab Combined) ^† 1 [1]	1/2391 (0.04%)	1/2395 (0.04%)
Iron deficiency anaemia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Leukocytosis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Leukoerythroblastic anaemia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Lymphadenopathy mediastinal ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Neutropenia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Neutropenia (AE & Lab Combined) ^† 1 [1]	1/2391 (0.04%)	0/2395 (0.00%)
Normochromic normocytic anaemia ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Pancytopenia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
White blood cell disorder ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Cardiac disorders
Angina unstable ^† 1	12/2391 (0.50%)	19/2395 (0.79%)
Angina pectoris ^† 1	12/2391 (0.50%)	6/2395 (0.25%)
Bradycardia ^† 1	5/2391 (0.21%)	2/2395 (0.08%)
Ventricular tachycardia ^† 1	0/2391 (0.00%)	7/2395 (0.29%)
Ischaemic cardiomyopathy ^† 1	1/2391 (0.04%)	4/2395 (0.17%)
Cardiac failure congestive ^† 1	1/2391 (0.04%)	3/2395 (0.13%)
Acute coronary syndrome ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Atrial fibrillation ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Atrial flutter ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Supraventricular tachycardia ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Ventricular extrasystoles ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Ventricular fibrillation ^† 1	3/2391 (0.13%)	0/2395 (0.00%)
Arrhythmia ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Sick sinus syndrome ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Atrioventricular block complete ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Cardiac arrest ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Cardiac failure ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Cardiogenic shock ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Cardiomegaly ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Cardiomyopathy ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Coronary artery dissection ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Coronary artery occlusion ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Coronary artery stenosis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Mitral valve disease ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Myocardial infarction ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Palpitations ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Pericardial effusion ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Pneumopericardium ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Sinus tachycardia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Tachycardia ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Congenital, familial and genetic disorders
Hydrocele ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Ear and labyrinth disorders
Vertigo ^† 1	0/2391 (0.00%)	3/2395 (0.13%)
Tinnitus ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Eye disorders
Retinal detachment ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Eye pain ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Glaucoma ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Retinal haemorrhage ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Retinal vein occlusion ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Visual impairment ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Gastrointestinal disorders
Gastrointestinal haemorrhage ^† 1	8/2391 (0.33%)	10/2395 (0.42%)
Abdominal pain ^† 1	9/2391 (0.38%)	6/2395 (0.25%)
Small intestinal obstruction ^† 1	5/2391 (0.21%)	6/2395 (0.25%)
Diarrhoea ^† 1	4/2391 (0.17%)	2/2395 (0.08%)
Pancreatitis acute ^† 1	2/2391 (0.08%)	3/2395 (0.13%)
Intestinal obstruction ^† 1	3/2391 (0.13%)	1/2395 (0.04%)
Pancreatitis ^† 1	1/2391 (0.04%)	3/2395 (0.13%)
Rectal haemorrhage ^† 1	3/2391 (0.13%)	1/2395 (0.04%)
Abdominal pain upper ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Colitis ^† 1	3/2391 (0.13%)	0/2395 (0.00%)
Gastritis ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Ascites ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Constipation ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Diarrhoea haemorrhagic ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Enteritis ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Gastric ulcer ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Gastrooesophageal reflux disease ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Inguinal hernia ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Lower gastrointestinal haemorrhage ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Mouth ulceration ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Nausea ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Retroperitoneal mass ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Stomatitis ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Umbilical hernia ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Vomiting ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Abdominal hernia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Dyspepsia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Enterocolitis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Gastric haemorrhage ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Haemorrhoids ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Hiatus hernia ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Ileus ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Irritable bowel syndrome ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Melaena ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Obstruction gastric ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Oesophageal obstruction ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Oesophagitis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Oral pain ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Pancreatic mass ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Peptic ulcer ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Tooth socket haemorrhage ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
General disorders
Chest pain ^† 1	76/2391 (3.18%)	67/2395 (2.80%)
Non-cardiac chest pain ^† 1	8/2391 (0.33%)	3/2395 (0.13%)
Chest discomfort ^† 1	4/2391 (0.17%)	3/2395 (0.13%)
Pyrexia ^† 1	3/2391 (0.13%)	2/2395 (0.08%)
Oedema peripheral ^† 1	0/2391 (0.00%)	4/2395 (0.17%)
Asthenia ^† 1	3/2391 (0.13%)	0/2395 (0.00%)
Systemic inflammatory response syndrome ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Adverse event ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Device malfunction ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Fatigue ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Malaise ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Medical device complication ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Oedema ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Organ failure ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Swelling ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Ulcer haemorrhage ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Hepatobiliary disorders
Cholecystitis ^† 1	5/2391 (0.21%)	2/2395 (0.08%)
Cholecystitis acute ^† 1	2/2391 (0.08%)	4/2395 (0.17%)
Cholelithiasis ^† 1	3/2391 (0.13%)	1/2395 (0.04%)
Hepatic cirrhosis ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Acute hepatic failure ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Bile duct stone ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Cholangitis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Hepatic lesion ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Liver disorder ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Pneumobilia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Immune system disorders
Hypersensitivity ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Infections and infestations
Pneumonia ^† 1	29/2391 (1.21%)	28/2395 (1.17%)
Cellulitis ^† 1	19/2391 (0.79%)	15/2395 (0.63%)
Urinary tract infection ^† 1	12/2391 (0.50%)	9/2395 (0.38%)
Sepsis ^† 1	12/2391 (0.50%)	7/2395 (0.29%)
Infection ^† 1	6/2391 (0.25%)	7/2395 (0.29%)
Diverticulitis ^† 1	4/2391 (0.17%)	8/2395 (0.33%)
Bronchitis ^† 1	7/2391 (0.29%)	2/2395 (0.08%)
Osteomyelitis ^† 1	8/2391 (0.33%)	1/2395 (0.04%)
Gastroenteritis ^† 1	2/2391 (0.08%)	4/2395 (0.17%)
Influenza ^† 1	1/2391 (0.04%)	4/2395 (0.17%)
Localised infection ^† 1	4/2391 (0.17%)	0/2395 (0.00%)
Pyelonephritis ^† 1	1/2391 (0.04%)	3/2395 (0.13%)
Septic shock ^† 1	1/2391 (0.04%)	3/2395 (0.13%)
Upper respiratory tract infection ^† 1	2/2391 (0.08%)	2/2395 (0.08%)
Appendicitis ^† 1	0/2391 (0.00%)	3/2395 (0.13%)
Bacteraemia ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Gastroenteritis viral ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Necrotising fasciitis ^† 1	0/2391 (0.00%)	3/2395 (0.13%)
Urosepsis ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Abdominal wall abscess ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Abscess limb ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Arthritis bacterial ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Bacterial disease carrier ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Bronchitis viral ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Escherichia bacteraemia ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Groin abscess ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Periorbital cellulitis ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Perirectal abscess ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Sinusitis ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Skin infection ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Staphylococcal infection ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Wound infection staphylococcal ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Abscess ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Anal abscess ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Atypical pneumonia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Bacterial sepsis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Cholecystitis infective ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Clostridium difficile colitis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Device related infection ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Diabetic foot infection ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Enterobacter infection ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Epididymitis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Escherichia infection ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Gangrene ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Gastroenteritis shigella ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Genital herpes ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Infected skin ulcer ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Labyrinthitis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Lower respiratory tract infection ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Lyme disease ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Meningitis aseptic ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Osteomyelitis chronic ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Perineal abscess ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Pharyngitis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Pneumonia bacterial ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Respiratory syncytial virus infection ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Respiratory tract infection ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Sialoadenitis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Staphylococcal bacteraemia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Tinea pedis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Urinary Tract Infection ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Viral infection ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Viral upper respiratory tract infection ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Wound infection ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Injury, poisoning and procedural complications
Fall ^† 1	3/2391 (0.13%)	5/2395 (0.21%)
Hip fracture ^† 1	4/2391 (0.17%)	1/2395 (0.04%)
Rib fracture ^† 1	2/2391 (0.08%)	2/2395 (0.08%)
Road traffic accident ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Subdural haematoma ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Upper limb fracture ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Femur fracture ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Lower limb fracture ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Abdominal injury ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Accidental overdose ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Alcohol poisoning ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Ankle fracture ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Clavicle fracture ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Concussion ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Contusion ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Facial bones fracture ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Femoral neck fracture ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Fibula fracture ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Head injury ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Meniscus injury ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Muscle strain ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Pelvic fracture ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Spinal cord injury ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Tendon rupture ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Testicular injury ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Thermal burn ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Thoracic vertebral fracture ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Toxicity to various agents ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Traumatic arthropathy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Vascular pseudoaneurysm ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Wound ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Wound dehiscence ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Investigations
Blood glucose increased ^† 1	2/2391 (0.08%)	5/2395 (0.21%)
Catheterisation cardiac ^† 1	6/2391 (0.25%)	1/2395 (0.04%)
Arteriogram coronary ^† 1	3/2391 (0.13%)	2/2395 (0.08%)
Liver function test abnormal ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
White blood cell count decreased ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Biopsy bladder ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Stress echocardiogram abnormal ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Alanine aminotransferase increased ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Aspiration pleural cavity ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Biopsy breast ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Biopsy liver ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Biopsy lung ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Blood creatinine increased ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Blood glucose decreased ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Blood pressure increased ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Blood triglycerides increased ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Blood urine present ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Bronchoscopy ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Cardiac stress test abnormal ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Cystoscopy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Haemoglobin increased ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Hepatic enzyme increased ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Hepatitis C virus test positive ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Lipase increased ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Platelet count decreased ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Prostatic specific antigen increased ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Red blood cell count decreased ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Shift to the right ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Transaminases increased ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Troponin increased ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Weight decreased ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Weight increased ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
White blood cell count increased ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Metabolism and nutrition disorders
Dehydration ^† 1	2/2391 (0.08%)	7/2395 (0.29%)
Hypoglycaemia ^† 1	4/2391 (0.17%)	3/2395 (0.13%)
Hyperglycaemia ^† 1	2/2391 (0.08%)	3/2395 (0.13%)
Diabetic ketoacidosis ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Hypercalcaemia ^† 1	3/2391 (0.13%)	0/2395 (0.00%)
Hyperkalaemia ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Hyponatraemia ^† 1	0/2391 (0.00%)	3/2395 (0.13%)
Diabetes mellitus inadequate control ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Hypokalaemia ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Obesity ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Electrolyte imbalance ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Hypomagnesaemia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Hypovolaemia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain ^† 1	2/2391 (0.08%)	5/2395 (0.21%)
Arthralgia ^† 1	3/2391 (0.13%)	3/2395 (0.13%)
Back pain ^† 1	3/2391 (0.13%)	3/2395 (0.13%)
Flank pain ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Pain in extremity ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Rhabdomyolysis ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Rheumatoid arthritis ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Spinal osteoarthritis ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Ankylosing spondylitis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Cervical spinal stenosis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Compartment syndrome ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Intervertebral disc protrusion ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Lumbar spinal stenosis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Musculoskeletal pain ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Neck mass ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Osteitis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Osteitis deformans ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Osteoarthritis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Pain in jaw ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Soft tissue mass ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer ^† 1	7/2391 (0.29%)	13/2395 (0.54%)
Squamous cell carcinoma ^† 1	7/2391 (0.29%)	2/2395 (0.08%)
Basal cell carcinoma ^† 1	5/2391 (0.21%)	2/2395 (0.08%)
Breast cancer ^† 1	3/2391 (0.13%)	4/2395 (0.17%)
Malignant melanoma ^† 1	2/2391 (0.08%)	5/2395 (0.21%)
Skin cancer ^† 1	5/2391 (0.21%)	1/2395 (0.04%)
Squamous cell carcinoma of skin ^† 1	3/2391 (0.13%)	3/2395 (0.13%)
Lung neoplasm malignant ^† 1	2/2391 (0.08%)	3/2395 (0.13%)
Bladder cancer ^† 1	2/2391 (0.08%)	2/2395 (0.08%)
Colon cancer ^† 1	2/2391 (0.08%)	2/2395 (0.08%)
Renal cell carcinoma ^† 1	0/2391 (0.00%)	4/2395 (0.17%)
Meningioma ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Pancreatic carcinoma ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Bladder neoplasm ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Leiomyosarcoma ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Neoplasm malignant ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Prostate cancer recurrent ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Renal cancer ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Acute lymphocytic leukaemia ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Acute myeloid leukaemia ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Adenocarcinoma Of The Prostate ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Adenocarcinoma of colon ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Basal & Squamous Cell Carcinoma's Discovered ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Bladder transitional cell carcinoma ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Brain Cancer ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Brain neoplasm ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Branchogenic Adenocarcinoma/Right Upper Lobectomy And M ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Cholangiocarcinoma ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Clear cell renal cell carcinoma ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Cytopathology Diagnosis Of Aus/Flus Or Follicular Hurth ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Diagnosed With Non Basal Cell Malignancy ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Diagnosis Of Bladder Cancer, Highly Invasive, With Live ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Diffuse large B-cell lymphoma ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Endometrial cancer ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Essential thrombocythaemia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Gastric cancer ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Hodgkin's disease ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Invasive Squamous Cell Carcinoma (Right Cheek) ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Laryngeal cancer ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Left Descending Colon Cancer ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Left Ureteropelvic Junction, Papillary Urothelial Carci ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Lesion, Mid-Parietal Scalp, Squamous Cell Carcinoma ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Liver Cancer ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Lung adenocarcinoma ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Lung carcinoma cell type unspecified stage IV ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Lymphoma ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Malignant Bladder Polyps ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Malignant Spindle Cell Neoplasm ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Malignant Transitional Cell Cancer Of The Bladder ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Metastases to central nervous system ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Metastatic Liver Cancer ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Micrometastatic Disease Melanoma ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
New Lung Cancer Diagnosis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Oesophageal adenocarcinoma ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Papillary Urothelial Carcinoma ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Parathyroid tumour benign ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Peritoneal Carcinomatosis From A Low-Grade Mucinous Tum ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Plasma cell myeloma ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Pt Newly Diagnosed With Stage 4 Cancer ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Recurrent Bladder Tumor ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Recurrent Bladder Tumor: Papillary Lesion , Proximal An ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Relapsed Non-Hodgkins Lymphoma ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Reported Diagnosis Lymphoma On Passive Follow Up ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Right Parietal Craniotomy For Benign Neoplasm Of Brain ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Ruptured Mucinous Neoplasm Of The Appendix With Periton ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Skin Biopsy- Possible Lymphoma ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Small cell lung cancer ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Sqamous Cell Carcinoma In Situ, Bowenoid Type ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Stage Ii Adenocarcinoma Of The Ascending Colon ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Stage Iv T2n0m1 Adenocarcinoma Of Theh Ead And Tail Of ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
T-cell lymphoma ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Throat cancer ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Treatment For Metastasized Clear Cell Renal Cell Carcin ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Uterine cancer ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Any Cancer ^† 2 [2]	52/2391 (2.17%)	30/2395 (1.25%)
Any Cancer ^† 1 [3]	106/2391 (4.43%)	95/2395 (3.97%)
Non-basal-cell skin cancer (not known if SAE) ^† 2 [2]	31/2391 (1.30%)	10/2395 (0.42%)
Non-basal-cell skin cancer (not known if SAE) ^† 1 [3]	33/2391 (1.38%)	12/2395 (0.50%)
Nervous system disorders
Syncope ^† 1	24/2391 (1.00%)	16/2395 (0.67%)
Transient ischaemic attack ^† 1	9/2391 (0.38%)	9/2395 (0.38%)
Dizziness ^† 1	6/2391 (0.25%)	3/2395 (0.13%)
Presyncope ^† 1	4/2391 (0.17%)	2/2395 (0.08%)
Convulsion ^† 1	2/2391 (0.08%)	3/2395 (0.13%)
Headache ^† 1	3/2391 (0.13%)	2/2395 (0.08%)
Dysarthria ^† 1	2/2391 (0.08%)	2/2395 (0.08%)
Dementia ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Encephalopathy ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Hemiparesis ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Migraine ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
VIIth nerve paralysis ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Aphasia ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Ataxia ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Carotid artery stenosis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Clonus ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Dyskinesia ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Epilepsy ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Facial paresis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Haemorrhage intracranial ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Hypertensive encephalopathy ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Lethargy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Loss of consciousness ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Metabolic encephalopathy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Myoclonus ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Neuromyopathy ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Paraesthesia ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Paresis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Parkinson's disease ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Radicular pain ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Radiculopathy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Subarachnoid haemorrhage ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Transient global amnesia ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Psychiatric disorders
Mental status changes ^† 1	1/2391 (0.04%)	4/2395 (0.17%)
Confusional state ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Depression ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Alcohol withdrawal syndrome ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Delirium ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Disorientation ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Suicidal ideation ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Renal and urinary disorders
Renal failure acute ^† 1	17/2391 (0.71%)	21/2395 (0.88%)
Haematuria ^† 1	4/2391 (0.17%)	4/2395 (0.17%)
Nephrolithiasis ^† 1	2/2391 (0.08%)	3/2395 (0.13%)
Renal failure ^† 1	3/2391 (0.13%)	2/2395 (0.08%)
Renal failure chronic ^† 1	3/2391 (0.13%)	1/2395 (0.04%)
Renal mass ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Urinary retention ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Calculus ureteric ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Bladder mass ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Dysuria ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Polyuria ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Proteinuria ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Urethral stenosis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Reproductive system and breast disorders
Benign prostatic hyperplasia ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Breast mass ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Female genital tract fistula ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Postmenopausal haemorrhage ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Prostatitis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Prostatomegaly ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Vaginal haemorrhage ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea ^† 1	13/2391 (0.54%)	12/2395 (0.50%)
Chronic obstructive pulmonary disease ^† 1	9/2391 (0.38%)	9/2395 (0.38%)
Acute respiratory failure ^† 1	7/2391 (0.29%)	4/2395 (0.17%)
Pleural effusion ^† 1	4/2391 (0.17%)	3/2395 (0.13%)
Epistaxis ^† 1	4/2391 (0.17%)	1/2395 (0.04%)
Pulmonary mass ^† 1	2/2391 (0.08%)	3/2395 (0.13%)
Respiratory failure ^† 1	2/2391 (0.08%)	3/2395 (0.13%)
Asthma ^† 1	2/2391 (0.08%)	2/2395 (0.08%)
Haemoptysis ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Hypoxia ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Interstitial lung disease ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Cough ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Dyspnoea exertional ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Pneumonia aspiration ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Pneumothorax ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Pulmonary fibrosis ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Acute pulmonary oedema ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Acute respiratory distress syndrome ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Choking ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Emphysema ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Haemothorax ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Nasal polyps ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Pneumomediastinum ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Pneumonitis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Pneumothorax spontaneous ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Pulmonary embolism ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Pulmonary oedema ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Skin and subcutaneous tissue disorders
Rash ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Diabetic foot ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Skin lesion ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Skin ulcer ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Actinic keratosis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Alopecia ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Angioedema ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Cutaneous lupus erythematosus ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Dermatitis ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Diabetic ulcer ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Surgical and medical procedures
Knee arthroplasty ^† 1	10/2391 (0.42%)	11/2395 (0.46%)
Hospitalisation ^† 1	4/2391 (0.17%)	6/2395 (0.25%)
Hip arthroplasty ^† 1	6/2391 (0.25%)	3/2395 (0.13%)
Surgery ^† 1	2/2391 (0.08%)	7/2395 (0.29%)
Spinal laminectomy ^† 1	3/2391 (0.13%)	4/2395 (0.17%)
Gastrectomy ^† 1	3/2391 (0.13%)	3/2395 (0.13%)
Implantable defibrillator insertion ^† 1	3/2391 (0.13%)	2/2395 (0.08%)
Cardiac pacemaker insertion ^† 1	4/2391 (0.17%)	0/2395 (0.00%)
Hip surgery ^† 1	2/2391 (0.08%)	2/2395 (0.08%)
Knee operation ^† 1	3/2391 (0.13%)	1/2395 (0.04%)
Toe amputation ^† 1	2/2391 (0.08%)	2/2395 (0.08%)
Cardiac ablation ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Carotid endarterectomy ^† 1	1/2391 (0.04%)	2/2395 (0.08%)
Gallbladder operation ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Joint arthroplasty ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Shoulder arthroplasty ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Aortic valve replacement ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Cardioversion ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Colectomy ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Gastric bypass ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Intervertebral disc operation ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Mitral valve repair ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Nephrectomy ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Penile prosthesis insertion ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Shoulder operation ^† 1	2/2391 (0.08%)	0/2395 (0.00%)
Stent placement ^† 1	0/2391 (0.00%)	2/2395 (0.08%)
Tooth extraction ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Abdominal hernia repair ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Ankle operation ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Aortic aneurysm repair ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Appendicectomy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Bladder neoplasm surgery ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Cancer surgery ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Cardiac pacemaker battery replacement ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Cataract operation ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Central venous catheterisation ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Cholecystectomy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Craniotomy ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Finger amputation ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Fistula repair ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Foot amputation ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Hernia repair ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Implantable defibrillator replacement ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Intestinal resection ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Lung lobectomy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Mastectomy ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Oesophagectomy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Oesophagogastric fundoplasty ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Partial lung resection ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Pelvic floor repair ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Prolapse repair ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Prostatectomy ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Radical cystectomy ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Radiotherapy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Removal of internal fixation ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Retinopexy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Small intestinal resection ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Spinal cord operation ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Spinal fusion surgery ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Thyroidectomy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Umbilical hernia repair ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Urinary cystectomy ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Vascular disorders
Hypotension ^† 1	8/2391 (0.33%)	3/2395 (0.13%)
Hypertension ^† 1	2/2391 (0.08%)	2/2395 (0.08%)
Orthostatic hypotension ^† 1	4/2391 (0.17%)	0/2395 (0.00%)
Aneurysm ^† 1	2/2391 (0.08%)	1/2395 (0.04%)
Aortic stenosis ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Hypertensive crisis ^† 1	1/2391 (0.04%)	1/2395 (0.04%)
Accelerated hypertension ^† 1	0/2391 (0.00%)	1/2395 (0.04%)
Aortic aneurysm ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Peripheral artery aneurysm ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
Temporal arteritis ^† 1	1/2391 (0.04%)	0/2395 (0.00%)
1 Term from vocabulary, MedDRA (15) 2 Term from vocabulary, CRFs † Indicates events were collected by systematic assessment [1] Data come from laboratory assays and adverse event reports [2] Reported in case-report forms from visits [3] Determined on the basis of a MedDRA query, case-report forms from visits and adverse-event reports
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Methotrexate	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	1488/2391 (62.23%)	1399/2395 (58.41%)
Blood and lymphatic system disorders
Any ^† 1 [1]	340/2391 (14.22%)	244/2395 (10.19%)
Leukopenia ^† 1 [2]	241/2391 (10.08%)	172/2395 (7.18%)
Gastrointestinal disorders
Any ^† 1 [1]	350/2391 (14.64%)	284/2395 (11.86%)
General disorders
Any ^† 1 [1]	279/2391 (11.67%)	254/2395 (10.61%)
Chest pain ^† 1	126/2391 (5.27%)	142/2395 (5.93%)
Infections and infestations
Any ^† 1 [1]	659/2391 (27.56%)	584/2395 (24.38%)
Injury, poisoning and procedural complications
Any ^† 1 [1]	150/2391 (6.27%)	163/2395 (6.81%)
Investigations
Any ^† 1 [1]	220/2391 (9.20%)	211/2395 (8.81%)
Musculoskeletal and connective tissue disorders
Any ^† 1 [1]	223/2391 (9.33%)	230/2395 (9.60%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Any ^† 1 [1]	124/2391 (5.19%)	101/2395 (4.22%)
Nervous system disorders
Any ^† 1 [1]	213/2391 (8.91%)	195/2395 (8.14%)
Respiratory, thoracic and mediastinal disorders
Any ^† 1 [1]	279/2391 (11.67%)	210/2395 (8.77%)
Skin and subcutaneous tissue disorders
Any ^† 1 [1]	97/2391 (4.06%)	121/2395 (5.05%)
Surgical and medical procedures
Any ^† 1 [1]	137/2391 (5.73%)	147/2395 (6.14%)
1 Term from vocabulary, MedDRA (15) † Indicates events were collected by systematic assessment [1] All diagnoses under the organ system [2] Data come from laboratory assays and adverse-event reports

Limitations and Caveats

The trial was terminated early because the pre-specified boundary for futility was crossed for both the original and the final primary endpoints and because of the lack of evidence of a reduction in hsCRP level with methotrexate treatment.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Dr. Paul Ridker and Dr. Robert Glynn
Organization:	Brigham & Women's Hospital
Phone:	617-732-4965
EMail:	pridker@bwh.harvard.edu

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

Cui J, Chasman DI, Raychaudhuri S, Xu C, Ridker PM, Solomon DH, Karlson EW. Genetics are not likely to offer clinically useful predictions for elevated liver enzyme levels in patients using low dose methotrexate. Semin Arthritis Rheum. 2022 Aug;55:152036. doi: 10.1016/j.semarthrit.2022.152036. Epub 2022 May 28.

Reiss AB, Teboul I, Kasselman L, Ahmed S, Carsons SE, De Leon J. Methotrexate effects on adenosine receptor expression in peripheral monocytes of persons with type 2 diabetes and cardiovascular disease. J Investig Med. 2022 Aug;70(6):1433-1437. doi: 10.1136/jim-2022-002355. Epub 2022 May 23.

Xu C, Selhub J, Jacques P, Paynter NP, MacFadyen JG, Glynn RJ, Ridker PM, Solomon DH. Adverse effects related to methotrexate polyglutamate levels: adjudicated results from the cardiovascular inflammation reduction trial. Rheumatology (Oxford). 2021 Jun 18;60(6):2963-2968. doi: 10.1093/rheumatology/keaa650.

Sparks JA, Dellaripa PF, Glynn RJ, Paynter NP, Xu C, Ridker PM, Solomon DH. Pulmonary Adverse Events in Patients Receiving Low-Dose Methotrexate in the Randomized, Double-Blind, Placebo-Controlled Cardiovascular Inflammation Reduction Trial. Arthritis Rheumatol. 2020 Dec;72(12):2065-2071. doi: 10.1002/art.41452. Epub 2020 Oct 7.

Ridker PM, MacFadyen JG, Glynn RJ, Bradwin G, Hasan AA, Rifai N. Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial. Eur Heart J. 2020 Aug 14;41(31):2952-2961. doi: 10.1093/eurheartj/ehaa160.

Solomon DH, Glynn RJ, Karlson EW, Lu F, Corrigan C, Colls J, Xu C, MacFadyen J, Barbhaiya M, Berliner N, Dellaripa PF, Everett BM, Pradhan AD, Hammond SP, Murray M, Rao DA, Ritter SY, Rutherford A, Sparks JA, Stratton J, Suh DH, Tedeschi SK, Vanni KMM, Paynter NP, Ridker PM. Adverse Effects of Low-Dose Methotrexate: A Randomized Trial. Ann Intern Med. 2020 Mar 17;172(6):369-380. doi: 10.7326/M19-3369. Epub 2020 Feb 18.

Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, Mam V, Hasan A, Rosenberg Y, Iturriaga E, Gupta M, Tsigoulis M, Verma S, Clearfield M, Libby P, Goldhaber SZ, Seagle R, Ofori C, Saklayen M, Butman S, Singh N, Le May M, Bertrand O, Johnston J, Paynter NP, Glynn RJ; CIRT Investigators. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med. 2019 Feb 21;380(8):752-762. doi: 10.1056/NEJMoa1809798. Epub 2018 Nov 10.

Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, Gupta M, Clearfield M, Libby P, Hasan AA, Glynn RJ, Ridker PM. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J. 2013 Aug;166(2):199-207.e15. doi: 10.1016/j.ahj.2013.03.018. Epub 2013 May 3.

Layout table for additonal information

Responsible Party:	Paul Ridker, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:	NCT01594333
Other Study ID Numbers:	2012P-000857 U01HL101422 ( U.S. NIH Grant/Contract ) U01HL101389 ( U.S. NIH Grant/Contract )
First Submitted:	May 1, 2012
First Posted:	May 9, 2012
Results First Submitted:	June 20, 2020
Results First Posted:	July 24, 2020
Last Update Posted:	July 24, 2020

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