CIRT: Cardiovascular Inflammation Reduction Trial

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01594333
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 4,786
• Locations: 470
• Arms: 2
• Duration (Months): 78.9
• Patients Per Site: 10.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The Cardiovascular Inflammation Reduction Trial (CIRT) is a randomized clinical trial investigating whether taking low-dose methotrexate reduces heart attacks, strokes, or death in people with type 2 diabetes or metabolic syndrome that have had a heart attack or multiple coronary blockages. This trial is funded by the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH).

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Disease	Drug: Methotrexate; Drug: Placebo	Phase 3

Detailed Description

While inflammation contributes crucially to atherothrombosis, it is unknown whether inhibition of inflammation per se will lower vascular event rates. The primary aim of the Cardiovascular Inflammation Reduction Trial (CIRT) is to directly test the inflammatory hypothesis of atherothrombosis by evaluating whether or not low-dose methotrexate (LDM) will reduce rates of myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease patients with type 2 diabetes or metabolic syndrome, conditions associated with an enhanced pro-inflammatory response. CIRT is a randomized, double-blind, placebo-controlled, multi-center, event-driven trial that will randomize 7,000 men and women from the United States and Canada. Following a five- to six-week open-label run-in (maximum 8 weeks), eligible participants who have either suffered documented myocardial infarction in the past or have angiographically demonstrated multivessel coronary artery disease in the past will be randomly allocated over a three to four year period to usual care plus placebo or usual care plus LDM. The target methotrexate dose among those allocated to active therapy is 15 to 20 mg po per week, a dose within the range of that commonly used for the treatment of rheumatoid arthritis. All study participants will additionally receive 1.0 mg oral folate to be taken daily six days per week. LDM complications will be minimized through education programs for all investigators and coordinators, through enhanced communication with study participants, by limiting enrollment to those with no evidence of malignancy, hepatitis, renal dysfunction, chronic infection, pulmonary disease, or other risk factors for toxicity; by conducting an initial 5- to 6-week active-therapy run-in (maximum 8 weeks) designed to eliminate individuals who are either intolerant of or unable to adhere to treatment before randomization; and through regular monitoring of liver function and hematologic indices using a centralized methodology designed to ensure participant safety, allow for dose adjustments while maintaining the study blind, and provide an efficient method to address issues of compliance and follow-up on a cost-effective centralized basis. The primary trial endpoint is the rate of myocardial infarction, stroke, or cardiovascular death. Secondary and tertiary endpoints include all-cause mortality, coronary revascularization, incident congestive heart failure, incident peripheral artery disease, incident venous thrombosis, clinically significant aortic stenosis, incident atrial fibrillation, incident diabetes among those with metabolic syndrome but not diabetes at study entry, and hemoglobin A1c (HbA1c) control among those with diabetes at study entry. The trial is event driven such that in the absence of extreme effects, the trial will conclude after accrual of at least 530 primary endpoints, an effect estimated to provide 90 percent power to detect a 25 percent relative risk reduction. The potential clinical impact of CIRT is broad as it has sufficient power to directly address core issues in the inflammatory hypothesis of atherothrombosis, and thus, if successful, will open major new directions for cardiovascular treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 4786 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Event-driven Trial of Weekly Low-dose Methotrexate (LDM) in the Prevention of Cardiovascular Events Among Stable Coronary Artery Disease Patients With Type 2 Diabetes or Metabolic Syndrome
• Study Start Date: Apr 1, 2013
• Actual Primary Completion Date: Apr 15, 2019
• Actual Study Completion Date: Oct 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Methotrexate Methotrexate: Tablet, Oral, Target dose 15-20mg weekly plus 1.0 mg folic acid 6 days/week	Drug: Methotrexate; Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week; Other Names: Trexall, TEVA Inc (brand of methotrexate)
Placebo Comparator: Placebo Placebo: Tablet, Oral weekly plus 1.0mg folic acid 6 days/week	Drug: Placebo; Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Major Adverse Cardiovascular Events [From randomization to trial end (April 2, 2018) up to a maximum of 5 years]

   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.

2. Number of Subjects With Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina That Led to Urgent Coronary Revascularization [From randomization to trial end (April 2, 2018) - up to a maximum of 5 years]

   The first occurrence of Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina that led to Urgent Coronary Revascularization.

Secondary Outcome Measures

1. Number of Subjects With All-cause Mortality [From randomization to the trial end (April 2, 2018) up to a maximum of 5 years]

   Subjects who died from any cause.

2. Number of Subjects With Major Adverse Cardiovascular Event or Any Coronary Revascularization [From randomization to the trial end (April 2, 2018) - up to a maximum of 5 years]

   The first occurrence of Major Adverse Cardiovascular Event or Any Coronary Revascularization.

3. Number of Subjects With Hospitalization for Congestive Heart Failure [From randomization to trial end (April 2, 2018) up to a maximum of 5 years]

   The first occurrence of Hospitalization for Congestive Heart Failure

4. Number of Subjects With Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality [From randomization to trial end (April 2, 2018) up to a maximum of 5 years]

   The first occurrence of Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality.

5. Number of Subjects With New Onset Type 2 Diabetes [From randomization to the trial end (April 2, 2018) - up to 5 years]

   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.

Other Outcome Measures

1. Number of Subjects With Hospitalization for Unstable Angina That Led to Unplanned Coronary Revascularization [From randomization to the trial end (April 2, 2018) up to 5 years]

   The first occurrence of hospitalization for unstable angina that led to unplanned coronary revascularization

2. Number of Subjects With Coronary Revascularization [From randomization to trial end (April 2, 2018) up to 5 years]

   The first occurrence of coronary revascularization

3. Number of Subjects With Peripheral Artery Disease [From randomization to the trial end (April 2, 2018) - up to 5 years]

   The first occurrence of new or worsening of peripheral artery disease

4. Number of Subjects With Deep Vein Thrombosis or Pulmonary Embolism [From randomization to the trial end (April 2, 2018) - up to 5 years]

   The first occurrence of symptomatic deep vein thrombosis or pulmonary embolism

5. Number of Subjects With Aortic Stenosis [From randomization to the trial end (April 2, 2018) - up to 5 years]

   The first occurrence of clinically significant aortic stenosis

6. Number of Subjects With Atrial Fibrillation [From randomization to the trial end (April 2, 2018) - up to 5 years]

   The first occurrence of new or worsening of atrial fibrillation

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age ≥ 18 years at screening

• Documented past history of myocardial infarction OR past evidence of multivessel coronary artery disease by angiography.

• To qualify on the basis of past history of myocardial infarction, the event must be documented either by hospital records or by evidence on current ECG of Q waves in two contiguous leads and/or an imaging test demonstrating wall motion abnormality or scar. The patient must also have completed any planned coronary revascularization procedures associated with the qualifying event, and be clinically stable for at least 60 days prior to screening.

• To qualify on the basis of multivessel coronary disease, there must be past angiographic evidence of atherosclerosis in at least 2 major epicardial vessels defined either as the presence of a stent, a coronary bypass graft, or an angiographic lesion of 60% or greater. Left main coronary artery disease that has been revascularized with a stent or bypass graft will qualify as multivessel disease, as will the presence of a 50% or greater isolated left main stenosis. The patient must also have completed any planned coronary revascularization procedures associated with the qualifying event, and be clinically stable for at least 60 days prior to screening.

• History of type 2 diabetes or metabolic syndrome at time of study enrollment

• Willingness to participate as evidenced by signing the study informed consent

Exclusion Criteria:

• Prior history of chronic infectious disease, tuberculosis, or severe fungal disease; chronic hepatitis B or C infection; renal insufficiency; interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis; known chronic pericardial effusion, pleural effusion, or ascites; chronic liver disease; myeloproliferative disorders in the past 5 years; non-basal cell malignancy or treated lymphoproliferative disease within the past 5 years; known HIV positive; life expectancy of < 3 years;

• Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative colitis or Crohn's disease

• White blood cell count < 3,500/ul, hematocrit < 32 percent, or platelet count < 75,000/ul

• Liver transaminase levels (AST or ALT) >upper limit of normal (ULN) or albumin < the lower limit of normal (LLN);

• Creatinine clearance < 40 ml/min as estimated with the Cockcroft-Gault equation;

• History of alcohol abuse or unwillingness to limit alcohol consumption to less than 4 drinks per week

• Women of child bearing potential, even if they are currently using contraception, and women intending to breastfeed.

• Men who plan to father children during the study period or who are unwilling to use effective forms of contraception.

• Requirement for use of drugs that alter folate metabolism (trimethoprim/sulfamethoxazol) or reduce tubular excretion (probenecid) or known allergies to antibiotics making avoidance of trimethoprim impossible;

• Current indication for methotrexate therapy;

• Chronic use of oral steroid therapy or other immunosuppressive or biologic response modifiers. Eligible study participants will be encouraged to have up to date pneumococcal and influenza vaccinations as recommended based on their age and underlying medical conditions.

• Chest X-ray evidence in the past 12 months of interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis. For participants who do not have a chest X-ray in the prior 12 months, a chest X-ray will be obtained at baseline as part of the study protocol.

• New York Heart Association Class IV congestive heart failure.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Appalachian Research Associates	Fort Payne	Alabama	United States	35967
3	Avant Research Associates, LLC	Guntersville	Alabama	United States	35976
4	Saadat Ansari MD LLC	Huntsville	Alabama	United States	35801
5	University of South Alabama: Division of Clinical Research	Mobile	Alabama	United States	36617
6	Heart Vascular of Northern Arizona	Cottonwood	Arizona	United States	86326
7	CardioVascular Associates of Mesa	Mesa	Arizona	United States	85206
8	Arizona Arthritis & Rheumatology Research	Phoenix	Arizona	United States	85032
9	Scottsdale Medical Imaging	Scottsdale	Arizona	United States	85258
10	The Heart Clinic	Scottsdale	Arizona	United States	85258
11	Pima Heart	Tucson	Arizona	United States	85718
12	Southern Arizona VA Health Care System	Tucson	Arizona	United States	85723
13	Arkansas Cardiology	Little Rock	Arkansas	United States	72205
14	Arkansas Heart Hospital	Little Rock	Arkansas	United States	72211
15	Oracle Clinical Research, Inc.	Anaheim	California	United States	92801
16	Medical Group of Culver City	Culver City	California	United States	90230
17	Touro University California- Solano County Affiliated Clinics	Fairfield	California	United States	94533
18	University Of California San Francisco	Fresno	California	United States	93701
19	VACCHCS	Fresno	California	United States	93703
20	UCSD Sulpizio Cardiovascular Center	La Jolla	California	United States	92037
21	University Of California San Diego	La Jolla	California	United States	92093
22	Desert Medical Care & Wellness	La Quinta	California	United States	92253
23	Kumar Medical Corporation	Lancaster	California	United States	93534
24	Loma Linda University Health	Loma Linda	California	United States	92354
25	VA Loma Linda Healthcare System	Loma Linda	California	United States	92357
26	Long Beach Center for Clinical Research	Long Beach	California	United States	90807
27	Cardiovascular Innovation and Research	Long Beach	California	United States	90813
28	Los Alamitos Cardiovascular	Los Alamitos	California	United States	90720
29	Faye Montegrande Md. Clinical Research	Los Angeles	California	United States	90004
30	Eastside Clinical Research Associates	Los Angeles	California	United States	90022
31	Salman Khan A. Medical Corporation	Los Angeles	California	United States	90033
32	University of Southern California	Los Angeles	California	United States	90033
33	West LA VA Medical Center	Los Angeles	California	United States	90049
34	VA Northern California Health Care	Mather	California	United States	95655
35	Valley Clinical Trials, Inc.	Northridge	California	United States	91325
36	Orange County Heart Institute & Research	Orange	California	United States	92868
37	University of CA Irvine Medical Center	Orange	California	United States	92868
38	Diverse Research Solutions	Oxnard	California	United States	93030
39	Huntington Memorial Hospital	Pasadena	California	United States	91105
40	Central Coast Cardiology	Salinas	California	United States	93901
41	Richard G. Friedman, MD	San Diego	California	United States	92103
42	Ritchken and First MDs	San Diego	California	United States	92117
43	Foundation for Cardiovascular Medicine	San Diego	California	United States	92121
44	San Diego Cardiac Center	San Diego	California	United States	92123
45	Veterans Affairs San Diego Healthcare System	San Diego	California	United States	92161
46	UCSF at Zuckerberg SF General Hospital	San Francisco	California	United States	94110
47	Coastal Heart Medical Group, Inc.	Santa Ana	California	United States	92704
48	Comprehensive Cardiovascular Care	Santa Maria	California	United States	93454
49	Pacific Heart and Vascular Medical Group	Stockton	California	United States	95210
50	Manoj D. Aswani M.D.	Thousand Oaks	California	United States	91360
51	Touro University California- Solano Public Health Affiliated Clinics	Vallejo	California	United States	94592
52	Munni R. Selagamsetty, Md, Pc	Colorado Springs	Colorado	United States	80910
53	Vijay - Aurora Denver Cardiology	Denver	Colorado	United States	80218
54	Colorado Health Medical Group Heart Center of the Rockies	Fort Collins	Colorado	United States	80528
55	Medical Center of the Rockies Research	Fort Collins	Colorado	United States	80528
56	Unrein - Rocky Vista University Health Center	Parker	Colorado	United States	80134
57	Connecticut Heart and Vascular Center	Bridgeport	Connecticut	United States	06606
58	Bridgeport Hospital	Bridgeport	Connecticut	United States	06610
59	Cardiology Physicians/Red Clay Research	Newark	Delaware	United States	19713
60	Boisey Barnes MD, PC	Washington	District of Columbia	United States	20024
61	GWU Medical Faculty Associatin, Inc.	Washington	District of Columbia	United States	20037
62	Pianko - Aventura Research Center, LLC	Aventura	Florida	United States	33180
63	North Ridge Heart Associates	Boca Raton	Florida	United States	33434
64	St. Francis Medical Institute	Clearwater	Florida	United States	33765
65	Gonzalez MD & Aswad MD Health Ser	Coral Gables	Florida	United States	33134
66	American Research Institute, Inc.	Cutler Bay	Florida	United States	33157
67	Daytona Heart Group	Daytona Beach	Florida	United States	32114
68	Daytona Heart Group	DeLand	Florida	United States	32720
69	Seidman Clinical Trials	Delray Beach	Florida	United States	33484
70	Steven Cohen MD	Delray Beach	Florida	United States	33484
71	Infinite Clinical Research	Doral	Florida	United States	33126
72	International Research Partners, LLC	Doral	Florida	United States	33166
73	Medical Research Institute at Doral, Inc.	Doral	Florida	United States	33178
74	Lake Internal Medicine Assocaties	Eustis	Florida	United States	32726
75	Invesclinic	Fort Lauderdale	Florida	United States	33308
76	Primary Care Associates	Fort Myers	Florida	United States	33907
77	Lee Physician Group	Fort Myers	Florida	United States	33908
78	The Cardiac and Vascular Institute	Gainesville	Florida	United States	32605
79	University of Florida	Gainesville	Florida	United States	32610
80	Qway Research	Hialeah	Florida	United States	33010
81	State of the Art Research	Hialeah	Florida	United States	33010
82	Healing Touch C&C Research	Hialeah	Florida	United States	33012
83	Luzmed Clinical Research Institute	Hialeah	Florida	United States	33012
84	Viviana Perez MD Research & Cosmetics	Hialeah	Florida	United States	33012
85	Elite Cardiac Research Center LLC	Hialeah	Florida	United States	33013
86	Nova Clinical Research Clinic	Hialeah	Florida	United States	33013
87	Best Quality Research, Inc.	Hialeah	Florida	United States	33016
88	South Florida Research Solutions, LLC	Hollywood	Florida	United States	33021
89	John Gutleber Medical Research Office	Homestead	Florida	United States	33030
90	Cardiovascular Medical Associates of Palm Beach	Jupiter	Florida	United States	33458
91	Hope Clinical Research	Kissimmee	Florida	United States	34758
92	SIH Research, LLC	Kissimmee	Florida	United States	34759
93	Lakes Research, LLC	Miami Lakes	Florida	United States	33014
94	Veritas Research Corp.	Miami Lakes	Florida	United States	33014
95	Ocean Blue Medical Research Center	Miami Springs	Florida	United States	33166
96	Medical Research Center of Florida	Miami	Florida	United States	33122
97	LG Diagnostics, Inc.	Miami	Florida	United States	33126
98	St. Paul Medical Research Center, Inc.	Miami	Florida	United States	33126
99	Team Medical Research	Miami	Florida	United States	33134
100	Paradise Clinical Research, LLC	Miami	Florida	United States	33144
101	GAD Research Center	Miami	Florida	United States	33155
102	Innovation Research Institute, Inc.	Miami	Florida	United States	33155
103	Sanitas Research	Miami	Florida	United States	33155
104	Segui - Med Care Research	Miami	Florida	United States	33165
105	South Florida Research Group, LLC	Miami	Florida	United States	33176
106	Vista Health Research, LLC	Miami	Florida	United States	33176
107	D De La Vega MD Research Group	Miami	Florida	United States	33186
108	Southwest Florida Research, LLC	Naples	Florida	United States	34102
109	Orlando Healthy Heart Institute	Orlando	Florida	United States	32806
110	Palm Beach Gardens Research Center, LLC	Palm Beach Gardens	Florida	United States	33410
111	Broward Research Center	Pembroke Pines	Florida	United States	33024
112	Pioneer Clinical Research	Pembroke Pines	Florida	United States	33024
113	Sandoval - Broward Research Center	Pembroke Pines	Florida	United States	33204
114	Bay Area Heart Center: 49th Street	Saint Petersburg	Florida	United States	33705
115	Bay Area Heart Center: 7th Avenue	Saint Petersburg	Florida	United States	33705
116	Lenus Research & Medical Group	Sweetwater	Florida	United States	33172
117	DBC Research	Tamarac	Florida	United States	33321
118	Asclepes Research Centers	Weeki Wachee	Florida	United States	34607
119	Gupta - Premier Heart and Vascular Center	Wesley Chapel	Florida	United States	33544
120	Athens Regional Medical Center	Athens	Georgia	United States	30606
121	Atlanta Veterans Affairs Medical Center	Atlanta	Georgia	United States	30033
122	Laureate Medical Group at Northside	Atlanta	Georgia	United States	30308
123	Synergy Therapeutic Partners	Atlanta	Georgia	United States	30308
124	Northside Hospital	Atlanta	Georgia	United States	30342
125	Atlanta Heart Specialists, LLC	Cumming	Georgia	United States	30041
126	Heart and Rhythm Specialists	Dalton	Georgia	United States	30720
127	Albert F. Johary MD, PC	Dunwoody	Georgia	United States	30338
128	Infinite Clinical Trials	Riverdale	Georgia	United States	30274
129	Atlanta Vanguard Medical Associates	Smyrna	Georgia	United States	30082
130	Herman Clinical Research, LLC	Suwanee	Georgia	United States	30024
131	Atlanta Heart Specialists, LLC	Tucker	Georgia	United States	30084
132	Cardiology Associates of Vidalia, P.C.	Vidalia	Georgia	United States	30474
133	VA Pacific Islands Health Care System	Honolulu	Hawaii	United States	96819
134	St. Luke's Idaho Cardiology Associates	Boise	Idaho	United States	83712
135	Clinical Research Prime	Idaho Falls	Idaho	United States	83404
136	Northwest Heart Clinical Research	Arlington Heights	Illinois	United States	60005
137	University of Chicago Medical Center	Chicago	Illinois	United States	60637
138	Advocate Med Group-Heart & Vascular Of Illinois	Chicago	Illinois	United States	60657
139	Illinois Heart & Lung Research Center, SC	Normal	Illinois	United States	61761
140	Captain James A. Lovell Federal Health	North Chicago	Illinois	United States	60064
141	Specialty Physicians of Illinois, LLC	Olympia Fields	Illinois	United States	60461
142	Advanced CardioVascular Consultants	Rock Island	Illinois	United States	61201
143	Cardiospecialists, LTD	Dyer	Indiana	United States	46311
144	Martin - Martin Family Practice and Research	Evansville	Indiana	United States	47714
145	Krannert Institute Of Cardiology	Indianapolis	Indiana	United States	46202
146	Community Hospital South	Indianapolis	Indiana	United States	46227
147	Indiana Heart Physicians	Indianapolis	Indiana	United States	46237
148	Medical Consultants, PC	Muncie	Indiana	United States	47303
149	Iowa Heart Center	West Des Moines	Iowa	United States	50266
150	Stahl - Midwest Heart & Vascular Specialists	Overland Park	Kansas	United States	66209
151	Professional Research Network of KS	Wichita	Kansas	United States	67203
152	Robert J. Dole VAMC	Wichita	Kansas	United States	67230
153	University of Kentucky	Lexington	Kentucky	United States	40536
154	Robley Rex VAMC	Louisville	Kentucky	United States	40202
155	Stoddard - University of Louisville	Louisville	Kentucky	United States	40202
156	Bays - L-MARC Research Center	Louisville	Kentucky	United States	40213
157	Research Integrity LLC	Owensboro	Kentucky	United States	42303
158	Dorothy H. Banish, MD, APMC Study Group	Covington	Louisiana	United States	70433
159	Avant Research Associates, LLC	Crowley	Louisiana	United States	70526
160	North Oaks Cardiology	Hammond	Louisiana	United States	70403
161	American Clinical Research, LLC	Marrero	Louisiana	United States	70072
162	Otis Barnum D.O.P.C.	Natchitoches	Louisiana	United States	71457
163	Tulane University Office of Health Research	New Orleans	Louisiana	United States	70112
164	Veterans Affairs Medical Center Shreveport	Shreveport	Louisiana	United States	71101
165	Maine Research Associates	Auburn	Maine	United States	04210
166	Paul A. Shapero, M.D.	Bangor	Maine	United States	04401
167	Southern Maine Health Care	Biddeford	Maine	United States	04005
168	InterMed, PA	Portland	Maine	United States	04101
169	Maine Medical Partners Maine Health Cardiology	South Portland	Maine	United States	04106
170	Maine Centers for Healthcare	Westbrook	Maine	United States	04092
171	Sinai Center for Thrombosis Research	Baltimore	Maryland	United States	21215
172	St. Mary's Medical Center	Charlotte Hall	Maryland	United States	20622
173	Calvert Memorial Hospital	Clinton	Maryland	United States	20735
174	Shah Associates, MD, LLC	Prince Frederick	Maryland	United States	20678
175	Peninsula Cardiology Associates	Salisbury	Maryland	United States	21804
176	IRC Clinics	Towson	Maryland	United States	21204
177	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
178	St. Elizabeth's Medical Center	Boston	Massachusetts	United States	02135
179	MGH Cardiology	Boston	Massachusetts	United States	02214
180	Joslin Diabetes Center	Boston	Massachusetts	United States	02215
181	Lahey Hospital and Medical Center	Burlington	Massachusetts	United States	01805
182	Massachusetts General Hospital - Chelsea Health Care Center	Chelsea	Massachusetts	United States	02150
183	Pentucket Medical Associates, Inc.	Haverhill	Massachusetts	United States	01830
184	VA Central Western Massachusetts Healthca	Leeds	Massachusetts	United States	01053
185	South Shore Internal Medicine	Milton	Massachusetts	United States	02186
186	Lahey Medical Center	Peabody	Massachusetts	United States	02149
187	North Shore Cardiovascular Associates	Salem	Massachusetts	United States	01907
188	Reliant Medical Group	Worcester	Massachusetts	United States	01608
189	Endeavor Medical Research	Alpena	Michigan	United States	49707
190	John D. Dingell Veterans Affairs Medical Center	Detroit	Michigan	United States	48201
191	Trace Research Group at Wayne State University	Detroit	Michigan	United States	48201
192	Henry Ford Hospital	Detroit	Michigan	United States	48202
193	Flint Clinical Research	Flint	Michigan	United States	48503
194	Apex Medical Research MI, Inc.	Flint	Michigan	United States	48504
195	Garden City Hospital	Garden City	Michigan	United States	48135
196	Genesys Regional Medical Center	Grand Blanc	Michigan	United States	48439
197	National Clinical LLC	Hamtramck	Michigan	United States	48212
198	Academic Cardiology Associates PC	Rochester Hills	Michigan	United States	48307
199	Beaumont Health Center	Royal Oak	Michigan	United States	48073
200	Covenant Medical Center, Inc.	Saginaw	Michigan	United States	48602
201	Mid-Michigan Heart & Vascular Center	Saginaw	Michigan	United States	48609
202	Centra Care Heart & Vascular Center at St. Cloud Hospital	Saint Cloud	Minnesota	United States	56303
203	United Heart and Vascular Clinic	Saint Paul	Minnesota	United States	55102
204	Gulfside Clinical Research, LLC	Gulfport	Mississippi	United States	39501
205	University of MS Medical Center	Jackson	Mississippi	United States	39216
206	David M. Headley M.D. PA Planters Clinic	Port Gibson	Mississippi	United States	39150
207	Stern Cardiovascular Foundation, Inc.	Southaven	Mississippi	United States	38671
208	Center for Advanced Medicine and Research LLC	Bridgeton	Missouri	United States	63044
209	Clinical Research Center University of Missouri	Columbia	Missouri	United States	65212
210	Quantum Research LLC	Festus	Missouri	United States	63028
211	Midwest Cardiology Associates	Independence	Missouri	United States	64057
212	Freeman Health System	Joplin	Missouri	United States	64804
213	VA Medical Center Kansas City	Kansas City	Missouri	United States	64128
214	Lake Regional Cardiovascular Institute	Osage Beach	Missouri	United States	65065
215	VA St. Louis Health Care System (VASTLHCS)	Saint Louis	Missouri	United States	63106
216	SLUCare Cardiology	Saint Louis	Missouri	United States	63110
217	Washington University	Saint Louis	Missouri	United States	63110
218	Clinical Investigators LLC	Saint Louis	Missouri	United States	63119
219	Consult and Research Associates	Saint Louis	Missouri	United States	63122
220	Center for Advanced Medicine and Research	Saint Peters	Missouri	United States	63303
221	CoxHealth: Wheeler Heart & Vascular Center	Springfield	Missouri	United States	65807
222	Mercy Medical Research Institute	Springfield	Missouri	United States	65807
223	Great Falls Clinic Clinical Research Deptartment	Great Falls	Montana	United States	59420
224	Cone - Montana Medical Research	Missoula	Montana	United States	59801
225	Barrett Clinic, P.C.	La Vista	Nebraska	United States	68128
226	Heart Consultants	Omaha	Nebraska	United States	68114
227	Alegent Creighton Health	Omaha	Nebraska	United States	68131
228	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
229	Internal Medicine Clinic	Las Vegas	Nevada	United States	89102
230	Red Rock Clinical Research, LLC	Las Vegas	Nevada	United States	89146
231	Sierra Nevada Health Care System	Reno	Nevada	United States	89502
232	Renown Inst for Heart & Vasc Health	Reno	Nevada	United States	89503
233	Lahey Cardiology	Nashua	New Hampshire	United States	03060
234	Family Health at Mount Olive	Flanders	New Jersey	United States	07836
235	Cardiocare	Hillsborough	New Jersey	United States	08844
236	New Jersey Heart	Linden	New Jersey	United States	07063
237	Jersey Shore University Medical Center	Neptune	New Jersey	United States	07753
238	Cardiovascular Institute	New Brunswick	New Jersey	United States	08901
239	Palisade Medical Center	North Bergen	New Jersey	United States	07047
240	The Valley Hospital	Ridgewood	New Jersey	United States	07450
241	Mercer Bucks Cardiology	Robbinsville	New Jersey	United States	08691
242	Cardio Metabolic Institute	Somerset	New Jersey	United States	08873
243	Holy Name Medical Center, Inc.	Teaneck	New Jersey	United States	07666
244	Total Cardiology Care, LLC	Wayne	New Jersey	United States	07470
245	Westwood Cardiology Associates	Westwood	New Jersey	United States	07675
246	Presbyterian Heart Group	Albuquerque	New Mexico	United States	87106
247	Albany Medical College	Albany	New York	United States	12208
248	Albany Stratton VA Medical Center	Albany	New York	United States	12208
249	Novel Research of New York, LLC	Bronx	New York	United States	10461
250	Montefiore Medical Center	Bronx	New York	United States	10467
251	Brown - SUNY Downstate Medical Center	Brooklyn	New York	United States	11203
252	Buffalo Heart Group	Buffalo	New York	United States	14215
253	Bassett Healthcare Network	Cooperstown	New York	United States	13326
254	NYU Hudson Valley Cardiology	Cortlandt Manor	New York	United States	10567
255	NYHQ	Flushing	New York	United States	11355
256	Jamaica Hospital Medical Center	Jamaica	New York	United States	11418
257	Long Island Heart Associates	Mineola	New York	United States	11501
258	Winthrop University Hospital	Mineola	New York	United States	11501
259	Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
260	Queens Long Island Medical Group	New Hyde Park	New York	United States	11577
261	Chinatown Cardiology, PC	New York	New York	United States	10013
262	Weill Cornell Medical College and NY Presbyterian	New York	New York	United States	10021
263	Mount Sinai School of Medicine	New York	New York	United States	10029
264	DiGiovanna Institute for Medical Education and Research	North Massapequa	New York	United States	11758
265	Champlain Valley Physician Hospital	Plattsburgh	New York	United States	12901
266	Cardiology Associates of Schenectady	Schenectady	New York	United States	12309
267	Clinical Study Center of Asheville	Asheville	North Carolina	United States	28801
268	Metrolina Internal Medicine	Charlotte	North Carolina	United States	28204
269	Gaffney Health Services	Charlotte	North Carolina	United States	28205
270	Carolinas Research Center	Charlotte	North Carolina	United States	28215
271	Eastern Carolina Cardiovascular, PA	Elizabeth City	North Carolina	United States	27909
272	Eastern Cardiology	Greenville	North Carolina	United States	27834
273	Northside Clinical Research	Lenoir	North Carolina	United States	28645
274	Lake Shore Clinical Research, LLC.	Mooresville	North Carolina	United States	28117
275	Carteret Medical Group	Morehead City	North Carolina	United States	28557
276	Cardiology Associates of Carolinas, PA	Morganton	North Carolina	United States	28655
277	Eastern Nephrology Associates, PLLC	New Bern	North Carolina	United States	28562
278	Boice Willis Clinic	Rocky Mount	North Carolina	United States	27804
279	Sanford Cardiology	Sanford	North Carolina	United States	27330
280	Natalie A. Doyle, MD, PA	Wilson	North Carolina	United States	27893
281	Altru Health System Rehab Center	Grand Forks	North Dakota	United States	58201
282	Akron General Medical Center	Akron	Ohio	United States	44307
283	Ohio University Heritage College of Osteopathic Medicine	Athens	Ohio	United States	45701
284	Diabetes and Endocrinology Associates of Stark Cit	Canton	Ohio	United States	44718
285	The Lindner Research Center	Cincinnati	Ohio	United States	45219
286	Cleveland Clinic	Cleveland	Ohio	United States	44195
287	Optimed Research, LTD	Columbus	Ohio	United States	43235
288	Dayton Heart Center	Dayton	Ohio	United States	45414
289	Dayton Veteran Affairs Medical Center	Dayton	Ohio	United States	45428
290	Colonnade Medical Group	Lancaster	Ohio	United States	43130
291	Middletown Cardiovascular Associates	Middletown	Ohio	United States	45044
292	Comprehensive Heart Care, Inc.	Toledo	Ohio	United States	43606
293	Mount Carmel Clinical Cardiovascular Care	Westerville	Ohio	United States	43081
294	Premier Physicians	Westlake	Ohio	United States	44154
295	Wooster Heart Group	Wooster	Ohio	United States	44691
296	Unity Clinical Research	Lindsay	Oklahoma	United States	73052
297	COR Clinical Research, LLC	Oklahoma City	Oklahoma	United States	73103
298	Thadani - VA Medical Center Oklahoma City, OK	Oklahoma City	Oklahoma	United States	73104
299	Today Clinical Research	Oklahoma City	Oklahoma	United States	73129
300	Cardiovascular Health Clinic	Oklahoma City	Oklahoma	United States	73134
301	Oklahoma State University Center for Health Sciences	Tulsa	Oklahoma	United States	74127
302	Samaritan Health Services	Corvallis	Oregon	United States	97330
303	Southern Oregon Cardiology, LLC	Medford	Oregon	United States	97504
304	Oregon Health & Science University	Portland	Oregon	United States	97239
305	Center for Clinical Res. Abington Health	Abington	Pennsylvania	United States	19001
306	St. Luke's University Hospital	Bethlehem	Pennsylvania	United States	18018
307	Renu-Ca Research Institute, Lower Bucks Hospital	Bristol	Pennsylvania	United States	19007
308	Main Line Health Center, Broomall	Broomall	Pennsylvania	United States	19008
309	Spirit Physician Services, Inc	Camp Hill	Pennsylvania	United States	17011
310	The Chambersburg Hospital	Chambersburg	Pennsylvania	United States	17201
311	Central Bucks Cardiology	Doylestown	Pennsylvania	United States	18901
312	Altoona Center for Clinical Research	Duncansville	Pennsylvania	United States	16635
313	Heart Specialists of Lancaster County	Ephrata	Pennsylvania	United States	17522
314	Saint Vincent Consultants in Cardiovascular Diseases, LLC	Erie	Pennsylvania	United States	16502
315	Feasterville Family Healthcare Center	Feasterville	Pennsylvania	United States	19053
316	Christiana Care Health System	Glen Mills	Pennsylvania	United States	19342
317	Pinnacle Health Cardiovascular Institute	Harrisburg	Pennsylvania	United States	17110
318	George Isajiw, MD	Lansdowne	Pennsylvania	United States	19050
319	Bucks County Clinical Research	Morrisville	Pennsylvania	United States	19067
320	Drexel University College of Medicine	Philadelphia	Pennsylvania	United States	19102
321	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
322	Lehigh Valley Health Services	Sellersville	Pennsylvania	United States	18960
323	Pish Medical Associates, Inc.	Uniontown	Pennsylvania	United States	15401
324	Lehigh Valley Family Practice	Whitehall	Pennsylvania	United States	18052
325	Wilkes-Barre VA Medical Center	Wilkes-Barre	Pennsylvania	United States	18711
326	Partners in Clinical Research	Cumberland	Rhode Island	United States	02864
327	Ocean State Clinical Research Prtnr	Lincoln	Rhode Island	United States	02865
328	Memorial Hospital of Rhode Island	Pawtucket	Rhode Island	United States	02860
329	The Miriam Hospital	Providence	Rhode Island	United States	02906
330	Ocean State Research Institute, Inc	Providence	Rhode Island	United States	02908
331	South Carolina Heart Center	Columbia	South Carolina	United States	29204
332	Amistad Research Center, LLC	Columbia	South Carolina	United States	29223
333	Charlotte Hearts	Indian Land	South Carolina	United States	29707
334	Miller - SC Internal Medicine Associates.: Irmo	Irmo	South Carolina	United States	29063
335	Inlet Cardiopulmonary & Associates	Pawleys Island	South Carolina	United States	29585
336	Fusion Clinical Research of Spartanburg	Spartanburg	South Carolina	United States	29301
337	Palmetto Research Center, LLC	Spartanburg	South Carolina	United States	29302
338	New Phase Research & Development	Chattanooga	Tennessee	United States	37409
339	Parkway Medical Group	Fayetteville	Tennessee	United States	37334
340	Stern Cardiovascular Foundation, Inc.	Germantown	Tennessee	United States	38138
341	Kore Cardiovascular Research Institutue	Jackson	Tennessee	United States	38305
342	New Phase Research & Development	Knoxville	Tennessee	United States	37909
343	Cardiovascular Research of Knoxville	Knoxville	Tennessee	United States	37917
344	Ramanathan - VAMC Memphis	Memphis	Tennessee	United States	38104
345	Clinical Research Center Meharry Medical College	Nashville	Tennessee	United States	37208
346	Avant Research Associates LLC	Austin	Texas	United States	78704
347	Texas Heart and Vascular Research, LLC	Austin	Texas	United States	78745
348	Southeast TX Clinical Research Center	Beaumont	Texas	United States	77702
349	Cornerstone Family Medicine	Big Spring	Texas	United States	79720
350	IMD Medical Center	Carrollton	Texas	United States	75006
351	Texas Health Physicians Group	Carrollton	Texas	United States	75010
352	Cardiovascular Research Institute of Dallas	Dallas	Texas	United States	75231
353	North Texas Health Center	Dallas	Texas	United States	75231
354	The Heart Center of Dallas	Dallas	Texas	United States	75235
355	Global Medical Research	DeSoto	Texas	United States	75115
356	The Medical Group of Texas	Fort Worth	Texas	United States	76104
357	Texas Health Physicians Group	Fort Worth	Texas	United States	76107
358	T&R Clinic, P.A.	Haltom City	Texas	United States	76117
359	Michele P. Sartori, MD	Houston	Texas	United States	77030
360	Grand Medical Care	Katy	Texas	United States	77494
361	Team Research Of Central Texas	Killeen	Texas	United States	76543
362	Houston Heart and Vascular Associates	Kingwood	Texas	United States	77339
363	Grace Research, LLC	Marshall	Texas	United States	75670
364	Valley Heart Consultants	McAllen	Texas	United States	78503
365	Heart Center, Palo Pinto General Hospital	Mineral Wells	Texas	United States	76067
366	Valley Central Research Inc	Mission	Texas	United States	78572
367	North Hills Medical Research, Inc	North Richland Hills	Texas	United States	76180
368	Grace Research, LLC	Palestine	Texas	United States	75801
369	Avant Research Associates, LLC	Port Arthur	Texas	United States	77640
370	Santoscoy - Health Texas Research Institute	San Antonio	Texas	United States	78212
371	Element Research Group	San Antonio	Texas	United States	78229
372	Schnitzler Cardiovascular Consultants	San Antonio	Texas	United States	78229
373	San Antonio Endovascular & Heart Institute	San Antonio	Texas	United States	78268
374	Acacia Medical Research Institute	Sugar Land	Texas	United States	77478
375	Health Plus Clinical Research	Sugar Land	Texas	United States	77478
376	Lone Star Heart and Vascular Center	Tomball	Texas	United States	77375
377	Northwest Houston Clinical Research	Tomball	Texas	United States	77375
378	Hillcrest Family Health Center	Waco	Texas	United States	76710
379	Utah Cardiology, P.C.	Layton	Utah	United States	84041
380	Utah Diabetes Center	Salt Lake City	Utah	United States	84108
381	VA Medical Center, White River Junction	White River Junction	Vermont	United States	05009
382	Burke Internal Medicine & Research	Burke	Virginia	United States	22015
383	Seven Corners Medical Research Center	Falls Church	Virginia	United States	22044
384	Hampton Family Practice Research	Hampton	Virginia	United States	23666
385	Tidewater Physicians Multispecialty Group	Hampton	Virginia	United States	23666
386	Virginia Cardiovascular Associates	Manassas	Virginia	United States	20109
387	Manassas Clinical Research Center	Manassas	Virginia	United States	20110
388	Tucker Cardiology Associates, P.C.	Mechanicsville	Virginia	United States	23116
389	TPMG Clinical Research	Newport News	Virginia	United States	23606
390	Sentara Norfolk General Hospital	Norfolk	Virginia	United States	23507
391	Roanoke Heart Institute PLC	Roanoke	Virginia	United States	24014
392	Cardinal Internal Medicine Associates	Woodbridge	Virginia	United States	22192
393	Tidewater Physicians Multispecialty Group	Yorktown	Virginia	United States	23690
394	Frandsen Family Medicine DBA Sound Medi	Port Orchard	Washington	United States	98366
395	Premier Clinical Research	Spokane	Washington	United States	99202
396	Kootenai Heart Clinics, LLC	Spokane	Washington	United States	99204
397	Northside Internal Medicine	Spokane	Washington	United States	99208
398	Northwest Medical Associates, P.S.	Vancouver	Washington	United States	98684
399	Cardiology Associates of Bellin Health	Green Bay	Wisconsin	United States	54115
400	Dean Foundation	Madison	Wisconsin	United States	53715
401	University Of Wisconsin	Madison	Wisconsin	United States	53715
402	Marshfield Clinic	Marshfield	Wisconsin	United States	54449
403	Columbia St. Mary's	Milwaukee	Wisconsin	United States	53211
404	Aurora St. Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
405	The Medical Arts Health Research Group	North Vancouver	British Columbia	Canada	V7M 2H4
406	The Medical Arts Health Research Group	Penticton	British Columbia	Canada	V2A 5C8
407	Winnipeg Clinic	Winnipeg	Manitoba	Canada	R3C 0N2
408	Bramalea Medical Centre	Brampton	Ontario	Canada	L6T 4S5
409	Brampton Research Associates	Brampton	Ontario	Canada	L6Z 4N5
410	Philippe R Beaudry Medicine Professional Corporation	Burlington	Ontario	Canada	L7R 4E2
411	Vizel Cardiac Research	Cambridge	Ontario	Canada	N1R7R1
412	Dr. Linda Sinnaeve's Office	Chatham	Ontario	Canada	N7L 1C1
413	Scisco Clinical Research	Cornwall	Ontario	Canada	K6H 4M4
414	Dr. Peter Spadafora Health Center	Guelph	Ontario	Canada	N1E 5G6
415	John Stimac, MD	Hamilton	Ontario	Canada	L8L 5G4
416	KMH Cardiology & Diagnostics: Hamilton	Hamilton	Ontario	Canada	L8P 3A9
417	Dr. William Liang	Hamilton	Ontario	Canada	L8W3J6
418	Source Unique Clinic	Hawkesbury	Ontario	Canada	K6A 1A1
419	Dr. Ronald Fowlis	Kitchener	Ontario	Canada	N2M 5NG
420	University Hospital	London	Ontario	Canada	N6A 5A5
421	Malton Medical Research	Mississauga	Ontario	Canada	L4T 4J2
422	KMH Cardiology & Diagnostics: Mississauga	Mississauga	Ontario	Canada	L5K 2L3
423	Sewa Ram Singal Medicine Professional Corporation	Mississauga	Ontario	Canada	L5U 0A6
424	Newmarket Cardiology Research Group	Newmarket	Ontario	Canada	l3y -8c3
425	Newmarket Cardiology Research Group	Newmarket	Ontario	Canada	L3Y 8C3
426	Portage Medical Centre	Niagara Falls	Ontario	Canada	I2E6A6
427	Humber River Regional Hospital	North York	Ontario	Canada	M3N2V6
428	Bakbak Medicine Professional Corporation	Oshawa	Ontario	Canada	L1H 1B9
429	Dr. James Y. Cha	Oshawa	Ontario	Canada	L1J2K1
430	University Of Ottawa Heart Institute	Ottawa	Ontario	Canada	k1y -4w7
431	Kawartha Cardiology Clinical Trials	Peterborough	Ontario	Canada	K9J0B2
432	Steeple Hill Medical Centre	Pickering	Ontario	Canada	L1V 2A6
433	Sarnia Institute Of Clinical Research	Sarnia	Ontario	Canada	N7T 4X3
434	Scarborough Cardiology Research	Scarborough	Ontario	Canada	M1E5E9
435	Scarborough General Hospital Cardiology Research Associates	Scarborough	Ontario	Canada	M1PT27
436	Milliken Medical Centre	Scarborough	Ontario	Canada	M1V5P6
437	Canadian Centre for Research on Diabetes	Smith Falls	Ontario	Canada	K7A 4W8
438	Lake Shore Cardiology	St. Catharines	Ontario	Canada	L2S 2Y3
439	Sardar Medical Clinic	St. Thomas	Ontario	Canada	N5R 2R4
440	G.S. Cardiac Lab Medicine Professional Corp	Sudbury	Ontario	Canada	P3C 1S8
441	Dr. R. Labonte Professional Med Corp	Sudbury	Ontario	Canada	P3E 3B8
442	Dr. G. Garrioch, Independent Practice	Sudbury	Ontario	Canada	P3E 3C6
443	Dr. Laurence Gibbs Medicine Professional Corp.	Thedford	Ontario	Canada	N0M 2N0
444	Tillsonburg Medical Centre	Tillsonburg	Ontario	Canada	N4G 5A7
445	Humber River Hospital	Toronto	Ontario	Canada	M3M 0B2
446	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
447	St. Michael's Hospital	Toronto	Ontario	Canada	M5B 1W8
448	Mount Sinai Hospital	Toronto	Ontario	Canada	M5G 1X5
449	Toronto General Hospital	Toronto	Ontario	Canada	M5G 2N2
450	Weston Road Medical Clinic	Toronto	Ontario	Canada	M9N 2A7
451	Dr. Nigel Jagan Medicine Professional Corporation	Whitby	Ontario	Canada	L1N 2L1
452	Dr. Nwadiaro Medicine Professional Corp	Windsor	Ontario	Canada	N8X 1L9
453	Viacar Recherche Clinique Inc.	Brossard	Quebec	Canada	J4X1S4
454	Ecogene-21	Chicoutimi	Quebec	Canada	G7H 7K9
455	Q&T Research Chicoutimi	Chicoutimi	Quebec	Canada	G7H 7Y8
456	Viacar Recherche Clinique Inc.	Greenfield Park	Quebec	Canada	J4V2G8
457	CHUM Hotel-Dieu	Montreal	Quebec	Canada	H2W 1T8
458	Iucpq	Quebec City	Quebec	Canada	G1V 4G5
459	ALPHA Recherche Clinique	Québec	Quebec	Canada	G3K 2P8
460	CardioVasc HR	Saint-Jean-sur-Richelieu	Quebec	Canada	j3a-1c3
461	ViaCar Recherche Clinique Inc	Saint-Lambert	Quebec	Canada	J4P 2H4
462	Viacar Recherche Clinique	St. Lambert	Quebec	Canada	J4P 2J2
463	Hopital Pierre-Le Gardeur	Terrebonne	Quebec	Canada	J6V 2H2
464	Recherche Clinique Sigma, Inc.	Quebec		Canada	G1G3Z4
465	Instituto Sanacoop	Bayamón		Puerto Rico	00961
466	San Juan Bautista School of Medicine	Caguas		Puerto Rico	00727
467	Norma S. Severino-Pacheco, MD	Canovanas		Puerto Rico	00729
468	Cardiometabolic Research Center	Ponce		Puerto Rico	00717
469	Miguel Sosa-Padilla, MD	San Juan		Puerto Rico	00926-2832
470	Yolanda Sierra Quinones, MD	Toa Baja		Puerto Rico	00949

Sponsors and Collaborators

• Brigham and Women's Hospital
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Paul Ridker, MD, MPH, Brigham and Women's Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 30, 2014

More Information

Publications

None provided.

• Responsible Party: Paul Ridker, Director, Center for Cardiovascular Disease and Prevention, Brigham and Women's Hospital, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01594333
• Other Study ID Numbers: 2012P-000857; U01HL101422; U01HL101389
• First Posted: May 9, 2012
• Last Update Posted: Jul 24, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by Paul Ridker, Director, Center for Cardiovascular Disease and Prevention, Brigham and Women's Hospital, Brigham and Women's Hospital: Myocardial Infarction; Stroke; Cardiovascular death; Type 2 Diabetes; Metabolic Syndrome; Cardiovascular Inflammation; Atherothrombosis
• Additional relevant MeSH terms: Cardiovascular Diseases; Methotrexate

Study Results

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 Detail	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 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

Baseline Characteristics

Arm/Group Title	Methotrexate	Placebo	Total
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 Participants	2391	2395	4786
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	65.6	66.0	65.8
Sex: Female, Male (Count of Participants)
Female	461 19.3%	437 18.2%	898 18.8%
Male	1930 80.7%	1958 81.8%	3888 81.2%
Race/Ethnicity, Customized (Count of Participants)
Hispanic/Latino	206 8.6%	177 7.4%	383 8%
White/Non-hispanic or Latino	1801 75.3%	1837 76.7%	3638 76%
Asian	89 3.7%	92 3.8%	181 3.8%
Black or African American	186 7.8%	152 6.3%	338 7.1%
American Indian or Alaska Native	6 0.3%	6 0.3%	12 0.3%
Native Hawaiian or other Pacific Islander	3 0.1%	6 0.3%	9 0.2%
Multiracial	13 0.5%	7 0.3%	20 0.4%
Other	42 1.8%	45 1.9%	87 1.8%
White, Unknown Ethnicity	45 1.9%	73 3%	118 2.5%
Region of Enrollment (participants) [Number]
Canada	407 17%	404 16.9%	811 16.9%
Puerto Rico	19 0.8%	17 0.7%	36 0.8%
United States	1965 82.2%	1974 82.4%	3939 82.3%
Smoking status (Count of 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%	1861 38.9%
Alcohol use (Count of 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 (kilograms per meter squared) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kilograms per meter squared]	31.6	31.3	31.5
History of diagnosed hypertension (Count of Participants)
Yes	2153 90%	2169 90.6%	4322 90.3%
No	238 10%	225 9.4%	463 9.7%
Qualifying event (Count of 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 (Count of Participants)
Diabetes only	788 33%	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 (Count of Participants)
Yes	288 12%	332 13.9%	620 13%
No	2103 88%	2062 86.1%	4165 87%
History of percutaneous coronary intervention (Count of Participants)
Yes	1396 58.4%	1420 59.3%	2816 58.8%
No	995 41.6%	974 40.7%	1969 41.1%
History of coronary-artery bypass grafting (Count of Participants)
Yes	1010 42.2%	1032 43.1%	2042 42.7%
No	1381 57.8%	1362 56.9%	2743 57.3%
Family history of premature myocardial infarction (Count of Participants)
Yes	550 23%	536 22.4%	1086 22.7%
No	1568 65.6%	1580 66%	3148 65.8%
Family history of premature stroke (Count of Participants)
Yes	142 5.9%	136 5.7%	278 5.8%
No	2002 83.7%	2024 84.5%	4026 84.1%
Use of ACE inhibitor or ARB (Count of Participants)
Yes	1736 72.6%	1724 72%	3460 72.3%
No	655 27.4%	671 28%	1326 27.7%
Use of a statin (Count of 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 (Count of 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 (Count of Participants)
Yes	2082 87.1%	2054 85.8%	4136 86.4%
No	309 12.9%	341 14.2%	650 13.6%
Total cholesterol (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	141.0	140.9	141.0
Low density lipoprotein cholesterol (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	68.0	68.0	68.0
High density lipoprotein cholesterol (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	41.0	41.0	41.0
Triglycerides (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	135.4	136.0	135.4
High-sensitivity C-reactive protein level (mg/liter) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/liter]	1.53	1.50	1.51
Glycated hemoglobin level (%) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [%]	6.6	6.5	6.5

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 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 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
Measure Participants	2391	2395
Number [participants]	170 7.1%	167 7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
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
	Parameter Dispersion	Type: Value:
	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 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 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
Measure Participants	2391	2395
Number [participants]	201 8.4%	207 8.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
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
	Parameter Dispersion	Type: Value:
	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.
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 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
Measure Participants	2391	2395
Number [participants]	96 4%	83 3.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
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
	Parameter Dispersion	Type: Value:
	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 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 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
Measure Participants	2391	2395
Number [participants]	278 11.6%	288 12%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
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
	Parameter Dispersion	Type: Value:
	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
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 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
Measure Participants	2391	2395
Number [participants]	48 2%	53 2.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
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
	Parameter Dispersion	Type: Value:
	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 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 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
Measure Participants	2391	2395
Number [participants]	344 14.4%	345 14.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
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
	Parameter Dispersion	Type: Value:
	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. 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 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
Measure Participants	605	620
Count of Participants [Participants]	4 0.2%	6 0.3%

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 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 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
Measure Participants	2391	2395
Number [participants]	41 1.7%	50 2.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate
	Comments
	Type of Statistical Test	Superiority
	Comments
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
	Parameter Dispersion	Type: Value:
	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
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 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
Measure Participants	2391	2395
Number [participants]	190 7.9%	205 8.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Methotrexate, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
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
	Parameter Dispersion	Type: Value:
	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
Time Frame	From randomization to the trial end (April 2, 2018) - up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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 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 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
Measure Participants	0	0

12. Other Pre-specified Outcome

Title	Number of Subjects With 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 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
Measure Participants	0	0

13. Other Pre-specified Outcome

Title	Number of Subjects With 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

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

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 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 (%)	# Events	Affected / at Risk (%)	# Events
Total	96/2391 (4%)		83/2395 (3.5%)
Serious Adverse Events
	Methotrexate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	569/2391 (23.8%)		549/2395 (22.9%)
Blood and lymphatic system disorders
Anaemia	7/2391 (0.3%)		9/2395 (0.4%)
Febrile neutropenia	1/2391 (0%)		1/2395 (0%)
Leukopenia	2/2391 (0.1%)		0/2395 (0%)
Leukopenia (AE & Lab Combined)	2/2391 (0.1%)		0/2395 (0%)
Thrombocytopenia	1/2391 (0%)		1/2395 (0%)
Thrombocytopenia (AE & Lab Combined)	1/2391 (0%)		1/2395 (0%)
Iron deficiency anaemia	1/2391 (0%)		0/2395 (0%)
Leukocytosis	0/2391 (0%)		1/2395 (0%)
Leukoerythroblastic anaemia	1/2391 (0%)		0/2395 (0%)
Lymphadenopathy mediastinal	1/2391 (0%)		0/2395 (0%)
Neutropenia	1/2391 (0%)		0/2395 (0%)
Neutropenia (AE & Lab Combined)	1/2391 (0%)		0/2395 (0%)
Normochromic normocytic anaemia	0/2391 (0%)		1/2395 (0%)
Pancytopenia	1/2391 (0%)		0/2395 (0%)
White blood cell disorder	0/2391 (0%)		1/2395 (0%)
Cardiac disorders
Angina unstable	12/2391 (0.5%)		19/2395 (0.8%)
Angina pectoris	12/2391 (0.5%)		6/2395 (0.3%)
Bradycardia	5/2391 (0.2%)		2/2395 (0.1%)
Ventricular tachycardia	0/2391 (0%)		7/2395 (0.3%)
Ischaemic cardiomyopathy	1/2391 (0%)		4/2395 (0.2%)
Cardiac failure congestive	1/2391 (0%)		3/2395 (0.1%)
Acute coronary syndrome	2/2391 (0.1%)		1/2395 (0%)
Atrial fibrillation	2/2391 (0.1%)		1/2395 (0%)
Atrial flutter	2/2391 (0.1%)		1/2395 (0%)
Supraventricular tachycardia	1/2391 (0%)		2/2395 (0.1%)
Ventricular extrasystoles	1/2391 (0%)		2/2395 (0.1%)
Ventricular fibrillation	3/2391 (0.1%)		0/2395 (0%)
Arrhythmia	1/2391 (0%)		1/2395 (0%)
Sick sinus syndrome	2/2391 (0.1%)		0/2395 (0%)
Atrioventricular block complete	1/2391 (0%)		0/2395 (0%)
Cardiac arrest	0/2391 (0%)		1/2395 (0%)
Cardiac failure	1/2391 (0%)		0/2395 (0%)
Cardiogenic shock	0/2391 (0%)		1/2395 (0%)
Cardiomegaly	0/2391 (0%)		1/2395 (0%)
Cardiomyopathy	0/2391 (0%)		1/2395 (0%)
Coronary artery dissection	1/2391 (0%)		0/2395 (0%)
Coronary artery occlusion	1/2391 (0%)		0/2395 (0%)
Coronary artery stenosis	0/2391 (0%)		1/2395 (0%)
Mitral valve disease	1/2391 (0%)		0/2395 (0%)
Myocardial infarction	0/2391 (0%)		1/2395 (0%)
Palpitations	0/2391 (0%)		1/2395 (0%)
Pericardial effusion	1/2391 (0%)		0/2395 (0%)
Pneumopericardium	0/2391 (0%)		1/2395 (0%)
Sinus tachycardia	1/2391 (0%)		0/2395 (0%)
Tachycardia	0/2391 (0%)		1/2395 (0%)
Congenital, familial and genetic disorders
Hydrocele	1/2391 (0%)		0/2395 (0%)
Ear and labyrinth disorders
Vertigo	0/2391 (0%)		3/2395 (0.1%)
Tinnitus	0/2391 (0%)		1/2395 (0%)
Eye disorders
Retinal detachment	1/2391 (0%)		1/2395 (0%)
Eye pain	1/2391 (0%)		0/2395 (0%)
Glaucoma	0/2391 (0%)		1/2395 (0%)
Retinal haemorrhage	1/2391 (0%)		0/2395 (0%)
Retinal vein occlusion	0/2391 (0%)		1/2395 (0%)
Visual impairment	1/2391 (0%)		0/2395 (0%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	8/2391 (0.3%)		10/2395 (0.4%)
Abdominal pain	9/2391 (0.4%)		6/2395 (0.3%)
Small intestinal obstruction	5/2391 (0.2%)		6/2395 (0.3%)
Diarrhoea	4/2391 (0.2%)		2/2395 (0.1%)
Pancreatitis acute	2/2391 (0.1%)		3/2395 (0.1%)
Intestinal obstruction	3/2391 (0.1%)		1/2395 (0%)
Pancreatitis	1/2391 (0%)		3/2395 (0.1%)
Rectal haemorrhage	3/2391 (0.1%)		1/2395 (0%)
Abdominal pain upper	2/2391 (0.1%)		1/2395 (0%)
Colitis	3/2391 (0.1%)		0/2395 (0%)
Gastritis	1/2391 (0%)		2/2395 (0.1%)
Ascites	2/2391 (0.1%)		0/2395 (0%)
Constipation	1/2391 (0%)		1/2395 (0%)
Diarrhoea haemorrhagic	2/2391 (0.1%)		0/2395 (0%)
Enteritis	1/2391 (0%)		1/2395 (0%)
Gastric ulcer	1/2391 (0%)		1/2395 (0%)
Gastrooesophageal reflux disease	2/2391 (0.1%)		0/2395 (0%)
Inguinal hernia	1/2391 (0%)		1/2395 (0%)
Lower gastrointestinal haemorrhage	0/2391 (0%)		2/2395 (0.1%)
Mouth ulceration	2/2391 (0.1%)		0/2395 (0%)
Nausea	1/2391 (0%)		1/2395 (0%)
Retroperitoneal mass	0/2391 (0%)		2/2395 (0.1%)
Stomatitis	2/2391 (0.1%)		0/2395 (0%)
Umbilical hernia	1/2391 (0%)		1/2395 (0%)
Vomiting	0/2391 (0%)		2/2395 (0.1%)
Abdominal hernia	1/2391 (0%)		0/2395 (0%)
Dyspepsia	1/2391 (0%)		0/2395 (0%)
Enterocolitis	0/2391 (0%)		1/2395 (0%)
Gastric haemorrhage	1/2391 (0%)		0/2395 (0%)
Haemorrhoids	1/2391 (0%)		0/2395 (0%)
Hiatus hernia	0/2391 (0%)		1/2395 (0%)
Ileus	0/2391 (0%)		1/2395 (0%)
Irritable bowel syndrome	0/2391 (0%)		1/2395 (0%)
Melaena	1/2391 (0%)		0/2395 (0%)
Obstruction gastric	1/2391 (0%)		0/2395 (0%)
Oesophageal obstruction	1/2391 (0%)		0/2395 (0%)
Oesophagitis	1/2391 (0%)		0/2395 (0%)
Oral pain	1/2391 (0%)		0/2395 (0%)
Pancreatic mass	1/2391 (0%)		0/2395 (0%)
Peptic ulcer	0/2391 (0%)		1/2395 (0%)
Tooth socket haemorrhage	0/2391 (0%)		1/2395 (0%)
General disorders
Chest pain	76/2391 (3.2%)		67/2395 (2.8%)
Non-cardiac chest pain	8/2391 (0.3%)		3/2395 (0.1%)
Chest discomfort	4/2391 (0.2%)		3/2395 (0.1%)
Pyrexia	3/2391 (0.1%)		2/2395 (0.1%)
Oedema peripheral	0/2391 (0%)		4/2395 (0.2%)
Asthenia	3/2391 (0.1%)		0/2395 (0%)
Systemic inflammatory response syndrome	2/2391 (0.1%)		0/2395 (0%)
Adverse event	1/2391 (0%)		0/2395 (0%)
Device malfunction	1/2391 (0%)		0/2395 (0%)
Fatigue	0/2391 (0%)		1/2395 (0%)
Malaise	1/2391 (0%)		0/2395 (0%)
Medical device complication	1/2391 (0%)		0/2395 (0%)
Oedema	1/2391 (0%)		0/2395 (0%)
Organ failure	0/2391 (0%)		1/2395 (0%)
Swelling	0/2391 (0%)		1/2395 (0%)
Ulcer haemorrhage	1/2391 (0%)		0/2395 (0%)
Hepatobiliary disorders
Cholecystitis	5/2391 (0.2%)		2/2395 (0.1%)
Cholecystitis acute	2/2391 (0.1%)		4/2395 (0.2%)
Cholelithiasis	3/2391 (0.1%)		1/2395 (0%)
Hepatic cirrhosis	1/2391 (0%)		1/2395 (0%)
Acute hepatic failure	0/2391 (0%)		1/2395 (0%)
Bile duct stone	0/2391 (0%)		1/2395 (0%)
Cholangitis	1/2391 (0%)		0/2395 (0%)
Hepatic lesion	1/2391 (0%)		0/2395 (0%)
Liver disorder	0/2391 (0%)		1/2395 (0%)
Pneumobilia	1/2391 (0%)		0/2395 (0%)
Immune system disorders
Hypersensitivity	0/2391 (0%)		1/2395 (0%)
Infections and infestations
Pneumonia	29/2391 (1.2%)		28/2395 (1.2%)
Cellulitis	19/2391 (0.8%)		15/2395 (0.6%)
Urinary tract infection	12/2391 (0.5%)		9/2395 (0.4%)
Sepsis	12/2391 (0.5%)		7/2395 (0.3%)
Infection	6/2391 (0.3%)		7/2395 (0.3%)
Diverticulitis	4/2391 (0.2%)		8/2395 (0.3%)
Bronchitis	7/2391 (0.3%)		2/2395 (0.1%)
Osteomyelitis	8/2391 (0.3%)		1/2395 (0%)
Gastroenteritis	2/2391 (0.1%)		4/2395 (0.2%)
Influenza	1/2391 (0%)		4/2395 (0.2%)
Localised infection	4/2391 (0.2%)		0/2395 (0%)
Pyelonephritis	1/2391 (0%)		3/2395 (0.1%)
Septic shock	1/2391 (0%)		3/2395 (0.1%)
Upper respiratory tract infection	2/2391 (0.1%)		2/2395 (0.1%)
Appendicitis	0/2391 (0%)		3/2395 (0.1%)
Bacteraemia	1/2391 (0%)		2/2395 (0.1%)
Gastroenteritis viral	2/2391 (0.1%)		1/2395 (0%)
Necrotising fasciitis	0/2391 (0%)		3/2395 (0.1%)
Urosepsis	1/2391 (0%)		2/2395 (0.1%)
Abdominal wall abscess	1/2391 (0%)		1/2395 (0%)
Abscess limb	1/2391 (0%)		1/2395 (0%)
Arthritis bacterial	0/2391 (0%)		2/2395 (0.1%)
Bacterial disease carrier	1/2391 (0%)		1/2395 (0%)
Bronchitis viral	1/2391 (0%)		1/2395 (0%)
Escherichia bacteraemia	0/2391 (0%)		2/2395 (0.1%)
Groin abscess	1/2391 (0%)		1/2395 (0%)
Periorbital cellulitis	0/2391 (0%)		2/2395 (0.1%)
Perirectal abscess	0/2391 (0%)		2/2395 (0.1%)
Sinusitis	1/2391 (0%)		1/2395 (0%)
Skin infection	2/2391 (0.1%)		0/2395 (0%)
Staphylococcal infection	1/2391 (0%)		1/2395 (0%)
Wound infection staphylococcal	0/2391 (0%)		2/2395 (0.1%)
Abscess	0/2391 (0%)		1/2395 (0%)
Anal abscess	1/2391 (0%)		0/2395 (0%)
Atypical pneumonia	1/2391 (0%)		0/2395 (0%)
Bacterial sepsis	1/2391 (0%)		0/2395 (0%)
Cholecystitis infective	1/2391 (0%)		0/2395 (0%)
Clostridium difficile colitis	0/2391 (0%)		1/2395 (0%)
Device related infection	0/2391 (0%)		1/2395 (0%)
Diabetic foot infection	0/2391 (0%)		1/2395 (0%)
Enterobacter infection	0/2391 (0%)		1/2395 (0%)
Epididymitis	1/2391 (0%)		0/2395 (0%)
Escherichia infection	1/2391 (0%)		0/2395 (0%)
Gangrene	1/2391 (0%)		0/2395 (0%)
Gastroenteritis shigella	1/2391 (0%)		0/2395 (0%)
Genital herpes	1/2391 (0%)		0/2395 (0%)
Infected skin ulcer	0/2391 (0%)		1/2395 (0%)
Labyrinthitis	0/2391 (0%)		1/2395 (0%)
Lower respiratory tract infection	0/2391 (0%)		1/2395 (0%)
Lyme disease	0/2391 (0%)		1/2395 (0%)
Meningitis aseptic	0/2391 (0%)		1/2395 (0%)
Osteomyelitis chronic	1/2391 (0%)		0/2395 (0%)
Perineal abscess	0/2391 (0%)		1/2395 (0%)
Pharyngitis	1/2391 (0%)		0/2395 (0%)
Pneumonia bacterial	1/2391 (0%)		0/2395 (0%)
Respiratory syncytial virus infection	1/2391 (0%)		0/2395 (0%)
Respiratory tract infection	0/2391 (0%)		1/2395 (0%)
Sialoadenitis	0/2391 (0%)		1/2395 (0%)
Staphylococcal bacteraemia	1/2391 (0%)		0/2395 (0%)
Tinea pedis	0/2391 (0%)		1/2395 (0%)
Urinary Tract Infection	0/2391 (0%)		1/2395 (0%)
Viral infection	0/2391 (0%)		1/2395 (0%)
Viral upper respiratory tract infection	0/2391 (0%)		1/2395 (0%)
Wound infection	0/2391 (0%)		1/2395 (0%)
Injury, poisoning and procedural complications
Fall	3/2391 (0.1%)		5/2395 (0.2%)
Hip fracture	4/2391 (0.2%)		1/2395 (0%)
Rib fracture	2/2391 (0.1%)		2/2395 (0.1%)
Road traffic accident	2/2391 (0.1%)		1/2395 (0%)
Subdural haematoma	1/2391 (0%)		2/2395 (0.1%)
Upper limb fracture	1/2391 (0%)		2/2395 (0.1%)
Femur fracture	2/2391 (0.1%)		0/2395 (0%)
Lower limb fracture	1/2391 (0%)		1/2395 (0%)
Abdominal injury	1/2391 (0%)		0/2395 (0%)
Accidental overdose	0/2391 (0%)		1/2395 (0%)
Alcohol poisoning	0/2391 (0%)		1/2395 (0%)
Ankle fracture	0/2391 (0%)		1/2395 (0%)
Clavicle fracture	0/2391 (0%)		1/2395 (0%)
Concussion	1/2391 (0%)		0/2395 (0%)
Contusion	1/2391 (0%)		0/2395 (0%)
Facial bones fracture	0/2391 (0%)		1/2395 (0%)
Femoral neck fracture	1/2391 (0%)		0/2395 (0%)
Fibula fracture	1/2391 (0%)		0/2395 (0%)
Head injury	0/2391 (0%)		1/2395 (0%)
Meniscus injury	1/2391 (0%)		0/2395 (0%)
Muscle strain	1/2391 (0%)		0/2395 (0%)
Pelvic fracture	1/2391 (0%)		0/2395 (0%)
Spinal cord injury	0/2391 (0%)		1/2395 (0%)
Tendon rupture	1/2391 (0%)		0/2395 (0%)
Testicular injury	0/2391 (0%)		1/2395 (0%)
Thermal burn	0/2391 (0%)		1/2395 (0%)
Thoracic vertebral fracture	1/2391 (0%)		0/2395 (0%)
Toxicity to various agents	1/2391 (0%)		0/2395 (0%)
Traumatic arthropathy	1/2391 (0%)		0/2395 (0%)
Vascular pseudoaneurysm	0/2391 (0%)		1/2395 (0%)
Wound	1/2391 (0%)		0/2395 (0%)
Wound dehiscence	0/2391 (0%)		1/2395 (0%)
Investigations
Blood glucose increased	2/2391 (0.1%)		5/2395 (0.2%)
Catheterisation cardiac	6/2391 (0.3%)		1/2395 (0%)
Arteriogram coronary	3/2391 (0.1%)		2/2395 (0.1%)
Liver function test abnormal	2/2391 (0.1%)		1/2395 (0%)
White blood cell count decreased	1/2391 (0%)		2/2395 (0.1%)
Biopsy bladder	2/2391 (0.1%)		0/2395 (0%)
Stress echocardiogram abnormal	1/2391 (0%)		1/2395 (0%)
Alanine aminotransferase increased	1/2391 (0%)		0/2395 (0%)
Aspiration pleural cavity	0/2391 (0%)		1/2395 (0%)
Biopsy breast	0/2391 (0%)		1/2395 (0%)
Biopsy liver	0/2391 (0%)		1/2395 (0%)
Biopsy lung	1/2391 (0%)		0/2395 (0%)
Blood creatinine increased	1/2391 (0%)		0/2395 (0%)
Blood glucose decreased	1/2391 (0%)		0/2395 (0%)
Blood pressure increased	0/2391 (0%)		1/2395 (0%)
Blood triglycerides increased	0/2391 (0%)		1/2395 (0%)
Blood urine present	1/2391 (0%)		0/2395 (0%)
Bronchoscopy	0/2391 (0%)		1/2395 (0%)
Cardiac stress test abnormal	0/2391 (0%)		1/2395 (0%)
Cystoscopy	1/2391 (0%)		0/2395 (0%)
Haemoglobin increased	1/2391 (0%)		0/2395 (0%)
Hepatic enzyme increased	1/2391 (0%)		0/2395 (0%)
Hepatitis C virus test positive	1/2391 (0%)		0/2395 (0%)
Lipase increased	1/2391 (0%)		0/2395 (0%)
Platelet count decreased	1/2391 (0%)		0/2395 (0%)
Prostatic specific antigen increased	1/2391 (0%)		0/2395 (0%)
Red blood cell count decreased	0/2391 (0%)		1/2395 (0%)
Shift to the right	1/2391 (0%)		0/2395 (0%)
Transaminases increased	1/2391 (0%)		0/2395 (0%)
Troponin increased	0/2391 (0%)		1/2395 (0%)
Weight decreased	1/2391 (0%)		0/2395 (0%)
Weight increased	1/2391 (0%)		0/2395 (0%)
White blood cell count increased	1/2391 (0%)		0/2395 (0%)
Metabolism and nutrition disorders
Dehydration	2/2391 (0.1%)		7/2395 (0.3%)
Hypoglycaemia	4/2391 (0.2%)		3/2395 (0.1%)
Hyperglycaemia	2/2391 (0.1%)		3/2395 (0.1%)
Diabetic ketoacidosis	1/2391 (0%)		2/2395 (0.1%)
Hypercalcaemia	3/2391 (0.1%)		0/2395 (0%)
Hyperkalaemia	1/2391 (0%)		2/2395 (0.1%)
Hyponatraemia	0/2391 (0%)		3/2395 (0.1%)
Diabetes mellitus inadequate control	1/2391 (0%)		1/2395 (0%)
Hypokalaemia	0/2391 (0%)		2/2395 (0.1%)
Obesity	2/2391 (0.1%)		0/2395 (0%)
Electrolyte imbalance	0/2391 (0%)		1/2395 (0%)
Hypomagnesaemia	1/2391 (0%)		0/2395 (0%)
Hypovolaemia	1/2391 (0%)		0/2395 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	2/2391 (0.1%)		5/2395 (0.2%)
Arthralgia	3/2391 (0.1%)		3/2395 (0.1%)
Back pain	3/2391 (0.1%)		3/2395 (0.1%)
Flank pain	1/2391 (0%)		1/2395 (0%)
Pain in extremity	2/2391 (0.1%)		0/2395 (0%)
Rhabdomyolysis	0/2391 (0%)		2/2395 (0.1%)
Rheumatoid arthritis	2/2391 (0.1%)		0/2395 (0%)
Spinal osteoarthritis	2/2391 (0.1%)		0/2395 (0%)
Ankylosing spondylitis	1/2391 (0%)		0/2395 (0%)
Cervical spinal stenosis	0/2391 (0%)		1/2395 (0%)
Compartment syndrome	0/2391 (0%)		1/2395 (0%)
Intervertebral disc protrusion	0/2391 (0%)		1/2395 (0%)
Lumbar spinal stenosis	1/2391 (0%)		0/2395 (0%)
Musculoskeletal pain	0/2391 (0%)		1/2395 (0%)
Neck mass	1/2391 (0%)		0/2395 (0%)
Osteitis	0/2391 (0%)		1/2395 (0%)
Osteitis deformans	1/2391 (0%)		0/2395 (0%)
Osteoarthritis	1/2391 (0%)		0/2395 (0%)
Pain in jaw	1/2391 (0%)		0/2395 (0%)
Soft tissue mass	0/2391 (0%)		1/2395 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	7/2391 (0.3%)		13/2395 (0.5%)
Squamous cell carcinoma	7/2391 (0.3%)		2/2395 (0.1%)
Basal cell carcinoma	5/2391 (0.2%)		2/2395 (0.1%)
Breast cancer	3/2391 (0.1%)		4/2395 (0.2%)
Malignant melanoma	2/2391 (0.1%)		5/2395 (0.2%)
Skin cancer	5/2391 (0.2%)		1/2395 (0%)
Squamous cell carcinoma of skin	3/2391 (0.1%)		3/2395 (0.1%)
Lung neoplasm malignant	2/2391 (0.1%)		3/2395 (0.1%)
Bladder cancer	2/2391 (0.1%)		2/2395 (0.1%)
Colon cancer	2/2391 (0.1%)		2/2395 (0.1%)
Renal cell carcinoma	0/2391 (0%)		4/2395 (0.2%)
Meningioma	1/2391 (0%)		2/2395 (0.1%)
Pancreatic carcinoma	1/2391 (0%)		2/2395 (0.1%)
Bladder neoplasm	2/2391 (0.1%)		0/2395 (0%)
Leiomyosarcoma	0/2391 (0%)		2/2395 (0.1%)
Neoplasm malignant	1/2391 (0%)		1/2395 (0%)
Prostate cancer recurrent	2/2391 (0.1%)		0/2395 (0%)
Renal cancer	1/2391 (0%)		1/2395 (0%)
Acute lymphocytic leukaemia	0/2391 (0%)		1/2395 (0%)
Acute myeloid leukaemia	0/2391 (0%)		1/2395 (0%)
Adenocarcinoma Of The Prostate	1/2391 (0%)		0/2395 (0%)
Adenocarcinoma of colon	0/2391 (0%)		1/2395 (0%)
Basal & Squamous Cell Carcinoma's Discovered	1/2391 (0%)		0/2395 (0%)
Bladder transitional cell carcinoma	0/2391 (0%)		1/2395 (0%)
Brain Cancer	0/2391 (0%)		1/2395 (0%)
Brain neoplasm	1/2391 (0%)		0/2395 (0%)
Branchogenic Adenocarcinoma/Right Upper Lobectomy And M	1/2391 (0%)		0/2395 (0%)
Cholangiocarcinoma	1/2391 (0%)		0/2395 (0%)
Clear cell renal cell carcinoma	1/2391 (0%)		0/2395 (0%)
Cytopathology Diagnosis Of Aus/Flus Or Follicular Hurth	0/2391 (0%)		1/2395 (0%)
Diagnosed With Non Basal Cell Malignancy	0/2391 (0%)		1/2395 (0%)
Diagnosis Of Bladder Cancer, Highly Invasive, With Live	0/2391 (0%)		1/2395 (0%)
Diffuse large B-cell lymphoma	1/2391 (0%)		0/2395 (0%)
Endometrial cancer	0/2391 (0%)		1/2395 (0%)
Essential thrombocythaemia	1/2391 (0%)		0/2395 (0%)
Gastric cancer	1/2391 (0%)		0/2395 (0%)
Hodgkin's disease	0/2391 (0%)		1/2395 (0%)
Invasive Squamous Cell Carcinoma (Right Cheek)	1/2391 (0%)		0/2395 (0%)
Laryngeal cancer	0/2391 (0%)		1/2395 (0%)
Left Descending Colon Cancer	1/2391 (0%)		0/2395 (0%)
Left Ureteropelvic Junction, Papillary Urothelial Carci	0/2391 (0%)		1/2395 (0%)
Lesion, Mid-Parietal Scalp, Squamous Cell Carcinoma	1/2391 (0%)		0/2395 (0%)
Liver Cancer	0/2391 (0%)		1/2395 (0%)
Lung adenocarcinoma	1/2391 (0%)		0/2395 (0%)
Lung carcinoma cell type unspecified stage IV	1/2391 (0%)		0/2395 (0%)
Lymphoma	1/2391 (0%)		0/2395 (0%)
Malignant Bladder Polyps	1/2391 (0%)		0/2395 (0%)
Malignant Spindle Cell Neoplasm	0/2391 (0%)		1/2395 (0%)
Malignant Transitional Cell Cancer Of The Bladder	0/2391 (0%)		1/2395 (0%)
Metastases to central nervous system	0/2391 (0%)		1/2395 (0%)
Metastatic Liver Cancer	1/2391 (0%)		0/2395 (0%)
Micrometastatic Disease Melanoma	0/2391 (0%)		1/2395 (0%)
New Lung Cancer Diagnosis	1/2391 (0%)		0/2395 (0%)
Oesophageal adenocarcinoma	1/2391 (0%)		0/2395 (0%)
Papillary Urothelial Carcinoma	0/2391 (0%)		1/2395 (0%)
Parathyroid tumour benign	1/2391 (0%)		0/2395 (0%)
Peritoneal Carcinomatosis From A Low-Grade Mucinous Tum	1/2391 (0%)		0/2395 (0%)
Plasma cell myeloma	1/2391 (0%)		0/2395 (0%)
Pt Newly Diagnosed With Stage 4 Cancer	0/2391 (0%)		1/2395 (0%)
Recurrent Bladder Tumor	0/2391 (0%)		1/2395 (0%)
Recurrent Bladder Tumor: Papillary Lesion , Proximal An	0/2391 (0%)		1/2395 (0%)
Relapsed Non-Hodgkins Lymphoma	0/2391 (0%)		1/2395 (0%)
Reported Diagnosis Lymphoma On Passive Follow Up	1/2391 (0%)		0/2395 (0%)
Right Parietal Craniotomy For Benign Neoplasm Of Brain	1/2391 (0%)		0/2395 (0%)
Ruptured Mucinous Neoplasm Of The Appendix With Periton	1/2391 (0%)		0/2395 (0%)
Skin Biopsy- Possible Lymphoma	1/2391 (0%)		0/2395 (0%)
Small cell lung cancer	1/2391 (0%)		0/2395 (0%)
Sqamous Cell Carcinoma In Situ, Bowenoid Type	1/2391 (0%)		0/2395 (0%)
Stage Ii Adenocarcinoma Of The Ascending Colon	0/2391 (0%)		1/2395 (0%)
Stage Iv T2n0m1 Adenocarcinoma Of Theh Ead And Tail Of	0/2391 (0%)		1/2395 (0%)
T-cell lymphoma	1/2391 (0%)		0/2395 (0%)
Throat cancer	0/2391 (0%)		1/2395 (0%)
Treatment For Metastasized Clear Cell Renal Cell Carcin	0/2391 (0%)		1/2395 (0%)
Uterine cancer	0/2391 (0%)		1/2395 (0%)
Any Cancer	52/2391 (2.2%)		30/2395 (1.3%)
Any Cancer	106/2391 (4.4%)		95/2395 (4%)
Non-basal-cell skin cancer (not known if SAE)	31/2391 (1.3%)		10/2395 (0.4%)
Non-basal-cell skin cancer (not known if SAE)	33/2391 (1.4%)		12/2395 (0.5%)
Nervous system disorders
Syncope	24/2391 (1%)		16/2395 (0.7%)
Transient ischaemic attack	9/2391 (0.4%)		9/2395 (0.4%)
Dizziness	6/2391 (0.3%)		3/2395 (0.1%)
Presyncope	4/2391 (0.2%)		2/2395 (0.1%)
Convulsion	2/2391 (0.1%)		3/2395 (0.1%)
Headache	3/2391 (0.1%)		2/2395 (0.1%)
Dysarthria	2/2391 (0.1%)		2/2395 (0.1%)
Dementia	1/2391 (0%)		2/2395 (0.1%)
Encephalopathy	1/2391 (0%)		2/2395 (0.1%)
Hemiparesis	2/2391 (0.1%)		1/2395 (0%)
Migraine	1/2391 (0%)		2/2395 (0.1%)
VIIth nerve paralysis	0/2391 (0%)		2/2395 (0.1%)
Aphasia	1/2391 (0%)		0/2395 (0%)
Ataxia	0/2391 (0%)		1/2395 (0%)
Carotid artery stenosis	1/2391 (0%)		0/2395 (0%)
Clonus	0/2391 (0%)		1/2395 (0%)
Dyskinesia	0/2391 (0%)		1/2395 (0%)
Epilepsy	0/2391 (0%)		1/2395 (0%)
Facial paresis	0/2391 (0%)		1/2395 (0%)
Haemorrhage intracranial	0/2391 (0%)		1/2395 (0%)
Hypertensive encephalopathy	0/2391 (0%)		1/2395 (0%)
Lethargy	1/2391 (0%)		0/2395 (0%)
Loss of consciousness	0/2391 (0%)		1/2395 (0%)
Metabolic encephalopathy	1/2391 (0%)		0/2395 (0%)
Myoclonus	0/2391 (0%)		1/2395 (0%)
Neuromyopathy	0/2391 (0%)		1/2395 (0%)
Paraesthesia	0/2391 (0%)		1/2395 (0%)
Paresis	0/2391 (0%)		1/2395 (0%)
Parkinson's disease	0/2391 (0%)		1/2395 (0%)
Radicular pain	0/2391 (0%)		1/2395 (0%)
Radiculopathy	1/2391 (0%)		0/2395 (0%)
Subarachnoid haemorrhage	1/2391 (0%)		0/2395 (0%)
Transient global amnesia	0/2391 (0%)		1/2395 (0%)
Psychiatric disorders
Mental status changes	1/2391 (0%)		4/2395 (0.2%)
Confusional state	1/2391 (0%)		2/2395 (0.1%)
Depression	1/2391 (0%)		1/2395 (0%)
Alcohol withdrawal syndrome	0/2391 (0%)		1/2395 (0%)
Delirium	0/2391 (0%)		1/2395 (0%)
Disorientation	0/2391 (0%)		1/2395 (0%)
Suicidal ideation	0/2391 (0%)		1/2395 (0%)
Renal and urinary disorders
Renal failure acute	17/2391 (0.7%)		21/2395 (0.9%)
Haematuria	4/2391 (0.2%)		4/2395 (0.2%)
Nephrolithiasis	2/2391 (0.1%)		3/2395 (0.1%)
Renal failure	3/2391 (0.1%)		2/2395 (0.1%)
Renal failure chronic	3/2391 (0.1%)		1/2395 (0%)
Renal mass	1/2391 (0%)		2/2395 (0.1%)
Urinary retention	1/2391 (0%)		2/2395 (0.1%)
Calculus ureteric	1/2391 (0%)		1/2395 (0%)
Bladder mass	0/2391 (0%)		1/2395 (0%)
Dysuria	0/2391 (0%)		1/2395 (0%)
Polyuria	1/2391 (0%)		0/2395 (0%)
Proteinuria	0/2391 (0%)		1/2395 (0%)
Urethral stenosis	1/2391 (0%)		0/2395 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/2391 (0%)		1/2395 (0%)
Breast mass	0/2391 (0%)		1/2395 (0%)
Female genital tract fistula	1/2391 (0%)		0/2395 (0%)
Postmenopausal haemorrhage	1/2391 (0%)		0/2395 (0%)
Prostatitis	0/2391 (0%)		1/2395 (0%)
Prostatomegaly	0/2391 (0%)		1/2395 (0%)
Vaginal haemorrhage	1/2391 (0%)		0/2395 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	13/2391 (0.5%)		12/2395 (0.5%)
Chronic obstructive pulmonary disease	9/2391 (0.4%)		9/2395 (0.4%)
Acute respiratory failure	7/2391 (0.3%)		4/2395 (0.2%)
Pleural effusion	4/2391 (0.2%)		3/2395 (0.1%)
Epistaxis	4/2391 (0.2%)		1/2395 (0%)
Pulmonary mass	2/2391 (0.1%)		3/2395 (0.1%)
Respiratory failure	2/2391 (0.1%)		3/2395 (0.1%)
Asthma	2/2391 (0.1%)		2/2395 (0.1%)
Haemoptysis	2/2391 (0.1%)		1/2395 (0%)
Hypoxia	1/2391 (0%)		2/2395 (0.1%)
Interstitial lung disease	2/2391 (0.1%)		1/2395 (0%)
Cough	1/2391 (0%)		1/2395 (0%)
Dyspnoea exertional	2/2391 (0.1%)		0/2395 (0%)
Pneumonia aspiration	2/2391 (0.1%)		0/2395 (0%)
Pneumothorax	1/2391 (0%)		1/2395 (0%)
Pulmonary fibrosis	1/2391 (0%)		1/2395 (0%)
Acute pulmonary oedema	1/2391 (0%)		0/2395 (0%)
Acute respiratory distress syndrome	1/2391 (0%)		0/2395 (0%)
Choking	1/2391 (0%)		0/2395 (0%)
Emphysema	0/2391 (0%)		1/2395 (0%)
Haemothorax	0/2391 (0%)		1/2395 (0%)
Nasal polyps	1/2391 (0%)		0/2395 (0%)
Pneumomediastinum	0/2391 (0%)		1/2395 (0%)
Pneumonitis	1/2391 (0%)		0/2395 (0%)
Pneumothorax spontaneous	0/2391 (0%)		1/2395 (0%)
Pulmonary embolism	0/2391 (0%)		1/2395 (0%)
Pulmonary oedema	0/2391 (0%)		1/2395 (0%)
Skin and subcutaneous tissue disorders
Rash	1/2391 (0%)		2/2395 (0.1%)
Diabetic foot	0/2391 (0%)		2/2395 (0.1%)
Skin lesion	2/2391 (0.1%)		0/2395 (0%)
Skin ulcer	0/2391 (0%)		2/2395 (0.1%)
Actinic keratosis	0/2391 (0%)		1/2395 (0%)
Alopecia	0/2391 (0%)		1/2395 (0%)
Angioedema	0/2391 (0%)		1/2395 (0%)
Cutaneous lupus erythematosus	0/2391 (0%)		1/2395 (0%)
Dermatitis	0/2391 (0%)		1/2395 (0%)
Diabetic ulcer	1/2391 (0%)		0/2395 (0%)
Surgical and medical procedures
Knee arthroplasty	10/2391 (0.4%)		11/2395 (0.5%)
Hospitalisation	4/2391 (0.2%)		6/2395 (0.3%)
Hip arthroplasty	6/2391 (0.3%)		3/2395 (0.1%)
Surgery	2/2391 (0.1%)		7/2395 (0.3%)
Spinal laminectomy	3/2391 (0.1%)		4/2395 (0.2%)
Gastrectomy	3/2391 (0.1%)		3/2395 (0.1%)
Implantable defibrillator insertion	3/2391 (0.1%)		2/2395 (0.1%)
Cardiac pacemaker insertion	4/2391 (0.2%)		0/2395 (0%)
Hip surgery	2/2391 (0.1%)		2/2395 (0.1%)
Knee operation	3/2391 (0.1%)		1/2395 (0%)
Toe amputation	2/2391 (0.1%)		2/2395 (0.1%)
Cardiac ablation	1/2391 (0%)		2/2395 (0.1%)
Carotid endarterectomy	1/2391 (0%)		2/2395 (0.1%)
Gallbladder operation	2/2391 (0.1%)		1/2395 (0%)
Joint arthroplasty	2/2391 (0.1%)		1/2395 (0%)
Shoulder arthroplasty	2/2391 (0.1%)		1/2395 (0%)
Aortic valve replacement	0/2391 (0%)		2/2395 (0.1%)
Cardioversion	2/2391 (0.1%)		0/2395 (0%)
Colectomy	2/2391 (0.1%)		0/2395 (0%)
Gastric bypass	1/2391 (0%)		1/2395 (0%)
Intervertebral disc operation	2/2391 (0.1%)		0/2395 (0%)
Mitral valve repair	2/2391 (0.1%)		0/2395 (0%)
Nephrectomy	0/2391 (0%)		2/2395 (0.1%)
Penile prosthesis insertion	2/2391 (0.1%)		0/2395 (0%)
Shoulder operation	2/2391 (0.1%)		0/2395 (0%)
Stent placement	0/2391 (0%)		2/2395 (0.1%)
Tooth extraction	1/2391 (0%)		1/2395 (0%)
Abdominal hernia repair	1/2391 (0%)		0/2395 (0%)
Ankle operation	0/2391 (0%)		1/2395 (0%)
Aortic aneurysm repair	0/2391 (0%)		1/2395 (0%)
Appendicectomy	1/2391 (0%)		0/2395 (0%)
Bladder neoplasm surgery	0/2391 (0%)		1/2395 (0%)
Cancer surgery	1/2391 (0%)		0/2395 (0%)
Cardiac pacemaker battery replacement	0/2391 (0%)		1/2395 (0%)
Cataract operation	1/2391 (0%)		0/2395 (0%)
Central venous catheterisation	0/2391 (0%)		1/2395 (0%)
Cholecystectomy	1/2391 (0%)		0/2395 (0%)
Craniotomy	0/2391 (0%)		1/2395 (0%)
Finger amputation	0/2391 (0%)		1/2395 (0%)
Fistula repair	0/2391 (0%)		1/2395 (0%)
Foot amputation	1/2391 (0%)		0/2395 (0%)
Hernia repair	0/2391 (0%)		1/2395 (0%)
Implantable defibrillator replacement	0/2391 (0%)		1/2395 (0%)
Intestinal resection	1/2391 (0%)		0/2395 (0%)
Lung lobectomy	1/2391 (0%)		0/2395 (0%)
Mastectomy	0/2391 (0%)		1/2395 (0%)
Oesophagectomy	1/2391 (0%)		0/2395 (0%)
Oesophagogastric fundoplasty	1/2391 (0%)		0/2395 (0%)
Partial lung resection	0/2391 (0%)		1/2395 (0%)
Pelvic floor repair	0/2391 (0%)		1/2395 (0%)
Prolapse repair	1/2391 (0%)		0/2395 (0%)
Prostatectomy	0/2391 (0%)		1/2395 (0%)
Radical cystectomy	0/2391 (0%)		1/2395 (0%)
Radiotherapy	1/2391 (0%)		0/2395 (0%)
Removal of internal fixation	0/2391 (0%)		1/2395 (0%)
Retinopexy	1/2391 (0%)		0/2395 (0%)
Small intestinal resection	0/2391 (0%)		1/2395 (0%)
Spinal cord operation	0/2391 (0%)		1/2395 (0%)
Spinal fusion surgery	0/2391 (0%)		1/2395 (0%)
Thyroidectomy	1/2391 (0%)		0/2395 (0%)
Umbilical hernia repair	1/2391 (0%)		0/2395 (0%)
Urinary cystectomy	1/2391 (0%)		0/2395 (0%)
Vascular disorders
Hypotension	8/2391 (0.3%)		3/2395 (0.1%)
Hypertension	2/2391 (0.1%)		2/2395 (0.1%)
Orthostatic hypotension	4/2391 (0.2%)		0/2395 (0%)
Aneurysm	2/2391 (0.1%)		1/2395 (0%)
Aortic stenosis	1/2391 (0%)		1/2395 (0%)
Hypertensive crisis	1/2391 (0%)		1/2395 (0%)
Accelerated hypertension	0/2391 (0%)		1/2395 (0%)
Aortic aneurysm	1/2391 (0%)		0/2395 (0%)
Peripheral artery aneurysm	1/2391 (0%)		0/2395 (0%)
Temporal arteritis	1/2391 (0%)		0/2395 (0%)
Other (Not Including Serious) Adverse Events
	Methotrexate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1488/2391 (62.2%)		1399/2395 (58.4%)
Blood and lymphatic system disorders
Any	340/2391 (14.2%)		244/2395 (10.2%)
Leukopenia	241/2391 (10.1%)		172/2395 (7.2%)
Gastrointestinal disorders
Any	350/2391 (14.6%)		284/2395 (11.9%)
General disorders
Any	279/2391 (11.7%)		254/2395 (10.6%)
Chest pain	126/2391 (5.3%)		142/2395 (5.9%)
Infections and infestations
Any	659/2391 (27.6%)		584/2395 (24.4%)
Injury, poisoning and procedural complications
Any	150/2391 (6.3%)		163/2395 (6.8%)
Investigations
Any	220/2391 (9.2%)		211/2395 (8.8%)
Musculoskeletal and connective tissue disorders
Any	223/2391 (9.3%)		230/2395 (9.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Any	124/2391 (5.2%)		101/2395 (4.2%)
Nervous system disorders
Any	213/2391 (8.9%)		195/2395 (8.1%)
Respiratory, thoracic and mediastinal disorders
Any	279/2391 (11.7%)		210/2395 (8.8%)
Skin and subcutaneous tissue disorders
Any	97/2391 (4.1%)		121/2395 (5.1%)
Surgical and medical procedures
Any	137/2391 (5.7%)		147/2395 (6.1%)

Limitations/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.

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Certain Agreements

All Principal Investigators ARE 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.