Document 9669874

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Primary Results
8th June 2015
TECOS
• Initiated in advance of FDA requirements, but consistent with that
guidance
• Large, international trial designed to assess the impact of sitagliptin
versus placebo on cardiovascular event rates
– When added to usual diabetes care
– Minimize difference in glycemia between groups
• Randomized, double-blind, placebo-controlled
• Academically led in collaboration with industry sponsorship
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Pragmatic Study Design
• Integration with usual diabetes care
– Management of diabetes, hypertension and dyslipidaemia
remain responsibility of usual care provider
– All laboratory results collected locally as available, except
HbA1c, from the usual care setting
– TECOS investigator responsible for dose adjustment of blinded
study drug according to eGFR
• Streamlined data collection
• Streamlined safety reporting
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Primary Objective
To demonstrate that the risk of cardiovascular
events in patients treated with sitagliptin in addition
to usual care was non-inferior to that in patients
treated without sitagliptin in addition to usual care.
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
4
Primary Composite
Cardiovascular Outcome
Time to first occurrence of:
– Cardiovascular-related death
– Nonfatal myocardial infarction
– Nonfatal stroke
– Hospitalization for unstable angina
A Clinical Endpoints Committee, blinded to therapy allocation,
reviewed all potential CVD endpoints independently.
5
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Secondary Cardiovascular Outcomes
Time to —
– Secondary composite CV outcome
(nonfatal MI, nonfatal stroke, or CV-related death)
– First confirmed component event in the primary outcome
(Cardiovascular-related death, nonfatal myocardial infarction,
nonfatal stroke, hospitalization for unstable angina)
– First fatal or nonfatal MI
– First fatal or nonfatal stroke
– All-cause mortality
– Hospitalization for heart failure
– Hospitalization for heart failure or CV-related death
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
6
Other Secondary Outcomes
• Change in HbA1c over time
• Change in renal function over time
– eGFR
– urinary albumin/creatinine ratio
• In patients not receiving insulin at baseline,
time to initiation of chronic insulin therapy
• In all patients, time to next co-interventional agent
(next AHA or chronic insulin)
• Medical resource utilization
(e.g., hospitalizations, outpatient visits) — data not shown today
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Major Inclusion Criteria
• Type 2 diabetes (A1c ≥6.5% and ≤8.0%)
– Stable monotherapy OR dual combination therapy with metformin,
pioglitazone, or sulfonylurea or *stable dose of insulin with or without
metformin
• ≥50 years old
• Preexisting vascular disease defined as having:
– History of myocardial infarction
– Prior coronary revascularization
– Coronary angiography with at least one ≥50% stenosis
– History of ischemic stroke
– Carotid arterial disease with ≥50% carotid stenosis
– Peripheral arterial disease with objective evidence
• Able to see usual care provider at least twice yearly
*Amended 13Sept2010
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Major Exclusion Criteria
• Type 1 diabetes or history of ketoacidosis
• History of ≥2 episodes of severe hypoglycemia during the
12 months prior to enrollment
• Estimated glomerular filtration rate (eGFR) <30mL/min/1.73 m2
• Use of another DPP-4 inhibitor, GLP-1 analogue, or
thiazolidinedione other than pioglitazone in previous three months
• Cirrhosis of the liver
• Planned revascularization procedure
• Pregnancy or planned pregnancy
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Statistical Analysis Plan
Primary analysis for non-inferiority performed in the per
protocol (PP) population
– Consistent with ICH E-9/CONSORT statement
– Supporting intention-to-treat (ITT) analysis also performed
• Prespecified conditional hierarchical analyses,
each at =0.025 one-sided:
– Non-inferiority for the secondary composite CV outcome
(PP population)
– Superiority for primary CV outcome (ITT population)
– Superiority for the secondary composite CV outcome
(ITT population)
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
10
Prohibited Medications
• Use of open-label DPP-4 inhibitors or GLP-1 receptor agonists
• Use of rosiglitazone as concomitant therapy subsequent to
enrollment was discouraged, but not prohibited
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Recruitment:
= country involved in TECOS
December 2008 – July 2012
ITT population
North America
2594, 17.7%
Western Europe
2076, 14.2%
Eastern Europe
3965, 27.0%
Asia Pacific
4565, 31.1%
Latin America
1471,10.0%
Total 14,671
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Consort
Diagram
14,735
randomized
64 excluded from all analyses
• 11 did not consent
• 53 at one site excluded
for GCP deviations
14,671
included in ITT analysis
7332 sitagliptin ITT
7339 placebo ITT
7180 (97.9%) VS known
7123 (97.0%) VS known
6972 (95.1%) completed
6905 (94.1%) completed
61 (0.8%) LTFU
71 (1.0%) LTFU
29 (48%) VS known
33 (46%) VS known
299 (4.1%) Withdrawn
363 (4.9%) Withdrawn
179 (60%) VS known
185 (51%) VS known
ITT = intention-to-treat; LTFU = lost to follow-up;
VS = vital status, GCP = Good Clinical Practice
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Per Protocol Population
Sitagliptin
Placebo
7332
7339
75 (1.0%)
73 (1.0%)
7257
7266
Censored early for primary composite
1494 (20.4%)
1654 (22.5%)
Early study drug discontinuation
1378 (18.8%)
1505 (20.5%)
Initiation of prohibited medication
70 (1.1%)
102 (1.4%)
Other
46 (0.6%)
47 (0.6%)
136 (1.9)
151 (2.1%)
ITT Population (n)
Completely excluded for major protocol violation
PP Population (n)
# Primary events censored
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Baseline Characteristics
Characteristic
Sitagliptin
n=7332
Placebo
n=7339
Age (years)
65.4 ± 7.9
65.5 ± 8.0
2134 (29.1%)
2163 (29.5%)
White
4955 (67.6%)
5002 (68.2%)
Black
206 (2.8%)
241 (3.3%)
Asian
1654 (22.6%)
1611 (22.0%)
Other
517 (7.1%)
485 (6.6%)
Hispanic or Latino
886 (12.1%)
912 (12.4%)
BMI (kg/m2)
30.2 ± 5.6
30.2 ± 5.7
eGFR (mL/min/1.73 m2)*
74.9 ± 21.3
74.9 ± 20.9
Women
Race
Values are mean ±SD for continuous variables or n,% for categorical variables.
*MDRD formula used to calculate eGFR. Site-reported values are presented.
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Baseline Characteristics—
CV Risk Management
Characteristic
Sitagliptin
n=7332
Placebo
n=7339
Systolic blood pressure (mmHg)
135 ± 16.9
135 ± 17.1
Diastolic blood pressure (mmHg)
77.1 ± 10.3
77.2 ± 10.6
Total cholesterol (mg/dL)
166.1 ± 44.8
165.4 ± 45.9
LDL-C (mg/dL)
91.2 ± 63.8
90.7 ± 51.2
HDL-C (mg/dL)
43.5 ± 12.0
43.4 ± 13.0
166.0 ± 101.0
164.8 ± 98.8
Aspirin use
5764 (78.6%)
5754 (78.4%)
Statin use
5851 (79.8%)
5868 (80.0%)
Triglycerides (mg/dL)
Medication
Values are mean ±SD for continuous variables or n,% for categorical variables.
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Baseline Characteristics—
CV Disease
Sitagliptin
n=7332
Placebo
n=7339
Prior cardiovascular disease
5397 (73.6%)
5466 (74.5%)
Myocardial infarction
3133 (42.7%)
3122 (42.5%)
PCI
2814 (38.9%)
2900 (40.1%)
CABG
1845 (25.2%)
1819 (24.8%)
≥50% coronary stenosis
3804 (51.9%)
3883 (52.9%)
1806 (24.6%)
1782 (24.3%)
1297 (17.7%)
1258 (17.1%)
TIA
280 (3.8%)
286 (3.9%)
≥50% carotid stenosis
431 (5.9%)
429 (5.8%)
Peripheral arterial disease
1217 (16.6%)
1216 (16.6%)
History of heart failure
1303 (17.8%)
1340 (18.3%)
Characteristic
Prior cerebrovascular disease
Stroke
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Baseline Characteristics—
Diabetes
Sitagliptin
n=7332
Placebo
n=7339
Duration of diabetes (years)
11.6 ± 8.1
11.6 ± 8.1
HbA1c (%)
7.2 ± 0.5
7.2 ± 0.5
Metformin
5936 (81.0%)
6030 (82.2%)
Sulfonylurea
3346 (45.6%)
3299 (45.0%)
196 (2.7%)
200 (2.7%)
1724 (23.5%)
1684 (22.9%)
50 (33, 80)
50 (32, 80)
Monotherapy
3496 (47.7%)
3498 (47.7%)
Dual combination therapy
3766 (51.4%)
3768 (51.3%)
Characteristic
Medication taken alone or in combination
Thiazolidinedione
Insulin
Median daily dose (units)
Values are mean ±SD or median (IQR) for continuous variables
or n,% for categorical variables.
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Participant Follow-up
Follow-up
Follow-up, years
Primary outcome
Median (IQR)
2.84 (2.19, 3.61)
Secondary outcome
Median (IQR)
2.87 (2.21, 3.63)
All-cause mortality
Median (IQR)
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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3.02 (2.31, 3.76)
Cumulative Proportion of Participants Lost
or Withdrawn from Study
At the end of
Year 1
At the end of
Year 2
At the end of
Year 3
Sitagliptin: 2.7%
Sitagliptin: 4.0%
Sitagliptin: 5.0%
Placebo: 3.3%
Placebo: 5.1%
Placebo: 6.0%
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Cumulative Proportion of Participants
Discontinuing Study Drug
At the end of
Year 2
At the end of
Year 1
Sitagliptin: 11.1%
Sitagliptin: 17.9%
Placebo: 19.9%
Placebo: 12.2%
At the end of
Year 3
Sitagliptin: 24.5%
Placebo: 26.6%
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Glycemic Control
Least Squares Mean HbA1c ±
1SD
Overall LS Mean difference
-0.29% (-0.32, -0.27), p<0.0001
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Initiation of Additional
Antihyperglycemic Agents
Sitagliptin
n=7332
Placebo
n=7339
Initiation of next antidiabetic medication
ITT HR 0.72 (95% CI 0.68, 0.77), p<0.001
# Patients
1591 (21.7%)
2046 (27.9%)
8.5
11.6
1 year, % (95% CI)
6.7 (6.1, 7.3)
9.3 (8.6, 10.0)
2 years, % (95% CI)
14.9 (14.1, 15.7)
20.3 (19.4, 21.3)
3 years, % (95% CI)
23.4 (22.2, 24.5)
31.3 (30.1, 32.6)
4 years, % (95% CI)
33.1 (31.4, 34.9)
41.5 (39.6, 43.3)
Event rate per 100 pyrs
Cumulative incidence (%) of event
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Initiation of
Chronic Insulin Therapy
Sitagliptin*
n=5608
Placebo*
n=5655
Initiation of insulin
ITT HR 0.70 (95% CI 0.63, 0.79) p<0.001
# Patients
542 (9.7%)
744 (13.2%)
3.44
4.85
1 year, % (95% CI)
3.2 (2.8, 3.7)
4.8 (4.3, 5.4)
2 years, % (95% CI)
6.4 (5.8, 7.1)
9.7 (8.9, 10.5)
3 years, % (95% CI)
9.8 (9.0, 10.7)
14.1 (13.1, 15.1)
4 years, % (95% CI)
13.2 (12.1, 14.5)
17.5 (16.3, 18.9)
Event rate per 100 pyrs
Cumulative incidence (%) of event
*Patients not on insulin at baseline
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Estimated Glomerular Filtration Rate (eGFR)
Mean ± 1SD
Estimated overall mean difference*:
-1.34 ml/min/1.73m2 (95%CI -1.76, -0.91), p<0.0001
*Mixed model with random intercept & slope, adjusted for baseline value and region
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Severe Hypoglycemia*
ITT HR (95% CI): 1.12 (0.89–1.40), p=0.33
Events per 100 patient-years
Sitagliptin
Placebo
Participants with event
n (%)
Participants with event
n (%)
160 (2.2%)
143 (1.9%)
0.78
0.70
*Hypoglycemia requiring assistance
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Confirmed Acute Pancreatitis
and Pancreatic Cancer
ITT HR 1.93 (0.96, 3.88), p=0.065
Patients
Events
Sitagliptin
(n=7332)
Placebo
(n=7339)
Sitagliptin
Placebo
23 (0.3%)
12 (0.2%)
25
17
Severe
4
0
4
0
Mild
19
11
21
16
Unknown severity
0
1
0
1
Acute pancreatitis
ITT HR 0.66 (0.28, 1.51), p=0.32
Pancreatic cancer
Sitagliptin
n=7332
Placebo
n=7339
9 (0.1%)
14 (0.2%)
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Confirmed Charter Defined Malignancy*
ITT HR 0.91 (0.77, 1.08), p=0.27
Event
Sitagliptin
n=7332
Placebo
n=7339
278
308
268 (3.7%)
290 (4.0%)
41 (0.6%)
43 (0.6%)
21 (0.3%)
28 (0.4%)
15 (0.2%)
49 (0.7%)
35 (0.5%)
34 (0.5%)
25 (0.3%)
11 (0.1%)
9 (0.1%)
14 (0.2%)
Total number of malignancies
Number of patients with malignancy
5 most common types of malignancy
Prostate
Lung (bronchus)
Colon (large intestine, cecum, appendix)
Bladder
Melanoma
Pancreatic cancer
*Newly diagnosed malignancy or 1st recurrence of previously
diagnosed malignancy during the study period
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Serious Adverse Events*
Serious Adverse Events
Sitagliptin
N=7332
Placebo
N=7339
Patients
n (%)
Events
Patients
n (%)
Events
Neoplasms benign, malignant and
unspecified
341 (4.7%)
405
371 (5.1%)
470
Injury, poisoning and procedural
complications
146 (2.0%)
165
133 (1.8%)
153
Gastrointestinal disorders
130 (1.8%)
143
102 (1.4%)
121
Musculoskeletal and connective
tissue disorders
118 (1.6%)
136
93 (1.3%)
102
Respiratory, thoracic and
mediastinal disorders
66 (0.9%)
81
77 (1.0%)
95
*System Organ Classes with incidence ≥1% in either group
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
29
Primary Composite Cardiovascular Outcome*
PP Analysis for Non-inferiority
* CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Primary Composite Cardiovascular Outcome*
ITT Analysis for Superiority
* CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Primary Composite Cardiovascular Outcome
ITT Population
Numbers of patients with events
Sitagliptin
n=7332
Placebo
n=7339
Primary composite CV Outcome
839 (11.4%)
851 (11.6%)
4.06 per 100 pyrs
4.17 per 100 pyrs
ITT HR=0.98 (0.89, 1.08), p=0.65
Individual components
• CV death
311 (4.2%)
291 (4.0%)
• Nonfatal MI
275 (3.8%)
286 (3.9%)
• Nonfatal stroke
145 (2.0%)
157 (2.1%)
• Hospitalization for unstable angina
108 (1.5%)
117 (1.6%)
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Secondary Composite Cardiovascular Outcome*
ITT Analysis for Superiority
* CV death, nonfatal MI, nonfatal stroke
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Secondary Composite Cardiovascular Outcome
ITT Population
Numbers of patients with events
Sitagliptin
n=7332
Placebo
n=7339
Secondary composite CV outcome
745 (10.2%)
746 (10.2%)
3.58 per 100 pyrs
3.62 per 100 pyrs
ITT HR=0.99 (0.89, 1.10), p=0.84
Individual components
•
CV death
313 (4.3%)
293 (4.0%)
•
Nonfatal MI
285 (3.9%)
294 (4.0%)
•
Nonfatal stroke
147 (2.0%)
159 (2.2%)
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
All-cause Mortality (ITT Population)
All-cause mortality
Sitagliptin
n=7332
Placebo
n=7339
547 (7.5%)
537 (7.3%)
2.48 per 100 pyrs
2.45 per 100 pyrs
ITT HR=1.01 (0.90, 1.14), p=0.88
Non-cardiovascular
167 (2.3%)
171 (2.3%)
Unknown*
109 (1.5%)
107 (1.5%)
Cardiovascular
•
Sudden cardiac death
72 (1.0%)
73 (1.0%)
•
Acute myocardial infarction
21 (0.3%)
27(0.4%)
•
Heart failure
28 (0.4%)
35 (0.5%)
•
Stroke
29 (0.4%)
36 (0.5%)
•
Other cardiovascular
8 (0.1%)
5 (0.1%)
•
Presumed cardiovascular
113 (1.5%)
83 (1.1%)
* Counted as cardiovascular for the primary analysis
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Hospitalization for Heart Failure*
ITT Analysis
* Adjusted for history of heart failure at baseline
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Hospitalization for Heart Failure*
ITT Population
Numbers of patients with events
Sitagliptin
n=7332
Placebo
n=7339
Hospitalization for heart failure†
228 (3.1%)
229 (3.1%)
1.07 per 100 pyrs
1.09 per 100 pyrs
ITT HR=1.00 (0.83, 1.20), p=0.98
Hospitalization for heart failure or
cardiovascular death†
538 (7.3%)
525 (7.2%)
2.54 per 100 pyrs
2.50 per 100 pyrs
ITT HR=1.02, (0.90, 1.15), p=0.74
* Adjusted for history of heart failure at baseline
† Prespecified analyses
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Primary Composite Cardiovascular Outcome
Prespecified Subgroup Analyses* (1)
* ITT Population
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Primary Composite Cardiovascular Outcome
Prespecified Subgroup Analyses* (2)
* ITT Population
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Primary Composite Cardiovascular Outcome
Prespecified Subgroup Analyses* (3)
* ITT Population
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Primary Composite Cardiovascular Outcome
Prespecified Subgroup Analyses* (4)
* ITT Population
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Primary Composite Cardiovascular Outcome
Prespecified Subgroup Analyses* (5)
* ITT Population
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Summary of Results (1)
• For the primary composite cardiovascular outcome
(CV death, nonfatal MI, nonfatal stroke, or hospitalization for
unstable angina) sitagliptin, compared with placebo, was
noninferior, and not superior
• For the secondary composite cardiovascular outcome
(CV death, nonfatal MI, or nonfatal stroke) sitagliptin,
compared with placebo, was noninferior, and not superior
• The rate of hospitalization for heart failure did not differ
between sitagliptin and placebo treatment groups
• The incidence of severe hypoglycemia did not differ
between sitagliptin and placebo treatment groups
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Summary of Results (2)
• The rates of infections, and deaths from infection, did not
differ between sitagliptin and placebo treatment groups
• The incidence of overall malignancies did not differ
between sitagliptin and placebo treatment groups
• Overall, confirmed events of acute pancreatitis
were uncommon, but numerically more frequent
in the sitagliptin group
• Overall, confirmed events of pancreatic cancer
were uncommon, but numerically more frequent
in the placebo group
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Summary of Results (3)
• TECOS was a cardiovascular safety study
• The study aimed for glycemic equipoise to minimize possible
glycemic confounding effects on the outcomes of interest,
with the result that there was only a small difference in the
HbA1c levels between the sitagliptin and placebo groups
• The utility of sitagliptin as a glucose-lowering agent was
confirmed by the more frequent initiation of insulin therapy
and the greater need for additional antihyperglycemic agents
in the placebo group compared with the sitagliptin group
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Acknowledgements
TECOS Executive Committee*
Rury Holman, Joint Chair
Eric Peterson, Joint Chair
Paul Armstrong
John Buse
Robert Josse
Keith Kaufman
Joerg Koglin
Scott Korn
John Lachin
Darren McGuire
Eberhard Standl
Peter Stein
Shailaja Suryawanshi
Frans Van de Werf
* Robert M. Califf served as Joint Chair until taking up the
post of deputy FDA commissioner on March 1, 2015
TECOS was conducted jointly by
…in an academic collaboration with
Data and Safety Monitoring Board
Marc Pfeffer, Chair
Stuart Pocock
John McMurray
Hertzel Gerstein
Leif Groop
Independent statistician
Tim Clayton
Operations Committee
Argentina: Isaac Sinay,
Australia: David Brieger, Steve Stranks,
Belgium: Andre Scheen,
Brazil: Antonio Chacra, Renato Lopes
Bulgaria: Tsvetalina Tankova
Canada: Irene Hramiak
Chile: Carlos Raffo Grado
China: Junbo Ge, Yang Wen Ying
Colombia: Pablo Aschner
Czech Republic: Jan Skrha
Estonia: Anu Ambos
Finland: Timo Strandberg
France: Michel Marre, Florence Travert
Germany: Markof Hanefeld, Axel Riefflin
Hong Kong: Juliana Chan
Hungary: Peter Ofner
India: Priyadarshini Arambam,
Johann Christopher, Mukul Manchanda,
Atul Mathur, Sanjay Mittal, N. K. Reddy,
Naresh Trehan
Israel: Julio Wainstein
Italy: Giuseppe Ambrosio
Latvia: Valdis Pirags
Lithuania: Neli Jakuboniene
Malaysia: Mafauzy Mohamed
Netherlands: Jan H. Cornel
New Zealand: Russell Scott, Harvey White
Norway: Sigrun Halvorsen
Poland: Andrzej Tykarski
Romania: Ioan Andrei Veresiu
Russia: Alexander V. Dreval, Inna Misinkova
Singapore: E. Shyong Tai
Slovakia: Boris Krahulec
South Africa: Larry Distiller
South Korea: Yong Soo Park
Spain: Adela Rovira
Sweden: Michael Alvarsson
Taiwan: Lee-Ming Chuang
Turkey: Tuncay Delibasi
United Kingdom: Amanda Adler
United States: Helena Rodbard
Patients and Sites
• We thank the patients, without whom this study and these
analyses would not have been possible
• We also thank the many investigators and their staff from
673 sites in 38 countries who worked diligently to help
ensure TECOS was run to the highest possible standards
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