Clinical trial NCT02874092
Conditions: Rheumatoid Arthritis
Keywords: Methotrexate (MTX) Ticagrelor
Sponsor: NYU Langone Health
Start date: 2016-11-15; Completion date: 2019-06-19
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open label study to assess the improvement in the Disease Activity Score for 28-joint counts (DAS28) with ticagrelor given at 90 mg twice daily in patients with RA who have active disease despite MTX therapy (as defined by the inclusion/exclusion criteria). There will also be a cross sectional analysis of baseline platelet activity in subjects with rheumatoid arthritis and osteoarthritis. Subjects in the OA cohort will not receive any study medication, and will only have one study visit.

Patients will receive 90 mg ticagrelor orally bid. The patients will receive drug for 30-days. Methotrexate dose will remain stable throughout the study duration.

Detailed description:
The two main goals of this study are to demonstrate the heightened cardiovascular risk in RA by comparing platelet activity, inflammation and endothelial function in baseline rheumatoid arthritis versus age- and sex-matched patients with osteoarthritis; and 2) to demonstrate the effect of ticagrelor in rheumatoid arthritis by the pre- and post- measures of clinical RA severity, platelet activity, inflammation and endothelial function in rheumatoid arthritis before and after ticagrelor therapy.

Arms: arm 1: -Receiving Methotrexate at stable doses of 10 to 25 mg weekly for at least 12 weeks arm 2: -Diagnosis of osteoarthritis made by physician.
Interventions: intervention 1: Ticagrelor intervention 2: MTX therapy
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor
Study Title: Ticagrelor in Methotrexate-Resistant Rheumatoid Arthritis (TIMERA)
Proposing Investigators: 
Jeffrey S. Berger, MD, MS
Associate Professor of Medicine and Surgery
Director of Cardiovascular Thrombosis
New York University School of Medicine
530 First Avenue, Skirball 9R, New York, NY 10016
Tel. 212-263-4004; Fax. 212-263-3988
E-mail: jeffrey.berger@nyumc.org
Bruce N. Cronstein, MD
Paul R. Esserman Professor of Medicine
Director, NYU-HHC Clinical and Translational Science Institute
Director, Division of Translational Medicine
550 First Ave, New York, NY 10016
Tel: 212-263-6404
E-mail: bruce.cronstein@nyumc.org
Co-Investigators
Yusuf Yazici, MD
Assistant Professor; Director Seligman Center for Advanced Therapeutics 
Stuart Katz, MD
Helen L. and Martin S. Kimmel Professor of Advanced CardiacTherapeutics
Pamela Rosenthal, MD
Assistant Professor; Section Chief Rheumatology, Bellevue Hospital and Director of Arthritis Clinic at 
Bellevue Hospital
Version Date: March 27, 2018
Clinical Research Protocol


TIMERA
 Page 1
Version Date: March 27, 2018
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
1
Introduction
This document is a protocol for a human research study. This study is to be conducted in accordance with US 
government research regulations, and applicable international standards of Good Clinical Practice, and 
institutional research policies and procedures.
1.1
Background
In addition to significant morbidity from RA morbidity, the risk of myocardial infarction is increased nearly 2-
fold in the setting of RA.(Meune et al., 2010; Solomon et al., 2006) Rheumatoid arthritis induced activation of 
systemic inflammatory pathways and endothelial dysfunction has been implicated in this increased risk.(Sattar 
et al., 2003) Inflammation mediates many aspects of disease pathogenesis in atherosclerosis, involving 
diverse cell types and mediating signals.(Hansson, 2005) Platelets have been implicated in atherosclerosis 
because of their pro-inflammatory and thrombogenic effects.(Gawaz et al., 2005) Moreover, pathological and 
clinical studies demonstrated the importance of platelet activity in cardiovascular events.  It is likely that 
increased platelet reactivity in patients with RA contributes to the increased risk of myocardial infarction and 
also contributes to the joint inflammation as well. 
1.2
Investigational Agent
This study is looking at the investigational agent ticagrelor. Subjects who are already receiving MTX at stable 
doses of 10 to 25 mg weekly for at least 12 weeks will receive 90 mg of ticagrelor given orally bid.  Ticagrelor 
is an oral, direct-acting, reversibly binding P2Y12 receptor antagonist,that is approved for the treatment of 
patients with acute coronary syndrome and prior myocardial infarction.  In addition to its antiplatelet effects, 
ticagrelor can inhibit adenosine cell uptake, likely through inhibition of the equilibrative nucleoside transporter 
1. Ticagrelor also significantly increases coronary blood flow velocity via an adenosine mediated mechanism.
1.3
Preclinical Data
Methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA) although many patients 
will not achieve a complete response to MTX alone. (Weinblatt, 2013) In general, the onset of action of MTX 
is delayed (onset by 2-3 months) although generally most physicians will not add another agent for the 
treatment of RA until three months after the patient started MTX therapy and has not achieved a significant 
clinical response. (Weinblatt, 2013) In prior studies we have shown (Chan and Cronstein, 2013) that many, if 
not most, of the anti-inflammatory effects of MTX are mediated by an increase in extracellular levels of 
adenosine, a potent anti-inflammatory agent acting at its receptors (primarily A2A and A3). We postulate that 
insufficient levels of adenosine to suppress inflammation are reached in many patients not achieving an 
adequate response to MTX therapy; generally speaking these patients will be prescribed biologic agents (e.g. 
anti-TNF agents). Because ticagrelor blocks adenosine uptake (Cattaneo et al., 2014) and adenosine 
contributes to the therapeutic effects of ticagrelor we further hypothesize that ticagrelor will enhance the anti-
inflammatory effects of MTX in the treatment of RA. Thus, if addition of ticagrelor enhances MTX response 
then it may be possible for patients to avoid use of a biologic therapy.
1.4
Dose Rationale
Ticagrelor 90 mg twice daily will be used in this study. This dose was chosen based on ticagrelor’s antiplatelet 
effect at this dose and use in other indications (acute coronary syndrome, prior myocardial infarction). In 
addition, there is a concentration-dependent response for ticagrelor in vitro in terms of conservation of added 
adenosine to whole blood.  There is also an effect on adenosine induced coronary blood flow of a 180mg 
loading dose of ticagrelor in healthy subjects (Wittfeldt 2013) and after 90mg in ACS patients (Alexopolous 
2013). This effect is mediated by inhibition of the adenosine transporter ENT1 (type 1 equilibrative nucleoside 
transporter), which provides protection for adenosine from intracellular metabolism, thus increasing its 
concentration and biological activity.  Study medication will be taken orally, twice a day. Safety and tolerability 
will be monitored closely during the study. The 30-day study duration is considered sufficient to investigate 
acute safety and efficacy in ticagrelor in RA. 


TIMERA
 Page 2
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
1.5
Research Risks & Benefits
1.5.1
Risk of Study Drug
Ticagrelor can cause bleeding that can be serious and sometimes lead to death. Instances of serious 
bleeding, including internal bleeding, may require blood transfusions or surgery. Subjects taking ticagrelor 
may bruise and bleed more easily and be more likely to have nosebleeds. Bleeding will also take longer than 
usual to stop. Subjects who experience any of these symptoms will be informed to call their study doctor 
immediately and call 911 in the event of an emergency. 
Patients who are taking ticagrelor are also at a greater risk of dyspnea. If ticagrelor must be temporarily 
discontinued (e.g., to treat bleeding or for significant surgery) it should be restarted as soon as possible. 
Because the primary route of ticagrelor elimination is hepatic metabolism, patients with severe hepatic 
impairment should not use ticagrelor. 
1.5.2
Risks of all study related procedures 
Blood draw: Possible side effects from drawing blood include: faintness, inflammation of the vein, pain, 
bruising, or bleeding at the site of puncture. There is also a slight possibility of infection.
Risk of brachial artery reactivity test: There are no known risks associated with the procedures for 
measurement of flow- mediated vasodilation. Inflation of a blood pressure cuff for 5 minutes for transient 
arterial occlusion may be associated with local arm discomfort that is rapidly relieved upon deflation of the 
cuff. Rarely, cuff inflation can be associated with local bruising.
Nitroglycerin may be associated with transient headache and lightheadedness due to lower blood pressure. 
Due to its short half-life, side effects would be expected to last < 30 minutes. To minimize risk of hypotension, 
nitroglycerin will not be administered if resting systolic blood pressure is <100 mmHg.
Loss of privacy and confidentiality: As with participation in any research study, there is always a risk that 
confidential or private information can be compromised. To minimize this risk, the study team will de-identify 
your samples and replace your identifying information, such as your name, with a bar code label that will not 
be associated with any date related to you (for example, your birthday or street address).
Risk of Genetic Testing: Any type of genetic evaluation can generate information about your personal health 
risks and can cause or increase anxiety, damage family relationships, and/or compromise insurability, 
employability and can even lead to discrimination. In order to protect against loss of confidentiality, sensitive 
information will be kept on a secured database and the samples will be de-identified before they are used in 
research. Your name and identifiers will not be mentioned in publications or reports, thereby greatly reducing 
the possibility of psychological or social risks that could arise from knowledge of this genetic information, such 
as risk for your employability or insurability or the risk of discrimination.
1.5.3
Potential benefits
The benefits of ticagrelor in patients with RA are currently unknown. 
2
Study Objectives
We propose to measure platelet activity in subjects with RA and OA and perform a preliminary clinical study in 
patients with rheumatoid arthritis that have active disease despite MTX therapy. Subjects will receive 
ticagrelor added to MTX for 30 days.  The primary outcome is improvement in the Disease Activity Score for 
28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) 
at 30 days. 


TIMERA
 Page 3
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
3
Study Design
3.1
General Design
This is an open label study to assess the improvement in the Disease Activity Score for 28-joint counts 
(DAS28) with ticagrelor given at 90 mg twice daily in patients with RA who have active disease despite MTX 
therapy (as defined by the inclusion/exclusion criteria).  There will also be a cross sectional analysis of 
baseline platelet activity in subjects with rheumatoid arthritis and osteoarthritis. Subjects in the OA cohort will 
not receive any study medication, and will only have one study visit. 
Patients will receive 90 mg ticagrelor orally twice daily. The patients will receive drug for 30-days.  
Methotrexate will be by prescription as per standard of care and the dose will remain stable throughout the 
study duration.
A summary of the study design is noted in the Supplemental Figure of Study Design. Briefly, there are 2 major 
goals: 1) we would like to demonstrate the heightened cardiovascular risk in RA by comparing platelet activity, 
inflammation and endothelial function in baseline rheumatoid arthritis versus age- and sex-matched patients 
with osteoarthritis; and 2) we would like to demonstrate the effect of ticagrelor in rheumatoid arthritis by the 
pre- and post- measures of clinical RA severity, platelet activity, inflammation and endothelial function in 
rheumatoid arthritis before and after ticagrelor therapy.
3.2
Secondary Study Endpoints
The primary outcomes of this study are: (1) investigate the heightened platelet profile in subjects with RA 
versus those with osteoarthritis, and (2) demonstrate the improvement in the Disease Activity Score for 28-
joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at 
30 days.  The DAS28 is a composite index of the number of swollen and tender joints, the erythrocyte 
sedimentation rate, and a patient-reported disease activity.(Prevoo et al., 1995) A decrease in the DAS28 of 
1.2 or more is considered to be a clinically meaningful improvement.(van Gestel et al., 1996) 
3.3
Secondary Study Endpoints
Rheumatoid Arthritis Severity
To assess whether ticagrelor 90 mg twice daily for 30 days improves:

American College of Radiology (ACR) 20, 50, and 70 responses, indicating 20%, 50%, and 70% 
reductions, respectively, in the number of both tender and swollen joints and equivalent improvement 
in at least three of five other criteria

Responses on the Clinical Disease Activity Index (CDAI), which is a composite score of the sum of 
tender and swollen joints (28 joints) and the patient and physician global assessments (each scored 
with the use of a scale ranging from 0 to 10), and 

Responses on the Routine Assessment of Patient Index Data 3 (RAPID3), which is a composite 
score of the sum of physical function, pain and patient global estimate

Functional outcomes, as measured with the use of the Multi-dimensional Health Assessment 
Questionnaire (MDHAQ)
Adenosine Activity
To assess whether ticagrelor for 30 days improves:

Vascular endothelial dysfunction 

Endothelial function will be measured by brachial artery reactivity testing (BART) before and after 
30 days of therapy because a) this measure has been shown to improve in response to short-term 
therapy in other inflammatory conditions,(Flammer et al., 2008; Gupta et al., 2008; Patti et al., 2011; 
Warnholtz et al., 2009) b) it is a validated noninvasive and minimal risk measure of cardiovascular 
health,(Liang et al., 1998; Sorensen et al., 1995) and c) it is predictive of incident cardiovascular 
events and mortality.(Celermajer et al., 1992)

Adenosine receptor expression on PBMCs


TIMERA
 Page 4
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
Platelet Activity
To assess whether ticagrelor for 30 days causes a greater decline in platelet activity than baseline using the 
following markers:

ADP-induced platelet aggregation 

Vasodilator-stimulated phosphoprotein (VASP) index

Monocyte – platelet aggregation
3.4
Primary Safety Endpoints
A safety objective of this study will be to assess the safety and tolerability of ticagrelor in participants with 
active RA despite MTX therapy.  Bleeding events will be analyzed using accepted bleeding definitions 
(PLATO, ISTH and BARC). Other adverse events will be reviewed within the context of the earlier safety 
experience with the drug.
3.5
Exploratory Endpoints
To determine the effect(s) of adding ticagrelor for 30-days to participants with active RA after MTX failure on 
the following exploratory objectives:

Soluble markers of inflammation, platelet and immune activation: IL-6, sCD14, hs-CRP, sCD40L, 
and sP-selectin, sCD163, and CXCL10/IP10. 

Intracellular cytokine concentration (TNF∝ and IL-6 from PBMCs)

Contingent upon significant improvement in the primary objective and additional funding, 
measurements of inflammatory transcripts may be performed upon stored frozen PBMCs by 
measuring cell associated RNA and DNA.
4
Subject Selection and Withdrawal
4.1
Inclusion Criteria
Inclusion Criteria (RA cohort):

Receiving MTX at stable doses of 10 to 25 mg weekly for at least 12 weeks 

Have a DAS28 of 3.2 or higher  (The level of disease activity is considered to be low if the DAS28 is 
3.2 or less) (Prevoo et al., 1995) 

Written informed consent prior to any study specific procedures

Over 18 years of age at time of enrollment.
Inclusion Criteria (OA cohort):

Age- and Sex- Matched to RA cohort. Subjects will not be selected based on grade of OA.

Diagnosis of osteoarthritis made by physician. 
4.2
Exclusion Criteria
Exclusion Criteria (RA cohort):

History of sensitivity to study medications or any of their excipients 

Previous intolerance to MTX

Current treatment with antiplatelet therapy

Absolute indication for anti-platelet therapy

Need for chronic oral anticoagulant therapy

Severe hepatic impairment (eg, ascites and/or clinical signs of coagulopathy)

Renal failure (eGFR <30 or requiring dialysis) by history

A known bleeding diathesis, hemostatic or coagulation disorder, or prior major bleeding

Prior stroke

Active pathological bleeding

History of intracranial haemorrhage 


TIMERA
 Page 5
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor

Life expectancy <12 months based on investigator’s judgement

Patients considered to be at risk of bradycardic events (e.g., known sick sinus syndrome or second or 
third degree atrioventricular [AV)] block) unless already treated with a permanent pacemaker

Anemia (hematocrit < 27%) by history

Platelet count < 100,000/ml by history

Concomitant use of strong CYP 3A inhibitors or inducers 

History of thrombocytopenia or neutropenia

Pregnant or nursing women, or females with a positive urine and/or serum pregnancy test at 
screening/baseline

Females of child bearing potential not using acceptable method of birth control prior to or during study

Concern for inability of the patient to comply with study procedures and/or follow-up (eg, alcohol or 
drug abuse)
Exclusion Criteria (OA cohort):

History of sensitivity to study medications or any of their excipients 

Current treatment with antiplatelet therapy

Absolute indication for anti-platelet therapy

Need for chronic oral anticoagulant therapy

Severe hepatic impairment (eg, ascites and/or clinical signs of coagulopathy)

Renal failure (eGFR <30 or requiring dialysis) by history

A known bleeding diathesis, hemostatic or coagulation disorder, or prior major bleeding

Prior stroke

Active pathological bleeding

History of intracranial haemorrhage 

Life expectancy <12 months based on investigator’s judgement

Anemia (hematocrit < 27%) by history

Platelet count < 100,000/ml by history

History of thrombocytopenia or neutropenia

Pregnant or nursing women, or females with a positive urine and/or serum pregnancy test at 
screening/baseline

Females of child bearing potential not using acceptable method of birth control prior to or during study

Concern for inability of the patient to comply with study procedures and/or follow-up (eg, alcohol or 
drug abuse)
4.3
Subject Recruitment and Screening
Recruitment of patients will come mainly through routine clinical care visits by rheumatologists in the faculty 
practice at the Center for Musculoskeletal Care. NYU is home to the Center for Musculoskeletal Care and has 
a special emphasis on Arthritis and Autoimmunity.  Over 20,000 rheumatology visits a year are captured at 
NYU Hospital for Joint Diseases. Approximately 70 new patients are seen each week in rheumatology clinics 
and practices which can provide 4 to 5 new RA patients a week. Subjects will be recruited by study 
physicians. Recruitment of patients will come mainly through routine clinical care visits by rheumatologists in 
the faculty practice at the Center for Musculoskeletal Care and other rheumatology clinics. Physicians at 
clinical sites will be aware of the current protocol and will be encouraged to speak with their patients. If there 
is a need for additional patient materials, a separate advertisement will be placed with prior IRB approval. 
Letters to affiliate physicians may also be written that also would be submitted for IRB approval. Management 
of DataCore will also be mining the database for our specific recruitment needs.
Target patient population
The target study population is male and female participants over the age of 18 who meet the 1987 American 
College of Rheumatology (ACR) classification criteria for RA (Arnett et al., 1988) or OA (Altman et al., 1991; 
Altman et al., 1990; Altman et al., 1986)  fulfilling all of the inclusion and none of the exclusion criteria. This 
study aims to have 25 subjects in the RA cohort complete all study activities, and 10 subjects with OA to 


TIMERA
 Page 6
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
match with the RA cohort. To achieve 35 subjects completing the entirety of the study, there will be a 
maximum total accrual of 60.  
4.4
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which they volunteer to participate. Freely given written 
informed consent must be obtained from every subject before clinical study participation, including informed 
consent for any screening procedures conducted to establish subject eligibility for the study. Written informed 
consent will be obtained by the research staff member designated by the PI. All written informed consent 
originals will be maintained for study purposes and review if needed.
4.5
Early Withdrawal of Subjects
4.5.1
Patient Withdrawal
Patients may withdraw from the study at any time and for any reason. Reason for study withdrawal will be 
documented and may include the following reasons:

Patient choice;

At the discretion of the Investigator;

Development of a contraindication to ticagrelor or MTX;

Development of a bleeding diathesis, hemostatic or coagulation disorder, or major bleeding; 

Pregnancy;

Death. 
4.5.2
Early Withdrawal Procedures
Patients who withdraw due to an AE or SAE require additional follow-up.

If a patient is early terminated from the study due to an AE, he/she will be followed until resolution 
of the event or for 30 days after discontinuation of study medication (whichever occurs first).

For SAE follow-up, please refer to Section 8.
Patients who are discontinued from study medication for any reason other than an SAE will be encouraged to 
remain on the study (not be officially withdrawn from the study) and complete all study visits.
5
Study Drug 
5.1
Administration of Study Drug
Patients will self-administer study medication twice daily, orally for 30 days. 
5.2
Subject Compliance Monitoring
Patients will be trained on study medication dosing prior to beginning treatment. Compliance will be discussed 
over the phone as needed and during the post dose visit (Day 30). 
5.3
Concomitant Medications
Concomitant medications will be reviewed at all study visits. 
5.4
Receiving, Storage, Dispensing and Return
5.4.1
Storage and dispensing of Study drug
The following will be supplied by the Sponsor:

90 mg Ticagrelor tablets
Records will be maintained indicating the receipt and dispensation of all medication supplies. 


TIMERA
 Page 7
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
The Study drug will be stored between 15° to 30° C. The study drug will be labeled according to local 
regulatory requirements.
5.4.2
Return or Destruction of Study Drug
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug 
remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated.  Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction of unused 
study drug.  Drug destroyed on site will be documented in the study files.
6
Study Procedures
Study participation includes a 30-day treatment period. Screening and baseline visits may be done 
on the same day if the subject is able to give fasting blood and does not meet any exclusion criteria.
Table 1: Schedule of Assessments.
Screening
Baseline
 1 and 2 
Week Phone 
call
Day 30
Visit #
1
1 or 2
2 or 3
Day#
− 30 − 3
0
30 ± 5
Informed consent
X
Medical history
X
X
Medications
X
X
X
Vital signs/physical exam
X
X
DAS28/CDAI/RAPID3/MDHAQ
X
X
X
ACR responses
X
X
Blood (fasting) collection
X
X
Urine and/or serum pregnancy test for 
WOCBP only
X
X
Platelet Activity
X
X
Brachial Artery Reactivity Testing (fasting)
X
X
Dispense study drug
X
Adverse events
X
X
X
X
Medication compliance/diary
X
X
6.1
Screening (Visit 1, Days -30 to -3)

Patients will sign a written informed consent form prior to undergoing any study-specific activities;

Patients will be assessed for inclusion/exclusion criteria;

Demographics, medical history, review of medications will be performed;


TIMERA
 Page 8
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor

DAS28, CDAI, RAPID3 and MDHAQ will be performed and records;

Adverse events will be collected.
6.2
Baseline (Visit 1 or 2, Day 0)

Medical history and review of medications will be performed;

Vitals will be recorded and the patient will have a physical exam;

DAS28, CDAI, RAPID3 and MDHAQ will be performed and recorded;

ACR responses will be measured by the physician using patient questionnaires and joint counts;

Fasting blood will be collected;

For each subject, no more than 75 cc of blood will be collected in red (no anticoagulant) top, Pax 
gene tube for genomics, lavender (EDTA anticoagulant) top, green (heparin) and blue (sodium citrate 
anticoagulant) top tubes. Approximately 40 cc of blood will be used for the different measurements of 
platelet function, inflammation, immune activation, and other markers of cardiovascular risk, and 
approximately 30 cc of blood will be used to purify cells, RNA and DNA and then stored in -80C/liquid 
nitrogen for genetic and functional profiling. The results of the genetic testing will not be shared with 
the subjects. 
o
The drawing of a maximum of 75 cc of blood is justified by the need for the above referenced 
tests, measurements and purification. These tubes will be drawn at the time of the standard 
of care blood draws for routine patient care monitoring. This amount of blood is medically 
safe to draw. The physician will always ensure the safety of drawing this volume of blood. 

Fasting brachial artery reactivity testing including one time dose of 0.4 mg of nitroglycerin given 
sublingual. To minimize risk of hypotension, nitroglycerin will not be administered if resting systolic 
blood pressure is <100 mmHg;

Study medication will be dispensed;

Adverse events will be collected.
6.3
Visit 2 or 3 (Day 30 +/-5): RA cohort only

Review of medications will be performed;

Vitals will be recorded and the patient will have a physical exam;

DAS28, CDAI, RAPID3 and MDHAQ will be performed and recorded;

ACR responses will be measured;

Fasting blood will be collected;

For each subject, no more than 75 cc of blood will be collected in red (no anticoagulant) top, Pax 
gene tube for genomics, lavender (EDTA anticoagulant) top, green (heparin) and blue (sodium citrate 
anticoagulant) top tubes. Approximately 40 cc of blood will be used for the different measurements of 
platelet function, inflammation, immune activation, and other markers of cardiovascular risk, and 
approximately 30 cc of blood will be used to purify cells, RNA and DNA and then stored in -80C/liquid 
nitrogen for genetic and functional profiling. The results of the genetic testing will not be shared with 
the subjects.

Fasting brachial artery reactivity testing including one time dose of 0.4 mg of nitroglycerin given 
sublingual. To minimize risk of hypotension, nitroglycerin will not be administered if resting systolic 
blood pressure is <100 mmHg;

Adverse events will be reviewed and recorded;

Medication compliance will be reviewed with the subject.
7
Sample storage for future research 
The samples will be stored in the PI’s lab without any identifying information other than a code number. The 
code number will not be based on any information that could be used to identify the subject (for example, 
social security number, initials, birth date, etc). The master list linking names to code numbers will be kept in a 
locked file cabinet, separate from all research information. All specimen handling, collection, processing, and 
storage, will be performed as per regulations and Tisch Laboratory and NYU policy. Specimens will be 


TIMERA
 Page 9
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
collected at CMC and transferred to Tisch Laboratory for analysis. Samples will be stored for 10 years after 
the end of the study, if subjects give permission in their consent form.
7.1
Optional permission to store samples for future use 
Subjects have the option to allow researchers to store their blood samples for future research, either for new 
research studies or in order to run additional tests on blood collected as part of this study. The consent form 
has a section that will allow subjects to explicitly grant permission for this by checking a box and initialing. 
This permission to store samples for future use is completely optional and voluntary. Samples kept for future 
research after the duration of this study will be stored in the same manner as they were stored during the 
course of the study. The samples will be stored in the lab of the PI, Dr. Jeffery Berger, located at New York 
University Langone Health, New Science Building, 435 East 30th Street, 7th floor, Lab # 723, New York, NY 
10016.  Samples would be stored for 10 years after the end of the study and then destroyed. Subjects may 
request, in writing, for their samples to be destroyed if they change their mind or for any other reason. The 
purpose of this possible future research is unknown, but will have the purpose of contributing to medical 
knowledge and understanding of human health. Genetic testing will not be performed on stored samples.  The 
stored samples will be available to the PI of this study and all co-investigators. Any new information derived 
from stored samples will be kept in a secure database matching all of the confidentiality requirements of any 
database use in this study. Samples will not be shared with other researchers outside the scope of this study. 
8
Statistical Plan
The primary end point of the trial is the Disease Activity Score for 28-joint counts (DAS28) at 30 days after 
randomization. The DAS28 is a composite index of the number of swollen and tender joints, the erythrocyte 
sedimentation rate, and a visual-analogue scale of patient-reported disease activity.(Prevoo et al., 1995) A 
decrease in the DAS28 of 1.2 or more is considered to be a clinically meaningful improvement.(van Gestel et 
al., 1996; Ward et al., 2014) A total of 25 subjects with RA would have 90% power to detect a before- and 
after difference of 1.2 in the DAS28 at 30 days (assuming a SD of 1.5), with a two-sided type I error of 5%, 
and a 20% attrition rate. 
Power and sample size analysis was performed to investigate appropriate sample size for evaluating platelet 
activity markers in subjects with RA versus age- and sex matched OA controls. Since patients with RA have a 
heightened inflammatory phenotype and at higher cardiovascular risk than osteoarthritis, we hypothesize that 
the mean measurement of platelet markers for RA is 35% greater (similar to previously demonstrated 
differences in high risk phenotypes) than age- and sex matched OA controls for each measurement. Based 
on two-sided two-sample t-tests with 25 patients in the RA group and 10 patients in the OA group, our power 
is listed in the table for each measure of platelet measure at the 0.05 significance level using mean/SDs from 
preliminary data in healthy controls.  
Measurement
Power        
Platelet Aggregation*
91%
PAC-1
87%
Monocyte platelet aggregates 
94%
Leukocyte platelet aggregates
93%
*Powered for low-dose epinephrine based on 
preliminary data (as described above)


TIMERA
 Page 10
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
If patients with RA do not have an increased platelet (and inflammatory) phenotype compared with OA – that would be an 
important finding we will report in this study.
9
Safety and Adverse Events
9.1
Definitions
Unanticipated Problems Involving Risk to Subjects or Others
Any incident, experience, or outcome that meets all of the following criteria: 

Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such as 
the IRB-approved protocol or consent form, package insert, etc)

Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research)

Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm).
Adverse Event
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality:

results in study withdrawal

is associated with a serious adverse event

is associated with clinical signs or symptoms

leads to additional treatment or to further diagnostic tests

is considered by the investigator to be of clinical significance
Serious Adverse Event
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is: 

fatal

immediately life-threatening

requires or prolongs hospital stay

results in persistent or significant disability or incapacity

a congenital anomaly or birth defect

an important medical event
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result in 
in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would typically 
be considered serious. 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events. 
Adverse Event Reporting Period
The study period during which adverse events must be reported is normally defined as the period from the 
initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 30 days following the last administration of study treatment. 
Preexisting Condition
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during the 
study period.


TIMERA
 Page 11
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
General Physical Examination Findings
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the end 
of the study, any new clinically significant findings/abnormalities that meet the definition of an adverse event 
must also be recorded and documented as an adverse event. 
Post-study Adverse Event
All unresolved adverse events should be followed by the investigator until the events are resolved, the subject 
is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the investigator 
should instruct each subject to report any subsequent event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study.  The investigator should notify 
the study sponsor of any death or adverse event occurring at any time after a subject has discontinued or 
terminated study participation that may reasonably be related to this study.  The sponsor should also be 
notified if the investigator should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a subject that has participated in this study. 
Abnormal Laboratory Values
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met: 

The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality

The abnormality suggests a disease and/or organ toxicity

The abnormality is of a degree that requires active management; e.g. change of dose, discontinuation 
of the drug, more frequent follow-up assessments, further diagnostic investigation, etc.
Hospitalization, Prolonged Hospitalization or Surgery
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the criteria for and 
adverse event. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse event 
in the following circumstances:

Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful.

Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study.

Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is a 
worsening or increase in frequency of hospital admissions as judged by the clinical investigator.
9.2
Recording of Adverse Events
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should recorded 
in the source document, though should be grouped under one diagnosis.
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation should be 
recorded and reported immediately.


TIMERA
 Page 12
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
9.3
Reporting of Serious Adverse Events and Unanticipated Problems
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats and 
requirements of the various entities to which they are responsible, but at a minimum those events that must 
be reported are those that are:

related to study participation,

unexpected, and 

serious or involve risks to subjects or others 
(see definitions, section 8.1).  
At the time an SAE is reported to the FDA via MedWatch, a copy of the report must be concurrently faxed to 
AstraZeneca at the time the event is reported to the FDA.  Use the cover page provided by AstraZeneca with 
a copy of the MedWatch form.  The cover page will contain the following:
•              External Sponsored Research (ESR)
•             The investigator’s name and address
•             The trial name/title and AstraZeneca ESR reference number
Investigative site must also indicate, either in the SAE report or the cover page, the causality of events in 
relation to all study medications and if the SAE is related to disease progression, as determined by the 
principal investigator.  Send SAE report and accompanying cover page by way of fax to AstraZeneca’s 
designated fax line: +1 302 886 4114.  Serious adverse events that do not require expedited reporting to the 
FDA need to be reported to AstraZeneca at least monthly.  
For Narrative Reports of Safety Events
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the 
initial report includes:

Study identifier

Study Center

Subject number

A description of the event

Date of onset

Concomitant medications

Current status

Whether study treatment was discontinued

The reason why the event is classified as serious

Investigator assessment of the association 
between the event and study treatment

Outcome of the event
9.3.1
Investigator reporting: notifying the IRB
Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems 
posing risks to subjects or others.  The following describes the NYULMC IRB reporting requirements, though 
Investigators at participating sites are responsible for meeting the specific requirements of their IRB of record. 
Report Promptly, but no later than 5 working days:
Researchers are required to submit reports of the following problems promptly but no later than 5 working 
days from the time the investigator becomes aware of the event:

Unanticipated problems including adverse events that are unexpected and related
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately reflected 
in the protocol-related documents, such as the IRB-approved research protocol, any applicable 
investigator brochure, and the current IRB-approved informed consent document and other 
relevant sources of information, such as product labeling and package inserts. 
– Related to the research procedures: An event is related to the research procedures if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be caused by 
the research procedures. 
– Harmful: either caused harm to subjects or others, or placed them at increased risk
Other Reportable events:
The following events also require prompt reporting to the IRB, though no later than 5 working days:


TIMERA
 Page 13
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor

Complaint of a research subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team.

Protocol deviations or violations (includes intentional and accidental/unintentional deviations from 
the IRB approved protocol) for any of the following situations: 
– one or more participants were placed at increased risk of harm 
– the event has the potential to occur again
– the deviation was necessary to protect a subject from immediate harm

Breach of confidentiality

Incarceration of a participant when the research was not previously approved under Subpart C and 
the investigator believes it is in the best interest of the subject to remain on the study.

New Information indicating a change to the risks or potential benefits of the research, in terms of 
severity or frequency. (e.g. analysis indicates lower-than-expected response rate or a more severe or 
frequent side effect; Other research finds arm of study has no therapeutic value; FDA labeling change 
or withdrawal from market)
Reporting Process
The reportable events noted above will be reported to the IRB using the : “Reportable New Information” 
function or as a written report of the event (including a description of the event with information regarding its 
fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or other study 
documentation).
Copies of each report and documentation of IRB notification and receipt will be kept in the Regulatory study 
file.
9.4
Cases of Pregnancy and Overdose
In case of pregnancy the patient should discontinue study medication and the study team notify AstraZeneca. 
The patient should be followed by the Investigator until completion of the pregnancy. If the pregnancy ends for 
any reason before the anticipated date, the Investigator should notify AstraZeneca. At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy. If the outcome of the pregnancy 
meets the criteria for immediate classification as an SAE (i.e, postpartum complication, spontaneous abortion, 
stillbirth, neonatal death, or congenital anomaly), the Investigator should follow the procedures for reporting a 
SAE.
9.5
Medical Monitoring
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, as 
well as the construction and implementation of a site data and safety-monitoring plan (see section 9 Auditing, 
Monitoring and Inspecting).  Medical monitoring will include a regular assessment of the number and type of 
serious adverse events.
9.5.1
Data and Safety Monitoring 
The monitoring plan includes the number and severity of adverse events as well as the overall dropouts and 
dropouts per group. The frequency and severity of the adverse events will continually be monitoring to 
determine if modifications to the protocol or consent form are required. In addition, a review of all potential 
safety data will be performed by the PI at least annually or as needed. Since the study is relatively small with 
only 35 subjects, there are no statistical measures for suspending enrollment. In the case of any severe 
adverse event, the PI will suspend enrollment till discussions can be made in conjunction with the NYU IRB 
on how (or if) to proceed. Efficacy will be assessed at the end of the study, after all subjects have completed 
all study-related events. 


TIMERA
 Page 14
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
10 Data Handling and Record Keeping
10.1 Confidentiality and Data storage 
Primary research data will be stored at the NYU Center for Musculoskeletal Care, where study visits take 
place. Source documents will be stored in study binders, which will remain in a locked room/cabinet at the 
study facility.
10.2 Record keeping
Records of patients, source documents, monitoring visit logs, CRFs, inventory of study product, regulatory 
documents, and other sponsor correspondence pertaining to the study must be kept in the appropriate study 
files at the site.  Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical study necessary for the evaluation and 
reconstruction of the clinical study. Source data are contained in source documents (original records or 
certified copies). These records will be retained in a secure file for the period as set forth in the Clinical Study 
Agreement. 
10.3 Confidentiality and HIPAA
Information about study subjects will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following: 

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information 

The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e. that the subject is alive) at the end of their scheduled study period.
11 Ethical Considerations
This study is to be conducted accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures.
This protocol and any amendments will be submitted to a properly constituted Institutional Review Board 
(IRB). 
12 Cost and payment to the subjects 
Subjects will not have to pay for anything to be in this study. AstraZeneca will provide the study medication. 
Subjects will be reimbursed $50 per study visit that they complete. 


TIMERA
 Page 15
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
13 Supplemental Figure of Study Design
14 References
Altman, R., Alarcon, G., Appelrouth, D., Bloch, D., Borenstein, D., Brandt, K., Brown, C., Cooke, T.D., 
Daniel, W., Feldman, D., et al. (1991). The American College of Rheumatology criteria for the classification 
and reporting of osteoarthritis of the hip. Arthritis and rheumatism 34, 505-514.
Altman, R., Alarcon, G., Appelrouth, D., Bloch, D., Borenstein, D., Brandt, K., Brown, C., Cooke, T.D., 
Daniel, W., Gray, R., et al. (1990). The American College of Rheumatology criteria for the classification and 
reporting of osteoarthritis of the hand. Arthritis and rheumatism 33, 1601-1610.
Altman, R., Asch, E., Bloch, D., Bole, G., Borenstein, D., Brandt, K., Christy, W., Cooke, T.D., Greenwald, 
R., Hochberg, M., et al. (1986). Development of criteria for the classification and reporting of osteoarthritis. 
Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American 
Rheumatism Association. Arthritis and rheumatism 29, 1039-1049.
Arnett, F.C., Edworthy, S.M., Bloch, D.A., McShane, D.J., Fries, J.F., Cooper, N.S., Healey, L.A., Kaplan, 
S.R., Liang, M.H., Luthra, H.S., et al. (1988). The American Rheumatism Association 1987 revised criteria 
for the classification of rheumatoid arthritis. Arthritis and rheumatism 31, 315-324.
Cattaneo, M., Schulz, R., and Nylander, S. (2014). Adenosine-mediated effects of ticagrelor: evidence and 
potential clinical relevance. Journal of the American College of Cardiology 63, 2503-2509.
Celermajer, D.S., Sorensen, K.E., Gooch, V.M., Spiegelhalter, D.J., Miller, O.I., Sullivan, I.D., Lloyd, J.K., 
and Deanfield, J.E. (1992). Non-invasive detection of endothelial dysfunction in children and adults at risk of 
atherosclerosis. Lancet 340, 1111-1115.
Chan, E.S., and Cronstein, B.N. (2013). Mechanisms of action of methotrexate. Bulletin of the Hospital for 
Joint Disease 71 Suppl 1, S5-8.
Flammer, A.J., Sudano, I., Hermann, F., Gay, S., Forster, A., Neidhart, M., Kunzler, P., Enseleit, F., Periat, 


TIMERA
 Page 16
Version Date: October 27, 2016
CONFIDENTIAL
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in 
writing by the study sponsor
D., Hermann, M., et al. (2008). Angiotensin-converting enzyme inhibition improves vascular function in 
rheumatoid arthritis. Circulation 117, 2262-2269.
Gawaz, M., Langer, H., and May, A.E. (2005). Platelets in inflammation and atherogenesis. The Journal of 
clinical investigation 115, 3378-3384.
Gupta, S.K., Johnson, R.M., Saha, C., Mather, K.J., Greenwald, M.L., Waltz, J.S., Rehman, J., and Dube, 
M.P. (2008). Improvement in HIV-related endothelial dysfunction using the anti-inflammatory agent 
salsalate: a pilot study. Aids 22, 653-655.
Hansson, G.K. (2005). Inflammation, atherosclerosis, and coronary artery disease. The New England journal 
of medicine 352, 1685-1695.
Liang, Y.L., Teede, H., Kotsopoulos, D., Shiel, L., Cameron, J.D., Dart, A.M., and McGrath, B.P. (1998). 
Non-invasive measurements of arterial structure and function: repeatability, interrelationships and trial sample 
size. Clinical science 95, 669-679.
Meune, C., Touze, E., Trinquart, L., and Allanore, Y. (2010). High risk of clinical cardiovascular events in 
rheumatoid arthritis: Levels of associations of myocardial infarction and stroke through a systematic review 
and meta-analysis. Archives of cardiovascular diseases 103, 253-261.
Patti, G., Grieco, D., Dicuonzo, G., Pasceri, V., Nusca, A., and Di Sciascio, G. (2011). High versus standard 
clopidogrel maintenance dose after percutaneous coronary intervention and effects on platelet inhibition, 
endothelial function, and inflammation results of the ARMYDA-150 mg (antiplatelet therapy for reduction of 
myocardial damage during angioplasty) randomized study. Journal of the American College of Cardiology 
57, 771-778.
Prevoo, M.L., van 't Hof, M.A., Kuper, H.H., van Leeuwen, M.A., van de Putte, L.B., and van Riel, P.L. 
(1995). Modified disease activity scores that include twenty-eight-joint counts. Development and validation in 
a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis and rheumatism 38, 44-48.
Sattar, N., McCarey, D.W., Capell, H., and McInnes, I.B. (2003). Explaining how "high-grade" systemic 
inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 108, 2957-2963.
Solomon, D.H., Goodson, N.J., Katz, J.N., Weinblatt, M.E., Avorn, J., Setoguchi, S., Canning, C., and 
Schneeweiss, S. (2006). Patterns of cardiovascular risk in rheumatoid arthritis. Annals of the rheumatic 
diseases 65, 1608-1612.
Sorensen, K.E., Celermajer, D.S., Spiegelhalter, D.J., Georgakopoulos, D., Robinson, J., Thomas, O., and 
Deanfield, J.E. (1995). Non-invasive measurement of human endothelium dependent arterial responses: 
accuracy and reproducibility. British heart journal 74, 247-253.
van Gestel, A.M., Prevoo, M.L., van 't Hof, M.A., van Rijswijk, M.H., van de Putte, L.B., and van Riel, P.L. 
(1996). Development and validation of the European League Against Rheumatism response criteria for 
rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World 
Health Organization/International League Against Rheumatism Criteria. Arthritis and rheumatism 39, 34-40.
Ward, M.M., Guthrie, L.C., and Alba, M.I. (2014). Clinically important changes in individual and composite 
measures of rheumatoid arthritis activity: thresholds applicable in clinical trials. Annals of the rheumatic 
diseases.
Warnholtz, A., Wild, P., Ostad, M.A., Elsner, V., Stieber, F., Schinzel, R., Walter, U., Peetz, D., Lackner, K., 
Blankenberg, S., et al. (2009). Effects of oral niacin on endothelial dysfunction in patients with coronary 
artery disease: results of the randomized, double-blind, placebo-controlled INEF study. Atherosclerosis 204, 
216-221.
Weinblatt, M.E. (2013). Methotrexate in rheumatoid arthritis: a quarter century of development. Transactions 
of the American Clinical and Climatological Association 124, 16-25.