COOrdinating CaRDIology CliNics RAndomized Trial of Interventions to Improve OutcomEs (COORDINATE) - Diabetes
Phase: NA
Conditions: Diabetes Mellitus, Type 2, Cardiovascular Diseases
Sponsor: Duke University

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V 25 October 2021 
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PROTOCOL 
Protocol Title: 
COOrdinating CaRDIology CliNics RAndomized Trial of Interventions to Improve OutcomEs 
(COORDINATE) - Diabetes 
Protocol Number: Pro00101556 
Study Phase: 
Phase 4  
Short Title:  
COORDINATE-Diabetes 
Principal Investigator:  
Christopher B. Granger, M.D.  
Regulatory Sponsor: 
Duke Clinical Research Institute 
Funding Source:  
Boehringer Ingelheim Pharmaceuticals, Inc. and Lilly USA, LLC  
Legal Registered Address:  
Duke Clinical Research Institute - Duke University 
300 W. Morgan St. 
Durham, NC  27701 
This document contains information that is privileged or confidential and may not be 
disclosed unless such disclosure is required by applicable laws and regulations. The 
information in this document is the property of Duke Clinical Research Institute (DCRI) 
and may not be reproduced, published, or disclosed to others without written 
authorization from DCRI.  
NCT03936660

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Contents 
Contents ..........................................................................................................................................2 
List of Tables ..................................................................................................................................2 
1. 
Protocol Summary ..........................................................................................................3 
1.1 
Rationale ...........................................................................................................................3 
1.2 
Trial Outcomes .................................................................................................................6 
2. 
Overall Design .................................................................................................................9 
3. 
Disclosure Statement ......................................................................................................9 
4. 
Study Arms, Data Collection, and Duration ................................................................9 
4.1 
Basic Education Arm ........................................................................................................9 
4.2 
Intensive Educational Intervention Arm .........................................................................10 
4.3 
Study Duration ................................................................................................................12 
4.4 
Clinic-Level Data Collection ..........................................................................................12 
5. 
Independent External Review Committee ..................................................................13 
6. 
Safety Management and Reporting of Adverse 
Events/Serious Adverse Events....................................................................................14 
6.1 
Definition of Adverse Events .........................................................................................14 
6.2 
Adverse Event and Serious Adverse Event Collection and 
Reporting ........................................................................................................................15 
7. 
Statistical Hypotheses, Randomization, and Sample Size 
Determination................................................................................................................16 
7.1 
Hypothesis ......................................................................................................................16 
7.2 
Randomization ................................................................................................................16 
7.3 
Sample Size Determination ............................................................................................17 
7.4 
Planned Statistical Analysis ............................................................................................17 
8. 
Electronic Health Record Study Plan .........................................................................18 
8.1 
EHR Study Cohort Creation and Longitudinal Assessment ...........................................18 
8.2 
Query Creation, Distribution, and Return .......................................................................18 
8.3 
Cohort Identification Query Impact ................................................................................19 
9. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ...............................................................................................................20 
9.1 
Regulatory and Ethical Considerations...........................................................................20 
9.2 
Informed Consent Process ..............................................................................................20 
9.3 
Data Protection ...............................................................................................................21 
9.4 
Participant Engagement ..................................................................................................21 
10. 
References ......................................................................................................................21 
 
 
List of Tables 
Table 1. 
Trial Summary Table .......................................................................................... 4 
Table 2. 
Trial Outcomes Table .......................................................................................... 7 
Table 3. 
Patient-Level Data Collection by the Site for Both Arms ............................... 132 
 
 
 

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1. 
Protocol Summary 
1.1 
Rationale 
Type 2 diabetes mellitus (T2DM) is an established independent risk factor for atherosclerotic 
cardiovascular disease (CVD) and is responsible for nearly 2.2 million deaths each year from 
ischemic heart disease and stroke worldwide.  Despite the enormous public health burden of 
T2DM, critical knowledge gaps exist with regard to contemporary patterns of diabetes 
management, quality of care, and long-term outcomes.  Greater understanding is needed on how 
evidence-based therapies and CVD risk management strategies influence long-term risk 
trajectories in patients with T2DM.  
The most important adverse outcomes for patients with T2DM are cardiovascular, including 
cardiovascular death.  Now, there are a variety of evidence-based treatments to reduce 
cardiovascular risk for patients with T2DM.  These include treatment of risk factors like 
hypertension and hyperlipidemia, avoiding smoking, diet and exercise, and use of anti-
hyperglycemic therapies proven to prevent cardiovascular outcomes.  Sodium-glucose 
cotransporter-2 (SGLT2) inhibitors and Glucagon-like peptide 1 (GLP-1) receptor agonists have 
recently been shown to be protective for patients with T2DM and cardiovascular disease or CVD 
risk.1, 2 
Despite proven effective therapies, they are used in a minority of patients who would benefit.  
Possible barriers to uptake include lack of “ownership” over prescribing these medications 
(primary care provider vs endocrinologist/diabetes care specialist vs cardiologist), lack of 
familiarity and comfort with prescribing these medications, lack of a system to measure and 
provide feedback on performance, and lack of a comprehensive clinical pathway to provide 
multi-disciplinary evidence-based care to patients with T2DM and CVD.3 
The most important opportunity to improve care is to more effectively implement proven risk 
factor management and tailored therapies.  There is a critical need to show how effective 
treatments can be implemented at the clinic level.  Few studies have been conducted in a 
rigorous way to test strategies to potentially improve implementation.      
COORDINATE-Diabetes is a cluster-randomized clinical trial to test the effectiveness of an 
innovative, clinic-level educational intervention to improve the management of patients with 
T2DM and CVD. The trial will be performed and interpreted in the context of clinical diabetes 
care in the U.S. using data from select electronic health record (EHR) sites. A subset of sites with 
EHR data available for querying in existing datamarts will be recruited to participate in two 
EHR-focused objectives: 1) to perform a baseline characterization of patients with T2DM and 
CVD, including demographics, treatment patterns and healthcare utilization such as 
hospitalization; and 2) to assist with the identification of patients eligible for the educational 
intervention trial. 
What follows is the protocol for the COORDINATE trial; the objectives and planned analyses of 
data from EHR sites is summarized in section 8 of this protocol. 
 
 

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Table 1. 
Trial Summary Table 

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Patient-level 
Inclusion and 
Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site-Level Inclusion 
Criteria 
Sites will be recruited based on sufficient patient volume, cardiologist and 
endocrinologist or diabetes care specialist commitment, and site capacity to 
perform the trial as well as ability to effectively communicate with the study team 
and patients. Attempts will be made to achieve geographic, investigator, and 
patient diversity.  
Individual patients eligible to enroll in the trial will have a diagnosis of T2DM 
and cardiovascular disease as listed in the Inclusion Criteria.  
Patient Inclusion Criteria: 
1. Age ≥ 18 years old 
2. Diagnosis of Type 2 diabetes mellitus (T2DM) as reported in the patient’s 
medical records.   
3. History of at least one of the following conditions: 
a. Coronary artery disease (defined as prior MI, coronary 
revascularization (CABG or PCI), and/or obstructive CAD (≥50%) as 
documented by angiography or CTA) 
b. Stroke and/or carotid artery stenosis (≥50%)  
c. Peripheral Arterial disease (defined as claudication with ABI<0.9, 
prior peripheral revascularization, and/or amputation due to 
circulatory insufficiency) 
4. Baseline composite score of guideline recommended therapy of <3 at baseline 
entry into the trial. Patients would receive a score of 1 for each of the 
following care elements: 
 
ACEi/ARB therapy 
 
High-intensity statin 
 
Most recent HbA1c<7% on metformin monotherapy 
5. Ability to communicate with site staff and understand and provide written 
informed consent and proof of Health Insurance Portability and 
Accountability Act (HIPAA) authorization 
Patient Exclusion Criterion: 
1. Determined to be highly unlikely to survive and/or to continue follow-up in 
that clinic for at least 1 year, as identified by site investigator  
2. GFR<30 mL/min/1.73m2 
3. Baseline composite score of 3 for guideline recommended therapy (as 
outlined in Patient Inclusion Criterion #4) 
4. Absolute contraindication to any of the 3 guideline recommended therapies 
(as outlined in Patient Inclusion Criterion #4) 
5. Already taking SGLT2i or GLP1RA therapy at baseline. 
Site Inclusion Criteria: 
1. Cardiology clinic that is willing and able to perform the interventions in the 
trial to improve the quality of care of their patients with T2DM and CVD. 
2. Have a cardiologist and endocrinologist or diabetes care specialist (for 
example, a PCP with experience in treating diabetes) who are willing to 
partner for the trial needs of creating and implementing care pathways with 
the support of the COORDINATE Diabetes Study Team; any site that has a 
highly organized partnership with cardiology-endocrinology with care 
pathways already established will not be included.   

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3. Presence of an electronic health record (EHR) system that will enable 
identification and follow-up of patients. 
Study Design 
The design is a cluster-randomized clinical implementation trial of a minimum of 
42 cardiology clinics in the United States. Sites will be randomized to a basic 
education arm or an intensive educational intervention arm, consisting of clinic-
level multifaceted educational intervention with the aim to improve evidenced-
based care for patients with diabetes and cardiovascular disease. The aim is to 
enroll approximately 25 patients at each site. The primary outcome is the 
proportion of patients achieving guideline-recommended management of diabetes 
and cardiovascular disease measured as a composite score of 3 at the last follow-
up visit. 
Treatment 
Regimen(s) 
Participants will receive care at their physicians’ discretion.  
 
The patients receiving care in clinics that are randomized to the intensive 
educational intervention arm will be cared for by cardiologists and staff 
where a multifaceted implementation program will be conducted to 
improve the use of guideline-recommended therapies for patients with 
T2DM and CV disease.  
 
The patients receiving care in clinics that are randomized to the basic 
education arm will be treated by clinicians who receive only basic 
information about guideline-based therapy. 
Duration of Study 
Participation 
Data collection will continue for all participants for 6 to 12 months after 
enrollment. For those who provide Social Security number information, we may 
collect vital status at up to 5 years following the last follow-up visit. 
End of Study 
Definition 
The trial will last for 6 to 12 months for all participants. Participants can 
withdraw from the trial at any time. Vital status will be obtained from all 
participants at the last follow-up visit. Vital status may be collected from the 
National Death Index at up to 5 years following the last follow-up visit. 
Minimum Number 
of clusters (Sites) 
Required 
42  
Average cluster size 
25 patients (yielding a total of 1050 patients) 
Total Sample Size 
Approximately 1050 patients* 
* Need to maintain an overall average of 25 pts per site from 42 sites 
 
1.2 
Trial Outcomes  
A variety of clinical, process of care, and implementation outcomes will be assessed in the trial. 
Primarily, we will measure whether our intensive education intervention successfully changes 
provider behavior and improves secondary prevention management in patients with T2DM and 
CVD by collecting and analyzing patient level data. Therefore, our outcomes will assess 
differences at the last follow-up visit in guideline-recommended therapy between the basic 
education and intensive education intervention groups.  
 

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Table 2. 
Trial Outcomes Table 
Trial Objectives 
Trial Outcomes  
Primary Objectives 
 
To test effectiveness of implementing a clinic-
level multifaceted intervention that includes 
establishing cardiology and endocrinology 
partnerships and evidence-based care pathways to 
improve the medical management and care of 
patients with T2DM and cardiovascular disease.   
 
 
The trial will examine the impact of the 
educational intervention on provider adherence to 
guideline-recommended therapy, which is the 
primary outcome, defined as the proportion of 
patients achieving guideline-recommended 
management for T2DM and CVD at the last 
follow-up visit, as initiated or confirmed by a 
cardiologist for all of the following (composite 
score of 3): 
 
1. Use of a regimen which includes an anti-
hyperglycemic agent indicated and/or 
guideline recommended to reduce 
cardiovascular risk* 
a. Acceptable alternative: metformin 
monotherapy with HbA1c<7%  
2. Guideline-recommended medical therapy* 
with ACEi/ARB 
3. Guideline-recommended medical therapy* 
with high-intensity statin: atorvastatin 40-
80mg daily OR rosuvastatin 20-40mg daily 
 
*As new consensus or evidence emerges and 
guidelines are updated, the composite score and 
requisites will be evaluated by the Steering 
Committee for needed updates on an ongoing 
basis. For the first component of the primary 
outcome (related to anti-hyperglycemic agents), 
patients will be evaluated according to the list of 
“indicated and/or guideline recommended” agents 
in effect at the time of their last follow-up visit. 
This decision was approved by the Steering 
Committee. Medications started during the study 
follow-up period that receive FDA 
indication/guideline recommendation during that 
time will count towards the primary outcome. 
 
It is important to note that the FDA indications 
and guideline recommendations will only become 
more liberal with time, not more restrictive. Of 
note, patients who are on any GLP1-RA or 
SGLT2i therapy at baseline will not be eligible for 
enrollment. 
Secondary Objectives 
 
 
 
All of the following secondary outcomes will be 
assessed at the last follow-up visit. 

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Assessment of cardiology provider behavior as 
measured by the following cardiologist-initiated 
medications for diabetes suggested by guidelines 
and FDA approved for CVD risk reduction: 
 
Proportion of patients achieving guideline-
recommended therapy for T2DM 
 
Proportion of patients with an ACEi/ARB 
treatment  
 
Proportion of patient with a high-intensity 
statin treatment  
 
Variations on the Primary Outcome: 
 
Proportion of patients achieving a 
composite score of ≥ 2 
 
Intermediate Outcomes: 
 
Changes from baseline to the last 
follow-up visit in the following: sBP, 
dBP, HbA1c, LDL-C 
 
Change from baseline to the last 
follow-up visit in proportion of 
patients achieving the following 
targets (individually and in 
combination): sBP<130 mmHg, 
dBP<80 mmHg, HbA1c<7%, LDL-
C<70 mg/dL 
 
Clinical time-to-event outcomes (While the 
primary outcome will be measured as of the 
last follow-up visit, data on clinical outcomes 
will be collected throughout the follow-up 
period for each patient): 
 
Composite of all-cause death; 
hospitalization for: MI, stroke, 
decompensated heart failure, or urgent 
revascularization (coronary, 
peripheral, carotid) 
 
Each of the clinical time-to-event 
outcomes will also be assessed 
individually 
Exploratory Objectives 
 
 
The following may be assessed at up to 5 years in 
patients who have provided social security number 
information: 
- all-cause mortality, as assessed by vital status 
obtained through the National Death Index 
Implementation Objectives 
 
 
 
 
 
Provider-level implementation outcomes: 
 
Acceptability 
 
Appropriateness 

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Since assessing differences in clinical outcomes is not the primary objective of this study, clinical 
events will not be independently adjudicated. 
2. 
Overall Design 
The design is a cluster-randomized clinical implementation trial of a minimum of 42 cardiology 
clinics in the United States. Clinics will be selected based on an interest in improving the quality 
of care of their patients with T2DM and CVD. Further, the clinics will need to demonstrate that 
they can identify and financially support the efforts of a clinical site leadership pair, consisting of 
an endocrinologist or diabetes care specialist and a cardiologist. Enrolled clinics will be 
randomized in a ratio of 1:1 either to a basic education arm or an intensive educational 
intervention arm. Each clinic will then enroll approximately 25 patients who have T2DM, CVD, 
and a baseline composite score < 3 at study entry. The study will be open-label, and 
randomization of clinics will be stratified according to clinic-level factors, including: 
 Site location : Urban or non-urban 
Randomization of clinics will occur after each clinic has been screened and deemed eligible— 
willing to participate in the trial and has IRB approval.  
3. 
Disclosure Statement 
This is a multifaceted implementation trial randomized at the clinic level to 2 arms, 1 intense 
educational intervention and 1 basic education or what is also referred to in these types of studies 
as usual care. 
4. 
Study Arms, Data Collection, and Duration 
4.1 
Basic Education Arm 
Clinics in the basic education arm will continue current standard of care (SOC). Sites will be 
compensated for their involvement including for patient recruitment and assessments. They will 
also receive basic education at study start to include the most updated ACC/AHA guidelines for 
cholesterol management and from the ADA about diabetes management as well as periodic 
educational updates.2, 5, 6 They will also receive clinic-level education related to drug safety, 
including statin side effects and potential side effects of anti-diabetes medications with CV 
benefit (such as hypoglycemia, DKA, etc.). Beyond this basic information, sites (and physicians) 
in the basic education arm will not receive other instructions or intensive educational 
interventions. They will be left to care for their patients as they normally would. Patients in the 
basic education arm will be seen by their healthcare provider at baseline, either in clinic or via 
virtual visit, per local standard of care. Follow-up visits (i.e., standard of care in-person or virtual 
visit, or telephone call) will be conducted by enrolling sites in the basic arm at 6 months from 
baseline visit, and at up to 12 months from baseline visit, with a maximum of two visits. The 
overall length of follow-up will be 6 to 12 months, with all patients having a minimum of 6 
months of follow-up.  The date of the last follow-up visit determined by the patient’s enrollment 
date. Data collected will be entered into an electronic data capture system. Clinic visits should be 
conducted as per standard of care. 

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4.2 
Intensive Educational Intervention Arm 
The cardiology clinics in the intensive educational intervention arm will receive guidance to 
develop an integrated, multi-disciplinary care pathway for patients with T2DM and CVD. The 
cardiologist and endocrinologist/diabetes care specialist co-PIs at each site will oversee this 
development. Prior to study start, a Manual of Operations will be developed by the trial team in 
conjunction with the trial Steering Committee. This manual will be available for dissemination 
after trial completion. It will build on professional society guidelines (such as ADA, ACC, as 
described in the primary endpoint) and will consist of evidence-based standards of care that 
should be included in the clinical pathway implemented at each site. Though these standards may 
be adapted to meet the needs of each individual site, the core components of the care pathway 
will be consistent across intensive educational intervention sites. Throughout the intervention, 
the care teams will be encouraged to communicate with the primary care physicians of individual 
patients to facilitate a team approach to patient care. Though the intensive educational 
intervention will not be specifically targeted towards primary care physicians, they are an 
integral part of optimal patient care and will be kept engaged throughout. 
The intensive educational intervention will consist of the following: 
 Each clinic is assigned a mentor pair of specialists from the COORDINATE-Diabetes 
National Academy Faculty (a cardiologist and endocrinologist/diabetes care specialist) and a 
DCRI quality improvement (QI) specialist (the “COORDINATE-Diabetes Trio”) 
 Each site’s clinic leadership pair and research coordinators will attend an implementation 
training session virtually conducted by the COORDINATE-Diabetes Trio. 
 This COORDINATE-Diabetes Trio will conduct a health system and clinic site visit prior to 
implementation training. This visit may be conducted on-site or virtually.  During the visit, 
the Trio will: 
o Conduct a health system-wide grand rounds education program (if possible) on 
identification and care of the cardiovascular diabetic population, and 
o Meet with the clinic leadership pair (cardiologist and endocrinologist/diabetes care 
specialist) and the research coordinator. The clinical leadership pair, research 
coordinator, patient advocate, and study staff (for prior authorizations and patient 
education) will constitute the core study team at each clinic site, and 
o Respond to the clinic’s current practice, care processes, and available outcomes data 
from the site survey, and help the clinic team develop a GAP analysis. This GAP 
analysis will be specific to each site. Each site will formally submit this GAP analysis 
within 2 weeks of site visit to the DCRI Project Lead. 
 The COORDINATE-Diabetes Trio assigned to each clinic site will work with the clinic site 
study team to establish the final Clinic Action Plan. This Clinic Action Plan will be largely 
based on the Standard Manual of Operations developed by the COORDINATE-Diabetes 
study team, but may include some site-specific adaptations as deemed necessary by each site 
team. The implementation of any adaptations and their content will be recorded in the study 
database. 
 Clinic healthcare providers will receive disease specific and study implementation training 
(Qualtrics Modules). 
Specific Educational Intervention site activities conducted by the COORDINATE-Diabetes staff 
will include: 

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 Building a multidisciplinary clinic site team (cardiology and endocrinology/diabetes care 
specialist leadership pair, site research coordinator, patient advocate, staff for prior 
authorization and patient education) 
 Conducting clinic-level education related to trial protocol, 2019 ADA guidelines5, 6, 2013 
ACC/AHA guidelines for management of blood cholesterol9, data from recent cardiovascular 
outcomes trials in diabetes, safety education related to prescribed medications (example, 
hypoglycemia, DKA), and FDA label indications for relevant medications. 
 Conducting clinic-level education related to drug safety, including statin side effects and 
potential side effects of anti-diabetes medications with CV benefit (such as hypoglycemia, 
DKA, etc). 
 Helping site teams refine and implement a care pathway for managing diabetes and CV risk 
factors.  
 Implementing audit and feedback system to improve the management of individual patients, 
and to improve systems of care in the clinics. We will establish a trial database that will 
provide regular reports to each clinical site team. The reports will track the progress of each 
enrolled patient against pre-defined metrics (as per the primary outcome) over time, and will 
also provide aggregate data across all patients in a given site. These reports will be sent to 
site teams monthly, with the expectation that the site teams will review them monthly. In 
addition, reports from each site will be reviewed quarterly by the COORDINATE-Diabetes 
National Academy Faculty, in conjunction with the clinical site teams. Feedback to providers 
at each site will occur in relation to specific enrolled patients who have yet to achieve 
optimal care (as per the primary outcome), and will largely be carried out through direct 
communication between the clinical site team and the providers. In addition, EHR-based 
communication may be employed at sites with this capability. 
Specific intervention site activities targeted towards the study site staff will include: 
 Educating in evidence-based management of patients with T2DM and CVD, as outlined 
above. This will occur at start of patient enrollment and will be standardized across sites, 
with at least one planned “booster” session during enrollment that will also be standardized 
across sites. Additional education sessions will be provided at the discretion of the clinic site 
teams who are monitoring the care being provided at each clinic, tailored to the needs of that 
specific clinic. 
 Administering questionnaires at study end to assess provider perspectives on the intervention. 
Questionnaires have been developed for individual studies in the past, and we will draw from 
standard approaches used in prior similar successful studies (including IMPACT-AF).4, 10  
 Assessing intervention acceptability and appropriateness via questionnaire at end of study, 
including assessing feedback from providers. We will develop these questionnaires to be 
specific to our intervention.  
Specific educational intervention site activities that will directly involve patients will include: 
 Consent of patients 
 Clinic visits: Patients in the intense intervention arm will be seen by their healthcare provider 
at baseline, either in clinic or via virtual visit, per local standard of care. Follow-up visits 
(i.e., standard of care in-person or virtual visit, or telephone call) will be conducted every 
three months by enrolling sites in the intervention arm.  All patients in the intervention arm 
will have two to four follow-up visits, with a minimum of 6 months of follow-up.  The 
overall length of follow-up will be 6 to 12 months.  The date of the last follow-up visit will 

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be determined by the patient’s enrollment date. Patient reported prescription data for 
medications of interest will be validated by sites via medical record collection. All data 
collected will be entered into an electronic data capture system. Clinic visits should be 
conducted as per standard of care.  
 Labs: The following laboratory assessments are collected from the patient’s electronic health 
record and are recommended as part of standard of care in all patients at baseline and at the 
last follow-up visit: basic metabolic panel, HbA1c, lipid panel. As part of standard of care, 
providers will be encouraged to also order a basic metabolic panel 1-2 weeks after each 
dosage change in ACEi/ARB, HbA1c every 3 months until it is <8%, and lipid panel 8 weeks 
after each statin dose titration. In summary, sites will be educated to guidelines and will not 
be mandated to collect specific labs at specific times from patients enrolled for the purpose of 
the study. Rather, the study will be collecting data including labs that have been performed as 
part of standard of care and are not required as part of the study. 
 
In both study arms, we will evaluate and compare various methods to communicate with and 
engage patients throughout the study. These engagement efforts may focus on encouraging the 
patients to enroll/comply with study requirements, and/or may focus on encouraging the patient 
to be engaged in their own health care, knowledgeable about their disease state(s), and adherent 
to their medications. 
4.3 
Study Duration 
Follow-up for the overall study will end approximately 6 months after enrollment of the final 
participant.  Participants will be followed for 12 months, except for those enrolled in the final 6 
months of enrollment, who will have their follow-up complete at a minimum of 6 months.  Thus, 
the last patient enrolled will have 6 months of follow-up, a patient enrolled 3 months before the 
end of enrollment will have 9 months of follow-up, and a patient enrolled 6 months before the 
end of enrollment will have 12 months of follow-up.  Shortly following the completion of 
enrollment, study sites will be notified of a specific date on which follow-up will conclude.   
4.4 
Clinic-Level Data Collection 
The following data will be collected in the clinic. All data will be entered by site personnel using 
an electronic data capture (EDC) system.  Access to the EDC system, IBM Clinical 
Development, employed for collection of the patient data will be controlled centrally by the 
DCRI through distribution of EDC study specific access codes.  DCRI data export services 
establishes regular exports of the data to be stored on the DCRI server. 
Baseline 
 Geographic classification: Urban vs non-urban will be collected by the DCRI study team 
prior to site activation. 
 
12 Months or End of Study (intervention sites only) 
A provider survey to be completed by the site investigator will be conducted to collect the 
following information: 
 Acceptability of educational intervention  
 Appropriateness of educational intervention  
 

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Table 3. Patient-Level Data Collection by the Site for Both Arms (gray shade denotes data 
that will be assessed in the intense education intervention arm only) 
 
Baseline 
3 months 
6 months 
9 months 
12 months  
Required 
contact 
w/ 
patient 
1) Informed 
Consent 
2) SSN # 
(unless 
patient opts 
out) 
3) Medications 
of interest, as 
reported by 
the patient 
 
Telephone (or 
visit if done as 
SOC between 2-4 
months after 
enrollment) 
 
1) Vital Status 
2) Medications 
of interest, as 
reported by 
the patient 
 
Telephone (or 
visit if done as 
SOC between 5-7 
months after 
enrollment) 
 
1) Vital status 
2)  Medications 
of interest, as 
reported by 
the patient 
3)  Clinical 
events 
assessment 
as reported 
by the 
patient 
Telephone (or 
visit if done as 
SOC between 8-
10 months after 
enrollment) 
 
1) Vital Status 
2) Medications 
of interest, as 
reported by 
the patient 
 
Telephone (or 
visit if done as 
SOC between 11-
13 months after 
enrollment) 
 
1) Vital Status 
2) Medications of 
interest, as 
reported by the 
patient 
3) Clinical events 
assessment as 
reported by the 
patient 
 
 
Required 
health 
record 
check 
1) Demographics 
(age, sex, race) 
2) Baseline visit 
vital signs (sBP, 
dBP, BMI) 
3) Most recent 
lab values 
(HbA1c, LDL-C, 
BMP) 
4) Medications of 
interest 
prescribed, as 
collected from 
health record 
1) Medications of 
interest 
prescribed, as 
collected from 
health record 
 
1) Medications of 
interest 
prescribed, as 
collected from 
health record 
2) Clinical events 
assessment, as 
collected from 
health record 
1) Medications of 
interest 
prescribed, as 
collected from 
health record 
 
1) Most recent 
vital signs (sBP, 
dBP, BMI), as 
collected from 
the health record 
2) Most recent 
lab values 
(HbA1c, LDL-C, 
BMP), as 
collected from 
the health record 
3) Medications 
prescribed, as 
collected from 
the health record 
4) Clinical events 
assessment, as 
collected from 
health record  
 
In addition to the above data collected by sites, the DCRI coordinating center may assess all-
cause mortality by using patient social security numbers to access the National Death Index. 
Vital status may be assessed for all patients who have provided SSN at up to 5 years after last 
patient follow-up visit. 
5. 
Independent External Review Committee 
This committee will be an independent body that will provide critical, independent, and unbiased 
review of all components of the trial during the design, conduct, and dissemination phases. The 
committee will be responsible to assure the trial is being conducted in a way to assure patient 

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safety and thus will periodically review safety and clinical outcome data.  This committee is 
analogous to a Data and Monitoring Committee to ensure protection of human participants. The 
committee may consist of 2 experts who meet several times over the course of the project and 
who will assess data. The data will be provided to the Independent External Review Committee 
via summary reports compiled by a statistician and programmer.   After review of the data, they 
will make recommendations to the steering committee if trial modification is needed to assure 
patient safety or improve trial integrity. A charter for this committee will be developed prior to 
start of study. 
6. 
Safety Management and Reporting of Adverse Events/Serious 
Adverse Events 
6.1 
Definition of Adverse Events 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. 
Adverse drug reaction (ADR) 
An adverse drug reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse drug reactions may 
arise from use of the product within or outside the terms of the marketing authorization or from 
occupational exposure. Conditions of use outside the marketing authorization include off-label 
use, overdose, misuse, abuse and medication errors. 
Serious adverse event 
A serious adverse event is defined as any AE which 
 results in death 
 is life-threatening  
 requires in-patient hospitalization or prolongation of existing hospitalization  
 results in persistent or significant disability or incapacity or is a congenital anomaly/birth 
defect  
Life-threatening in this context refers to a reaction in which the patient was at risk of death at the 
time of the reaction; it does not refer to a reaction that hypothetically might have caused death if 
more severe. 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse. Any suspected transmission via a medicinal product of an infectious agent is also 
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6.2 
Adverse Event and Serious Adverse Event Collection and Reporting 
If an adverse drug event is reported by the patient participant during the COORDINATE-
Diabetes study, the patient participant will be instructed to contact his or her study physician. 
The study physician is responsible for reporting via MedWatch, the FDA Safety Information and 
Adverse Event Reporting Program. The site Primary Investigator will be responsible for safety 
reporting AEs which occur during the conduct of the study to the competent regulatory 
authorities, accredited Institutional Review Boards and/or Independent Ethics Committee(s) 
(IRB/IEC(s)) in accordance with the applicable laws and regulations. 
Adverse event reporting to Boehringer-Ingelheim (BI) 
Each site shall report  
(i) 
all ADRs (serious and non-serious)  
(ii) 
all AEs with fatal outcome  
(iii) 
pregnancies in female participants and partners of male participants 
that are associated with the BI Drugs administered for the disease in scope of the study (e.g., 
empagliflozin, linagliptin and its combinations by fax to the BI Unique Entry Point using BI 
NIS SAE report form in following timelines. 
BI Unique Entry Point: 
Boehringer-Ingelheim Pharmaceuticals, Inc. 
 
FAX: 1-203-837-4329 
All serious ADRs and AEs with fatal outcome shall be forwarded immediately (within 24 hours 
or next business day whichever is shorter). 
All non-serious ADRs and Pregnancy Monitoring Forms shall be forwarded within7 days. 
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.  
DCRI is responsible for training the sites regarding the safety reporting to BI based on the 
agreement, protocol and BI training material. 
Causal relationship of adverse event 
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse reaction, 
in contrast to an adverse event, is characterized by the fact that a causal relationship between a 
medicinal product and an occurrence is suspected.  
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history.  
Causality should be assessed for each event as either “yes” or “no.” No other variation should be 
reported.  
Intensity of adverse event 
The intensity of the AE should be judged based on the following: 

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Mild: 
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe: 
Incapacitating or causing inability to work or to perform usual activities 
The intensity of adverse events should be classified and recorded according to the CTCAE 
Criteria in the NIS SAE form. 
Pregnancy 
In rare cases, pregnancy might occur in a study. Once a participant has been enrolled into the 
study, after having taken BI Drug administered for the disease in scope of the study, the 
investigator must report any drug exposure during pregnancy, which occurred in a female subject 
or in a partner to a male subject to the Sponsor by means of BI Pregnancy Monitoring Form 
provided. 
Reporting of related adverse events associated with any other BI drug 
The investigator is encouraged to report all adverse events related to any BI drug other than BI 
Drugs used for the disease in scope of the study according to the local regulatory requirements 
for spontaneous AE reporting at the investigator’s discretion by using the locally established 
routes and AE report forms. The term AE includes drug exposure during pregnancy and, 
regardless of whether an AE occurred or not, any abuse, off-label use, misuse, medication error, 
occupational exposure, lack of effect, and unexpected benefit. 
7. 
Statistical Hypotheses, Randomization, and Sample Size 
Determination 
7.1 
Hypothesis 
The trial hypothesis is that the primary outcome (proportion of patients achieving guideline-
recommended management for T2DM and CVD at 12 months, as initiated or confirmed by a 
cardiologist, with a composite score of 3) will be higher in the intensive educational intervention 
arm than in the basic education arm.   
The null hypothesis is that the proportion of patients achieving guideline-recommended 
management for T2DM and CVD at the last follow-up visit, as initiated or confirmed by a 
cardiologist, with a composite score of 3 will be similar between the intensive intervention 
educational arm and basic education arm. 
7.2 
Randomization 
Site randomization: Site will be randomized when eligibility to participate in the trial has been 
established. To minimize imbalance between population characteristics in the basic education 
and intensive educational intervention groups, a stratified randomization based on geographic 
classification (urban or non-urban) will be implemented to ensure that selected site 
characteristics are balanced within each stratum. Site randomization will be conducted through a 
database platform using the randomization scheme (block randomization based on stratification 
factors) generated by the study statistician and uploaded by data management. Site management 
has a “button” on their web portal that they can select when a site is ready to be randomized 
(must have IRB approval and contract executed). Randomized site will receive an official email 
with their randomization status/assignment.  
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The following processes will be implemented: 
 Education before randomization, after randomization, and throughout the enrollment 
process that sites should AVOID enrolling only a certain type of patient (i.e., either high- 
or low-risk only) 
 Assessment of patient enrollment characteristics once 25% and 50% of patients have 
been enrolled in the trial overall and by site to ensure that baseline characteristics are 
similar in the basic education arm and intensive educational intervention arm. If an 
imbalance is observed, measures will be taken to visit the involved sites and remedy the 
issue with the on-site clinical leads. 
 Outcomes will be adjusted for differences in baseline characteristics, to be detailed in the 
statistical analysis plan. 
7.3 
Sample Size Determination 
The primary outcome is the proportion of patients receiving guideline-recommended therapy, 
defined as a composite score of 3 at the last follow-up visit. The primary analysis is based on the 
comparison of primary outcome between the basic education and intensive educational 
intervention arms. The sample size provides adequate power to detect a clinically meaningful 
effect size of at least a 10% difference between treatment arms in the proportions of patients 
achieving a composite score of 3 by the last follow-up visit.  
In this cluster-randomized trial, where the experimental unit is site, the effective sample size and 
power is impacted by intra-cluster correlation (ICC). For the primary outcome, the sample size 
calculation is based on the ability to detect at least a 10% difference between treatment arms in 
the proportion of patients achieving guideline-recommended management for T2DM and CVD 
with composite score of 3. The effect size of a 10% change has been chosen as a clinically 
meaningful difference between the intensive educational intervention and basic education arms. 
A minimum of 42 sites (“clusters”) with an average cluster size of 25 patients per site (a total of 
1050 patients) will provide at least 85% power to detect a 10% difference in the primary 
outcome between educational intervention arms through the last follow-up visit (6 to 12 months). 
This estimate of a minimum of 21 sites per arm (average of 25 patients per site) is based on the 
assumption of 10% of patients in the basic education arm, and at least 20% in the intensive 
educational intervention arm, receiving guideline-recommended therapy at the last follow-up 
visit, with an intra-correlation coefficient (ICC) of 0.05, and two-sided type I error rate of 0.05. 
The sample size/power calculations were carried-out using R function “n4props” in (package 
“CRT Size”).11  
7.4 
Planned Statistical Analysis 
An initial SAP defining the analysis populations, known covariates of interest, and procedures 
for handling missing and spurious data will be established and archived prior to enrollment of the 
first patient. The full statistical analysis plan (SAP) will be finalized before database lock. This 
section is a summary of the planned statistical analyses of the primary and secondary outcome. 
The primary outcome will be analyzed using a multivariable logistic regression model with a 
generalized estimating equations (GEE) using a compound symmetry working correlation matrix 
to account for the effect of clustering, as well as adjustment for potential baseline factors as 

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covariates (including the baseline composite score). This model will provide the estimated 
adjusted odds ratio and 95% CI. 
For time-to-event outcomes, multivariable Cox proportional hazards models with shared frailties 
to account for clustering effects will be used. Adjusted hazard ratio and 95% CI will be estimated 
from the Cox model after adjustment for pre-specified baseline factors. The complete list of pre-
specified adjustment variables will be described in the final study SAP. 
Baseline comparisons of participant characteristics in each arm will be summarized as the mean 
(SD), median (25th, 75th percentiles) for continuous variables, and as counts (percentages) for 
categorical variables. Differences in baseline participant characteristics between randomized 
arms will be compared using a Wilcoxon rank-sum test for continuous variables and the 
Pearson’s chi-square test or the Fisher’s exact test for categorical variables. All trial objectives 
will be analyzed using the intention-to-treat principle. 
The primary database lock is planned after the last patient enrolled has completed 6 months of 
follow-up. Patient death will be reported to BI as an adverse event if the patient was identified to 
be on a BI drug for the disease in focus of the study.   
   
8. 
Electronic Health Record Study Plan 
In addition to the educational interventional trial, an observational analysis will be conducted in 
tandem with a subset of sites with existing datamarts containing EHR data in a common data 
model (CDM) format. The objectives of this observational analysis are to describe the clinical 
characteristics, management, and outcomes of patients with T2DM and CVD in current practice 
across an array of health systems in the United States and to characterize trends in the quality of 
care for patients with T2DM and CVD over time.   
8.1 
EHR Study Cohort Creation and Longitudinal Assessment 
Early in the project period, a query to describe the clinical characteristics, management, and 
longitudinal outcomes of patients with T2DM and CVD will be distributed to sites participating 
in the EHR study. Out of approximately 80 data partner (DataMart) sites, at least 15 are expected 
to return results for this first query. Sites that return query results are expected to be both those 
that do participate in the trial, as well as sites that have no further engagement. The results of this 
query will help establish a broad, national baseline to better understand this population and their 
management.  
 
Additionally, for the EHR sites that participate in the trial, patient recruitment will be facilitated 
by use of a cohort identification query. This query will be programmed centrally and distributed 
to each site to run at desired intervals to identify patients with designated inclusion and exclusion 
criteria, as listed in the Patient Inclusion and Exclusion section of the Trial Summary table. 
Results of the cohort identification query will be utilized and remain at each site.  
8.2 
Query Creation, Distribution, and Return 
The EHR query will be carefully created with input from the clinical and educational 
intervention team to include all relevant characteristics and possible management practices. 
While the final set of data elements will be selected by the study team based on feasibility and 
clinical relevance, elements of interest include (but are not limited to) the following and will be 

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selected from the PCORnet Common Data Model (CDM) v4.0 (see 
http://www.pcornet.org/pcornet-common-data-model/): 
 
 Demographics (age, sex, race) 
 Laboratory values (creatinine, hemoglobin A1C) 
 Body mass index 
 Blood pressure  
 Comorbidities (hypertension, lipid disorders, cancer, pulmonary disease, heart failure, 
retinopathy, stroke/TIA, serious mental illness, atrial fibrillation) 
 Medications (antithrombotics, antihypertensives, ACEI/ARB, beta blockers, calcium 
channel blockers, antiarrhythmics, lipid lowering medications, diuretics, oral 
glucocorticoids, metformin, sulfonylureas, meglitinides, thiazolidinediones, GLP-1 
receptor agonists, SGLT2 inhibitors, DPP4 inhibitors).  
 Inpatient and outpatient encounters within the health system, including cardiovascular 
and non-cardiovascular hospitalizations  
Once all elements are defined, code lists comprising ICD9-10 codes and LOINC codes will be 
created so as to represent these elements according to the PCORnet CDM. From these code lists, 
the SAS-based queries will be programmed (i.e., query creation). As described below, queries 
are distributed to data partners via a secure file transfer system. Once received, data partners run 
the query locally against their standardized local data set, and then return the results of the query 
back for compilation (i.e., return). Data partners that are eligible to receive the baseline, 
descriptive query will be those that have populated the prescribing medication table according to 
the PCORnet CDM  and have passed all relevant data quality checks during the most recent 
round of data curation (i.e., updating, which is conducted quarterly).  
Participating EHR data partners will participate in a study cohort query in order to examine 
essential baseline, covariate, and outcome data to ensure they are correctly populated within the 
sites CDM and within acceptable boundaries of validity prior to responding to the descriptive 
queries. The study query package will be transmitted via a secure file transfer system which will 
be established for each participating site and which will be used for all queries and query results.  
Each data partner will execute the study query package locally and return results to the 
coordinating center for review and approval. Upon notification that the data partner is approved, 
they will receive the descriptive query package and return results which will be compiled into a 
report for the sponsor and be used to inform the study education and implementation plan.  
Analyses of these data will be detailed in a separate statistical analysis plan.  All query results 
will be published in a manuscript.   
8.3 
Cohort Identification Query Impact  
The estimated 10 EHR sites that participate in the educational intervention study will be supplied 
with a cohort identification query. This query captures inclusion and exclusion criteria available 
in the EHR and returns a list of potentially eligible participants for further consideration.  The 
query can be run as frequently as the participating site decides once it has been initially 
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9. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
9.1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 Applicable ICH Good Clinical Practice (GCP) Guidelines, where applicable 
 Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., advertisements) will be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
 
The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
 Notifying the IRB/IEC and the Funder, BI of SAEs or other significant safety 
findings as required by IRB/IEC procedures and in as described in section 1.2 of the 
protocol 
 Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
9.2 
Informed Consent Process 
 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 
 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
HIPAA (Health Insurance Portability and Accountability Act ) requirements, where 
applicable, and the IRB/IEC or study center. 
 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF. 
 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 

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9.3 
Data Protection 
 
Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
 
The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant. 
 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
9.4 
Participant Engagement  
The DCRI and BI/Lilly are committed to ensuring robust and diverse patient representation and 
engagement throughout the trial process – from trial design, to implementation, to dissemination 
of results.  The DCRI’s Research Together program provides access to DCRI thought leaders 
who understand the science of engagement and can advise on both patient and clinical 
engagement throughout the trial. 
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