Development and Evaluation of an Electronic Health Record-based Medication Complete Communication (EMC2) Strategy (Phase 2)
Phase: NA
Conditions: Medication Adherence
Sponsor: Northwestern University

 
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                                                                                                              B3D-US-B029 (STU00207507) 
Protocol B3D-US-B029 (STU00207507) NCT03652272 
Development and Evaluation of an Electronic health Record-based Medication Complete 
Communication (EMC2) Strategy 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical 
investigators.  It is the property of Eli Lilly and Company or its subsidiaries and should not be 
copied by or distributed to persons not involved in the this, study unless such persons are bound by a 
confidentiality agreement with Eli Lilly and Company or its subsidiaries.    
Note to Regulatory Authorities:  This document may contain protected personal data and/or 
commercially confidential information exempt from public disclosure.  Eli Lilly and Company 
requests consultation regarding release/redaction prior to any public release.  In the United States, 
this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be 
reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its 
subsidiaries. 
 
We will conduct a 2-arm, multi-site, physician-clustered randomized trial to evaluate the impact and 
scalability of the Phase I, finalized  EMC2 strategy to promote actual safe medication use. 
 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
 
 
Protocol Electronically Signed and Approved by Lilly on date provided below. 
 
 
 

 
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Table of Contents 
1. 
Synopsis ...................................................................................................................................6 
2. 
Schedule of Activities ..............................................................................................................8 
3. 
Introduction .............................................................................................................................9 
3.1. 
Pragmatic Study Rationale .................................................................................................9 
3.2. 
Background.........................................................................................................................9 
3.3. 
Benefit/Risk Assessment ....................................................................................................9 
4. 
Objectives and Endpoints ......................................................................................................11 
5. 
Pragmatic Study Design ........................................................................................................12 
5.1. 
Overall Design ..................................................................................................................12 
5.2. 
Number of Patients ...........................................................................................................14 
5.3. 
End of Study Definition....................................................................................................14 
5.4. 
Scientific Rationale for Pragmatic Study Design .............................................................14 
5.5. 
Justification for Dose ........................................................................................................14 
6. 
Study Population ...................................................................................................................15 
6.1. 
Inclusion Criteria ..............................................................................................................15 
6.2. 
Exclusion Criteria .............................................................................................................15 
6.2.1. 
Medical Conditions ..................................................................................................16 
6.2.2. 
Lifestyle Restrictions ...............................................................................................16 
6.3. 
Screen Failures .................................................................................................................16 
7. 
Treatments .............................................................................................................................17 
7.1. 
Treatments Administered .................................................................................................17 
7.2. 
Treatment Regimens .........................................................................................................18 
7.2.1. 
Packaging and Labelling ..........................................................................................18 
7.2.2. 
Medical Devices .......................................................................................................18 
7.3. 
Method of Treatment Assignment ....................................................................................18 
7.3.1. 
Selection and Timing of Doses ................................................................................18 
7.4. 
Blinding ............................................................................................................................18 
7.5. 
Dosage Modification ........................................................................................................18 
7.6. 
Preparation/Handling/Storage/Accountability .................................................................18 
7.7. 
Treatment Compliance .....................................................................................................18 
7.8. 
Concomitant Therapy .......................................................................................................18 
7.9. 
Treatment after the End of the Study ...............................................................................18 
7.9.1. 
Study Extensions [if applicable] ..............................................................................18 
7.9.2. 
Continued Access .....................................................................................................19 
7.9.3. 
Special Treatment Considerations [if applicable] ....................................................19 
7.9.4. 
Patient Follow-Up in Pragmatic Trials [if applicable] .............................................19 

 
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8. 
Discontinuation Criteria ........................................................................................................20 
8.1. 
Discontinuation from Pragmatic Study Treatment ...........................................................20 
8.1.1. 
Permanent Discontinuation from Study Treatment .................................................20 
8.1.2. 
Temporary Discontinuation from Study Treatment .................................................20 
8.1.3. 
Discontinuation of Inadvertently Enrolled Patients .................................................20 
8.2. 
Lost to Follow-Up ............................................................................................................20 
9. 
Pragmatic Study Assessments and Procedures ......................................................................21 
9.1. 
Effectiveness Assessments ...............................................................................................21 
9.1.1. 
Primary Effectiveness Assessments .........................................................................21 
9.1.2. 
Secondary Effectiveness Assessments .....................................................................21 
9.1.3. 
Appropriateness of Assessments ..............................................................................21 
9.2. 
Adverse Events .................................................................................................................22 
9.2.1. 
Complaint Handling .................................................................................................22 
9.3. 
Treatment of Overdose .....................................................................................................22 
9.4. 
Safety ................................................................................................................................22 
9.4.1. 
Electrocardiograms ..................................................................................................22 
9.4.2. 
Vital Signs ................................................................................................................22 
9.4.3. 
Laboratory Tests ......................................................................................................22 
9.4.4. 
Other Tests ...............................................................................................................22 
9.4.5. 
Safety Monitoring ....................................................................................................22 
9.5. 
Pharmacokinetics ..............................................................................................................22 
9.6. 
Pharmacodynamics ...........................................................................................................23 
9.7. 
Pharmacogenomics OR Genetics .....................................................................................23 
9.7.1. 
[Whole Blood and/or Saliva] Sample[s] for Pharmacogenetic 
Research ...................................................................................................................23 
9.8. 
Biomarkers and specify other analyses ............................................................................23 
9.8.1. 
Samples for Immunogenicity Research ...................................................................23 
9.9. 
Health Economics [OR] Medical Resource Utilization and Health 
Economics ........................................................................................................................23 
10. Statistical Considerations ......................................................................................................24 
10.1. Sample Size Determination ..............................................................................................24 
10.2. Populations for Analyses ..................................................................................................24 
10.3. Statistical Analyses ...........................................................................................................24 
10.3.1. 
General Statistical Considerations ...........................................................................24 
10.3.2. 
Treatment Group Comparability ..............................................................................25 
10.3.3. 
Efficacy Analyses ....................................................................................................25 
10.3.4. 
Safety Analyses ........................................................................................................27 
10.3.5. 
Pharmacokinetic/Pharmacodynamic Analyses ........................................................27 

 
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10.3.6. 
Other Analyses .........................................................................................................27 
10.3.7. 
Interim Analyses ......................................................................................................27 
11. Appendices ............................................................................................................................28 
Attachment 1. 
Abbreviations and Definitions............................................................................29 
Attachment 2. 
Clinical Laboratory Tests ...................................................................................30 
Attachment 3. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process .....................................................................................................31 
Attachment 1. 
References ..........................................................................................................35 
Attachment 2. Example Patient Portal Medication Questionnaire ................................................37 
Attachment 3. Example Health Literate MedSheet .......................................................................39 
Attachment 4. Study Drugs ............................................................................................................40 
 
List of Tables 
Table 
Page 
Table 1……………..…. ..................................................................................................................8 
Table 2 ………….. ........................................................................................................................11 
Table 3………………... ................................................................................................................12 
Table 4…………………. ..............................................................................................................13 
Table 5……………... ....................................................................................................................24 
 
List of Figures 
Figure 
Page 
Figure 1. Illustration of Study Design 
 
 
 
 
 
 
     18  
 
 

 
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List of Appendices 
Appendix 
Page 
Appendix 1. 
Abbreviations and Definitions ...........................................................................29 
Appendix 2. 
Clinical Laboratory Tests ..................................................................................30 
Appendix 3. 
Regulatory and Ethical Considerations, Including the Informed Consent 
Process ...............................................................................................................31 
Appendix 4. 
Example Health Literate MedSheet ..................................................................39 
Appendix 5. 
References .........................................................................................................40 
 

 
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1. Synopsis 
Title of Study: 
Development and Evaluation of an Electronic health Record-based Medication Complete Communication (EMC2) 
Strategy: A Pragmatic, Physician Randomized Trial 
 
Rationale:  
There is a well-documented need for effective interventions that can help patients understand and safely adhere to 
prescribed medications, particularly those with greater potential for harm if not taken correctly. We will leverage 
health and consumer technologies with our EHR-based Medication Complete Communication (EMC2) Strategy 
to: 1) inform patients about medication risks and safe use, 2) promote provider education and counseling about 
prescribed drugs and 3) monitor patient adherence outside of visits. The EMC2 Strategy could be feasible, sustainable, 
and readily available to ambulatory care practices. 
 
Objective(s)/Endpoints: 
Objectives 
Endpoints 
Primary 
• 
Test the effectiveness of the EMC2 Strategy, 
compared to usual care on improvement in  
patient knowledge of prescribed 
medications 
 
  
• 
 Medication-specific knowledge measured by 
demonstrated 
proper 
understanding 
of 
indication,   risks and benefits, and side effects  
at 3 months.  
 
 
• 
  
Secondary 
• 
Test the effectiveness of the EMC2 Strategy, 
compared to usual care on improvement in  
safe use and adherence to prescribed 
medications 
 
 
 
• 
Medication adherence measured by fill, time to 
fill, demonstrated proper use, and the ASK-12. 
at 3 months 
Tertiary/Exploratory 
• 
Evaluate the fidelity of the EMC2  Strategy 
 
  
 
 
 
 
• 
Patient report of provider counseling 
• 
Patient report of receipt of print Rx information 
• 
Completion of EHR portal survey 
• 
Clinic follow-up (yes or no) for patients 
identifying Rx concerns via portal survey 
 
 
 
 
 
 
 
 
 
Summary of Pragmatic Study Design:   
Study B3D-US-B029 (STU00207507) is a 2-arm, multi-site, physician-randomized pragmatic trial to evaluate the 
impact and scalability of the Phase I EMC2 strategy to promote safe medication use and adherence. 

 
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Treatment Arms and Duration:   
Usual Care. Usual care includes 1) variable provider counseling with limited or variable EHR notifications or 
counseling support; 2) no distribution of print medication information materials, including FDA Medication Guides 
in clinics and variable distribution in pharmacies; and 3) limited or no active surveillance of medication use post-
visits.  
 
Intervention: EMC2 Strategy. The final, vetted version of the EMC2 intervention from Phase I will be imparted. In 
brief, there are several components to this strategy that will be embedded into the workflow via EHR/patient portal 
platforms, mostly automating their implementation. Following patient movement through a provider visit, the 
following activities will occur for a select list of pre-specified medications: 
1) Prescribers will receive a ‘Best Practices Alert’ which recommends patient counseling on medication use 
and provides an overview of key medication risks 
2) Patients will receive a Medication Guide + Summary with their After Visit Summary 
3) Patients will be asked to complete a brief questionnaire on medication use via the patient portal post visit 
(at both 1 week and 1 month post visit for this phase of the study) 
4) Portal assessment results and feedback will be provided to the clinic via an inbox message. Clinic staff will 
respond to any identified problems according to their own clinical care protocols.  
 
Number of Patients:  
While our expected sample size for this pragmatic study is 300, we will recruit 330 patients (~200 at NU, ~100 at 
ACCESS ; we anticipate 90% retention among the recruited sample by 3 months (n=297). We therefore will 
oversample to accommodate some attrition.  
Statistical Analysis:  
We will perform analyses to address each of the aims using SAS v9.4 (SAS Institute, Cary, NC). The proposed trial 
uses a cluster-randomized design where the prescribing physician will be randomized to one of two arms (usual 
care, EMC2). Given the brief follow-up period, we anticipate ~90% retention at T2 interview. These estimates result 
in 330 patients recruited with an anticipated 300 patients (150 per arm, 6 per physician) available for primary data 
analysis.   
We will use generalized linear mixed models (GLMM) to test treatment effects, specifying identity link 
for continuous and the logit link for binary outcomes using PROC GLIMMIX in SAS (v.9.4).    All tests 
of treatment effects will be conducted at a 2-sided alpha level of 0.05. 
Resources Available: 
This study is led by senior health services researchers with expertise in chronic disease management, health literacy, 
and complex research designs. Additionally, the project staff have worked on similar research projects and have 
adequate training to carry out the proposed pragmatic study. 
 
Setting: 
This study is being conducted with patients from clinics within Northwestern Medical Healthcare (NMHC) and Access 
Community Health Network (ACCESS). All physicians within the practice will be informed of the study.  
All telephone interviews will take place in a private space at all study sites.  
 
 
 

 
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2. Schedule of Activities 
 
Table 1 shows study timeline.  
Visit 
 
 
 
 
 
 
Days from Initial Index Visit 
1-2 
3-14 
15-21 
21-28 
29-36 
90-104 
 
Pragmatic Study Procedure 
 
 
 
 
 
 
Screening Phone Call 
X 
 
 
 
 
 
Written Informed consent 
X 
 
 
 
 
 
T1 In Person* Interview 
X 
X 
 
 
 
 
Patient sent email to complete portal 
questionnaire (expires after 2 weeks) 
 
X 
 
X 
 
 
If questionnaire not complete reminder 
email sent (sent two days after initial email 
to complete portal questionnaire) 
 
 
X 
 
X 
 
T2 Phone Interview 
 
 
 
 
 
X 
*T1 interview may be completed over the phone if an in-person interview cannot be conducted. 

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3. Introduction 
3.1. Pragmatic Study Rationale 
Research has repeatedly demonstrated that individuals lack essential information on how to safely take prescribed 
(Rx) medications(1-4). An Rx communication and adherence strategy may be helpful for prescribers to ensure that 
patients are adequately informed about the medications they are taking and activated to sustain safe, appropriate use. 
We are therefore proposing to refine and evaluate our EMC2 strategy to support safe prescription medication use.  
3.2. Background 
Inadequate patient knowledge has been cited as a root cause of unintentional misuse and non-adherence, which can 
lead to suboptimal treatment benefits and/or serious adverse drug events(5, 6). But this should not be surprising, as 
neither physicians nor pharmacists routinely counsel patients on their medication regimens(5, 7, 8). Instead, patients 
heavily depend on product labeling, such as package inserts, container labels, leaflets, and Medication Guides and/or 
Medication Summaries– all of which are limited in their clarity and effectiveness (5, 9, 10). Our team has found that 
even when evidence-based, health literacy best practices are employed to these written tools, the elderly and those 
with low literacy continue to be inadequately informed and are therefore at greater risk for medication errors and 
unintentional non-adherence(9).   
An Rx communication and adherence strategy may be helpful for prescribers to ensure that patients are adequately 
informed about the medications they are taking and activated to sustain safe, appropriate use. This is most salient for 
Rx regimens the Food & Drug Administration (FDA) has deemed to possess serious public health concerns, warranting 
additional risk minimization activities beyond the product label [including a Risk Evaluation and Mitigation Strategy 
(REMS)]. To our knowledge, no such strategy exists to support and monitor outpatient medication use in a cost-
sustainable manner.  
A pilot study was recently conducted to assess the feasibility and acceptability of an Electronic health record-based 
Medication Complete Communication (EMC2) strategy that leverages electronic health record (EHR) technologies to: 
1) prompt and guide provider counseling using ‘best practice alerts (BPAs); 2) automate the delivery of Medication 
Guides and/or plain language Medication Summaries (Medsheets) at prescribing; 3) activate patients post-visit via the 
patient portal to confirm they have sufficient Rx information and are taking their Rx regimens properly; and 4) engage 
the clinical team to help patients overcome any barriers to adherence or safety. The results of this pilot were positive; 
the EMC2 strategy was successfully implemented at two diverse, academic clinic practices utilizing the EPIC EHR. 
Findings include: 
 
 
≥80% threshold for success achieved for BPAs, Med Guide/Medsheet delivery;  
 
While the Portal Survey was able to be consistently sent out to patients, this was most reliable among patients 
who already had an active Epic MyChart account; 
 
Results indicate high levels of patient satisfaction with EMC2 tools and substantially higher rates of provider-
patient counseling than reported previously in the scientific literature 
 
Key lessons learned from the pilot were then used to inform this pragmatic trial to evaluate the efficacy of the  EMC2 
intervention, specific to its ability to improve counseling rates, patient understanding and safe use of select medications 
compared to usual care.  
 
3.3. Benefit/Risk Assessment 
Risk to Patients: 
Participation in the study poses minimal risk of psychological, social or economic harm. Informing patients in advance 
that they may decline to answer any questions asked during the interview will mitigate any risks associated with 
expressing their opinions (e.g., feeling uncomfortable). They will also be assured they can terminate their participation 
in the study at any time without penalty. The risk/benefit ratio is low. Minimal to no risk is expected for patients in 
this study.  
 
Potential Benefits to Patients: 
It is possible that patients enrolled in the intervention study arms may directly benefit in that they may have, as a 
result of this study, a better functional understanding of their medication. The results of this study may provide 

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important information regarding how strategies can be implemented via the EHR and computer technologies to 
support safe and appropriate medication use. 
 
Provisions to Protect the Privacy Interests of Patients: 
In order to preserve patients’ confidentiality rights, research patients will be assigned code numbers that will be used 
to identify all the information collected. Using these codes, none of the collection forms will contain the names of the 
patients. All electronic data will be stored on a password-protected computer. A master study tracking database via 
Microsoft Access, at Northwestern, will contain information linking patients to their study identification numbers. 
This database will be encrypted and password protected and/or, kept on a secure server, and only accessible by 
Northwestern study personnel. ACCESS participants will be additionally tracked in their EPIC EMR system, only 
accessible by ACCESS study personnel. Survey data will be stored in a REDCap. The data will not contain any 
identifiable information. Individual study identification numbers will be assigned to each patient and only this number 
will appear on the survey. 
 
All enrolled patients will provide written consent, include HIPAA authorization, for the collection of all data.  Only 
authorized personnel listed on the IRB and approved by the PI will have access to the data. 
 
 

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4. Objectives and Endpoints 
 
Table 2 shows the objectives and endpoints of the pragmatic study.  
Table.2. 
Objectives 
Endpoints 
Primary 
• 
Test the effectiveness of the EMC2 Strategy, 
compared to usual care on improvement in  
patient knowledge of prescribed 
medications 
 
  
• 
 Medication-specific knowledge measured by 
demonstrated 
proper 
understanding 
of 
indication,   risks and benefits, and side effects  
at 3 months.  
 
 
• 
  
Secondary 
• 
Test the effectiveness of the EMC2 Strategy, 
compared to usual care on improvement in  
safe use and adherence to prescribed 
medications 
 
 
 
• 
Medication adherence measured by fill, time to 
fill, demonstrated proper use, and the ASK-12. 
at 3 months 
Tertiary/Exploratory 
• 
Evaluate the fidelity of the EMC2  Strategy 
 
  
 
 
 
 
• 
Patient report of provider counseling 
• 
Patient report of receipt of print Rx information 
• 
Completion of EHR portal survey 
• 
Clinic follow-up (yes or no) for patients 
identifying Rx concerns via portal survey 
 
 
 
 
 
 
 
 
Abbreviations: EMC2- Electronic health Record-based Medication Complete Communication     

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5. Pragmatic Study Design 
5.1. Overall Design  
For Phase II, we will conduct a 2-arm, multi-site, physician-randomized pragmatic trial to evaluate the impact and 
scalability of a refined version of the Phase I, finalized EMC2 strategy to promote actual safe medication use. There 
will be two study arms: the EMC2 Strategy, as refined from findings in Phase I, or usual care. Prescribers will be 
randomized to study arm prior to the initiation of the study. As patients are enrolled in the study, they will be assigned 
to either intervention or usual care arms based upon the assignment of their physician (see 7.3 Method of Treatment 
Assignment). We will follow patients for up to three months after receiving a new prescription or a dose change (refills 
allowed at ACCESS sites only) to determine whether those receiving the EMC2 Strategy are more knowledgeable, 
more likely to be safely using their medication, and more adherent (as measured by fill (yes or no), time to fill (days 
from prescription order to pharmacy pick-up), self-reported behavior, and demonstrated use). We have powered this 
study as a randomized trial to detect meaningful effects of our intervention. As such, findings will support the more 
widespread EMC2 adoption and dissemination. 
Multi-Site Research:  
The performance sites include Northwestern University, Northwestern Medical Group, and Access Community 
Health Network.  All sites will be involved in the development of EHR tools.  Northwestern University will be the 
data management site and Northwestern RAs will conduct all data collection.  
 
All required approvals will be obtained at each site prior to project implementation. In addition: 
a. Once IRB approval is obtained at Northwestern University for study materials and protocol, Access 
Community Health Network will be sent approved materials via email.  Northwestern will send any 
modifications made to be approved prior to implementation. All study sites will have regular conference 
telephone calls during both phases of the study to discuss any problems and interim results, and to discuss 
any possible changes that need to be made to study materials and protocol. 
 
b. All non-compliance with the study protocol or applicable requirements will be reported in accordance 
with local policy. 
 
Study-Wide Recruitment Methods: 
Patient Recruitment Process: 
At all study sites, a research coordinator (RC) will log in to EPIC to look for an alert if a patient received a new 
prescription or a dose change for one of the study medications at the study clinic.  However, we anticipate that 
mostly patients with a new prescription will be recruited due to the design of the intervention within EPIC.  Alerts in 
EPIC will only be activated for patients that have not opted out of research.  RC will then review the EHR to 
confirm new or changed prescription and patient portal status. Recruitment will be done by the RC via telephone.  
Patients will be called via telephone within 1-14 days after their index clinic visit. If they are interested in 
participating or learning more about the study, the RC will obtain verbal permission to ask the patient a brief series 
of questions to determine eligibility. If eligible, the RC will schedule a time to complete the T1 interview in person 
and obtain written consent. If an in person interview is not able to be completed due to COVID-19 institutional  
policy, the RC will schedule a time to complete the T1 interview over the phone. If all T1 questions cannot be 
completed in person, they will be completed over the phone. 
Table 3 shows patient payment. 
Patient Payment: 
Research Interview 
Payment 
Form of Payment 
T1  
 $ 30 
Cash at close of interview for in person interview 
OR 
Money Order or PNC Visa gift card for telephone 
interview 

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T2  
 $ 40 
Money order or PNC Visa Gift Card sent at close 
of interview 
 
Research Coordinator Training.  The project lead will lead sessions to orient the research staff to the surveys and 
study protocols (e.g., interview process, use of laptop PCs, data security). All interviewers will be required to 
demonstrate competence in survey administration. All RCs have completed human subjects training (CITI) and 
intensive training from Drs. Wolf and Bailey in interview protocols and safe data transfer.  
 
Clinic Orientation. Within 1-2 weeks to the launch of the EMC2 Strategy at the clinic, Drs. Wolf, Bailey, and/or Dr. 
Wallia for Northwestern OR Danielle Lazar for ACCESS Community Health Network will describe the study and 
what to expect over the upcoming several months to clinic providers and staff. Additional meetings may be held with 
staff responsible for following up with patients. We anticipate little orientation will be needed as most these sites 
participated in Phase I.  
 
Study Timelines: 
An individual patient will be involved in the study for a total of up to 3 months.  They will complete a screener 
enrollment interview, a T1 in person or phone interview as soon as possible following the screener, and a final T2 
interview on the phone at 3 months.   
We anticipate that patient enrollment will actively take place until Q2, 2020. 
Our proposed/anticipated study timeline is below. 
Table 4 shows study measures and outcomes.  
 

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Figure.1 Illustrates the study design 
 
 
5.2. Number of Patients 
Patients will be screened to achieve 300 randomized and 300 evaluable patients for an estimated total of 150 
evaluable patients per treatment group.  Approximately 10 providers will recruited for study feedback. To address 
potential retention loss (estimate 90% retention), we will target 330 patients to be recruited and consented to the 
study, completing the baseline assessment. 
5.3. End of Study Definition 
The end of the study will be when the last visit by the last study patient is completed.   
5.4. Scientific Rationale for Pragmatic Study Design 
Control is usual care, as that is what patients currently receive. We are doing a physician randomization instead of 
patient randomization because of the potential for contamination (the intervention is diffuse) and the inability to pre-
randomize patients before their clinic visit. 
5.5. Justification for Dose 
Not applicable.  
ACCESS 

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6. Study Population 
Patients will be screened for eligibility via telephone within 7 days of patient’s clinic visit. 
6.1. Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following criteria at screening/enrollment: 
All patients. regardless of study arm, must meet the following eligibility criteria:  
1) Patient is age 18 and older 
2) Patient is English speaking 
3) Patient is primarily responsible for administering their own medication 
4) Patient must have received a new or changed prescription for a product(s), identified by Eli 
Lilly and the study team, within 7 days of recruitment*  
5) Patient must have access to the internet 
6) Patient must have a patient portal account  
 
*Eligibility criteria may include refills for study medications at ACCESS sites only for the following reasons: 
1) We have learned 60% of the BPAS are considered ineligible at ACCESS primarily due to 
refills. To meet BPA volume and milestone goals, Lilly USA and the study team will expand 
eligibility critiera for refills at these sites only.  
2) ACCESS patients do not have the appropriate equipment to at home to monitor health status 
(for ex. glucose monitor) thus the majority of patients are seeing their doctors to only refill 
medicines during the COVID-19 pandemic.  
 
Providers must meet the following eligibility criteria: 
1) Provider working at a study site during study dates. 
 
Type of Patient and Disease Characteristics  
We will be recruiting patients who have been prescribed at least one of our target medications.   
Informed Consent 
Patients must be able and willing to give written informed consent.  
6.2. Exclusion Criteria 
Patients will be excluded from study enrollment if they meet any of the following criteria at screening/enrollment: 
1) Severe, uncorrectable vision 
2) Severe hearing impairments 
3) Severe cognitive impairment  
4) No access to the internet or patient portal account 
Adults unable to consent, individuals under the age of 18, and prisoners will be excluded from this research. 
 
For many patient characteristics, we will be able to ascertain differences between those participating and those who 
refuse to be included in the study, to determine potential bias.  Additionally, research teams at both sites will limit 
recruitment of patients prescribed Metformin to 50 patients per site and will only recruit those with a new prescription. 
This quota has been set in place to ensure adequate representation of other study drugs with less volume compared to 
Metformin.  

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6.2.1. Medical Conditions 
Not applicable. 
6.2.2. Lifestyle Restrictions 
Not applicable. 
6.3. Screen Failures 
Eligibility screening will take place before the written informed consent. Verbal consent will be obtained to ask 
screening questions. Individuals who do not meet the criteria for participation in the study (screen failure) may be 
rescreened and invited to participate a second time if they are prescribed a study medication at a different time. 
Intervals will vary and will depend on the date on which the medication was prescribed.   

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7. Treatments 
7.1. Treatments Administered 
This pragmatic study involves a comparison of intervention administered with standard of care in routine care. 
Study Arms. 
Usual Care: For this study, current usual care includes 1) variable provider counseling without any EHR notifications 
or counseling support; 2) variable distribution of print medication information materials, including FDA Medication 
Guides in clinics and variable distribution in pharmacies; and 3) limited or variable active surveillance of medication 
use post-visits.  
Intervention: EMC2 Strategy: There are several components that will be embedded into the workflow via EHR/patient 
portal platforms, mostly automating their implementation.  Following patient movement through a provider visit, the 
following 6 activities will occur: 
1. Physician Medication Alert: If a prescribing physician attempts to place a new order or change to 
an existing study medication prescription, an EHR-generated alert will notify the provider that the 
medication requires patient counseling. Physicians can opt to ignore this alert.  
 
2. Provider Counseling Support:  Content from the 1-page, Med Guide Summary will appear on the 
screen, if selected by the provider, to orient and inform provider-patient discussion.  
 
3. Automated Delivery of Med Guide + Summary: When patients leave an encounter, the medication 
order in Epic will automatically cue printing of both the 1-page, health literate Med Guide Summary 
for study medications and a full Med Guide, if applicable (latter is required by FDA for certain 
medications only, the former designed to enhance comprehension). If the medication was ordered 
during a telemedicine encounter, the Med Guide Summary will automatically populate in the patient 
portal.  
 
4. Follow-Up Portal Questionnaire: Within 1 week post-visit, patients will receive an automated email 
prompting them to log on to the patient portal. Patients’ will be asked to fill out a short set of 
questions related to medication adherence, and other medication-related concerns (i.e. cost, side 
effects). If patients have not completed the questionnaire within 2 days, another email reminder will 
be sent.  The information submitted back by the patient will be stored in the EHR.  
 
Content in question form and corresponding responses for the portal questionnaire will be revised 
from prior evaluation scripts and written by Drs. Wolf, Bailey, Chung, and Wallia. 
 
The addition of the patient portal will provide opportunities to have ongoing communications with 
their clinic, access to regimen-specific medication information, and to provide a feedback loop 
informing healthcare providers of safety and adherence-related behaviors and concerns.  
 
5. EHR Inbox Message to Clinic: The results of the patient portal questionnaire will be sent back to 
the EHR, populating an inbox message notifying the nurse/clinic staff and/or physician if a patient 
has a medication risk alert, detailing the nature of the issue (i.e. education needed, adherence 
problem, side effect concerns, etc.). The system will be flexible and allow the clinic to specify 
actions to be taken according to their workflow preferences; the default plan is that patient contact 
will be undertaken by nurses/clinic staff involved with care management.  
 
6. Clinic Counseling: If a problem/concern is flagged during the review of the portal questionnaire, 
there will be an expectation for a clinic staff member to respond to the concern by calling the patient. 
A general orientation to staff at the clinic will provide guidance on how to perform brief counseling 
based on each specific clinic protocol. 

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7.2. Treatment Regimens 
Not applicable. 
7.2.1. Packaging and Labelling 
Not applicable. 
7.2.2. Medical Devices  
Not applicable. 
7.3. Method of Treatment Assignment 
As the EMC2 Strategy includes changes to healthcare delivery, the intervention itself is diffuse and individual patient 
randomization is not feasible. Therefore, randomization will occur at the provider (specifically, prescriber) level (N= 
~50 eligible clinicians). Specifically, prescribers will be randomized to study arm (EMC2 Strategy or usual care) prior 
to the initiation of the study. As patients are enrolled in the study, they will be automatically assigned to either 
intervention or usual care arms based upon the initial assignment of their physician. This specific strategy of “turning 
on” an EHR intervention with physician or clinic level randomization has been previously approved by the IRB at 
Northwestern University for three other AHRQ funded grants [P01HS021141-01, 1U19HS021093-01 & 
1R18HS017220-01].  To optimize the likelihood of obtaining similar populations in each study arm, physicians will 
be placed into 4 strata based on workload (full time vs. part time) and site  and randomly assigned to one of the two 
arms with an equal number assigned to each arm within each strata.    
7.3.1. Selection and Timing of Doses 
Not applicable. 
7.4. Blinding 
This is an open-label pragmatic study. As with most behavioral interventions, it will not be possible to fully blind 
researchers, healthcare providers, and study patients to intervention vs. usual care assignments. However, we have 
purposefully designed our trial to prevent certain threats to contamination between study arms. Patients will be told 
they will receive one of two models of care. While they will not be deliberately made aware of the approach not 
received, we do recognize that there is an unavoidable risk of patients learning from other patients involved in the 
study. 
7.5. Dosage Modification 
Not applicable. 
7.6. Preparation/Handling/Storage/Accountability 
Not applicable. 
7.7. Treatment Compliance 
Patient compliance with intervention will be assessed at end of intervention course.  Compliance will be assessed 
during patient interviews. 
7.8. Concomitant Therapy 
Not applicable. 
7.9. Treatment after the End of the Study 
7.9.1. Study Extensions [if applicable] 
Not applicable. 

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7.9.2. Continued Access 
Not applicable. 
7.9.3. Special Treatment Considerations [if applicable] 
Not applicable. 
7.9.4. Patient Follow-Up in Pragmatic Trials [if applicable] 
 The T2 interview will take place over the phone 3 months after T1.  Patients in the EMC2 strategy group will also 
receive portal questionnaires. 

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8. Discontinuation Criteria 
8.1. Discontinuation from Pragmatic Study Treatment 
8.1.1. Permanent Discontinuation from Study Treatment 
There are no anticipated circumstances when a patient would be withdrawn from the study without their consent, 
unless they pose a threat to themselves or research staff.  
 
Patients can choose to withdraw from the study at any time. If a patient chooses to withdraw from the research, any 
data collected up until the point of withdrawal will still be utilized, as it will not include identifying information. 
 
8.1.2. Temporary Discontinuation from Study Treatment  
Not applicable. 
8.1.3. Discontinuation of Inadvertently Enrolled Patients 
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor  and the investigator to determine if 
the patient may continue in the study.  If both agree it is appropriate to continue, documented approval 
from the sponsor will be obtained  to allow the inadvertently enrolled patient to continue in the study. 
Some possible reasons that may lead to permanent discontinuation include: 
• 
participation in the study needs to be stopped for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and good clinical practice (GCP) 
• 
investigator decision 
o 
the investigator decides that the patient should be discontinued from the study 
• 
patient decision 
o 
the patient or the patient’s designee, for example, parents or legal guardian requests to be 
withdrawn from the study 
8.2. Lost to Follow-Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and is unable 
to be contacted by the study site.  Site personnel are expected to make diligent attempts to contact patients who fail 
to return for a scheduled visit or were otherwise unable to be followed up by the site. 

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9. Pragmatic Study Assessments and Procedures 
 
Please see section 5 for the Schedule of Activities, with the study procedures and their timing. 
9.1. Effectiveness Assessments 
9.1.1. Primary Effectiveness Assessments 
Medication Knowledge. Medication-specific knowledge measures will be created to determine whether a 
patient has a basic understanding of their prescribed medication. This will comprise a set of objective, 
open-ended, yet targeted questions with predetermined correct responses known for each medication under 
study. Patients will be asked about their medication’s  1) indication, 2) risks or warnings (knowledge of at 
risk/warnings, correct or incorrect per warning), and 3) side effects (knowledge of at least two side effects, 
correct or incorrect per item). Correct answers will be tailored to the available content included in the 
MedGuide Summary, as done previously by our team.(11-14)  While patients are not given response 
options to facilitate their answer, interviewers will both document the verbatim response to each question 
and code it as correct or incorrect. A second, independent reviewer, blinded to the research interviewer’s 
code of correct/incorrect, will rate the responses. Any discordance will be resolved through team 
discussions. Total scores will range from 0-100, calculated reflecting the percent correct of possible points.  
9.1.2. Secondary Effectiveness Assessments 
Medication Adherence. Medication adherence refers to a patient’s medication taking behavior in terms of 
the extent to which he or she takes the medication as prescribed. We will assess medication adherence by 
1) treatment initiation (yes or no), 2) time to fill (# of days from prescription order to patient fill), 3) 
subjective self-report of medication adherence behaviors (ASK-12), 4) objective assessment of proper use.  
1) Treatment initiation. Patients will be asked whether they have filled their study prescription (yes or 
no), and whether they intend to fill it. 
2) Time to fill. We will calculate the number of days between the date the medication was ordered and 
when the medication was actually filled, based on the patient’s self-report of the date of fill stated on 
the medication’s prescription label from the pharmacy.  
3) ASK-12. The ASK-12 survey is a widely used and previously validated psychometric measure of 
adherence that covers three domains: inconvenience/forgetfulness, treatment beliefs and behavior(15). 
In a study among 112 adults with asthma, type II diabetes or congestive heart failure, the tool 
demonstrated good internal consistency reliability (Cronbach's α 0.75) and test-retest reliability 
(intraclass correlation 0.79); convergent validity was also demonstrated through correlations with 
multiple other measures (16, 17) and pharmacy claims data (15). Ask-12 scores range from 12-60, 
with higher scores translating to  greater barriers to adherence.  
4) Proper use. For the study medication, patients will be asked on what day they last took the medication. 
While most medications will be daily and the correct response would be ‘yesterday’ or ‘today’, some 
prescribed drugs of interest may be taken weekly or in another manner as directed by their physician. 
Patients will then be asked 1) How many times during the day did you take it? 2) At what hour/s of 
the day did you take this medicine? and 3) How much of this medicine did you take each time? A 
patient’s proper timing (last day and # of times per day), dosing (number of pills per dose), and spacing 
between doses (for BID, TID medications only) will be coded as correct or incorrect. Patients will be 
classified as having properly used their medication if they correctly reported all components. 
9.1.3. Appropriateness of Assessments 
There is no universally accepted measure of medication adherence, but following recommendations in 
the scientific literature, we will measure adherence using multiple assessments that seek to capture 
various facets of medication use as described in section 9.1.1. These self-report measures are appropriate 
given the study design. Since one or  two interviews will be conducted via phone, we would be unable to 
use assessments that require in-person administration or orientation (i.e. MeMS caps; pill counts). As 

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patients are enrolled in the study for three months, pharmacy fill data would also not provide a 
meaningful measure of adherence (beyond initial fill). Finally, as many of the medications targeted in 
this study are injectables, conducting a pill count would be unsuitable.  
9.2. Adverse Events 
Adverse Drug Events (ADE) will be assessed using a questionnaire administered by the RA during the 3 
month follow-up phone call. If the patient states that they have experienced an ADE and provides any 
details, the RA will fill out an adverse event form to send to Eli Lilly. Dr. Wallia at Northwestern (or 
another clinic contact in the event of her absence) or the Access Community Health Network clinical 
liaison will also be informed if the patient answers as described above and/or reports they have not 
contacted their doctor. They will use clinical expertise to determine appropriate next steps. This protocol 
will comply with our requirements that investigators and other study personnel are requested to report 
any suspected adverse reactions with any drug to the appropriate party (for example, regulators or the 
marketing authorization holder) as they would in normal practice as required by applicable laws, 
regulations, and practices. 
 
9.2.1. Complaint Handling 
Lilly collects product complaints on investigational products and drug delivery systems used in clinical 
studies in order to ensure the safety of study patients, monitor quality, and to facilitate process and 
product improvements. 
Patients will be instructed to contact the investigator as soon as possible if he or she has a complaint or 
problem with the investigational intervention so that the situation can be assessed. 
9.3. Treatment of Overdose 
Not applicable. 
9.4. Safety 
Not applicable. 
9.4.1. Electrocardiograms 
Not applicable. 
9.4.2. Vital Signs 
Not applicable. 
9.4.3.  Laboratory Tests 
Not applicable. 
9.4.4. Other Tests  
Not applicable. 
9.4.5. Safety Monitoring  
Not applicable. 
9.5. Pharmacokinetics 
Not applicable. 

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9.6. Pharmacodynamics 
Not applicable. 
9.7.  Pharmacogenomics OR Genetics 
Not applicable. 
9.7.1. [Whole Blood and/or Saliva] Sample[s] for Pharmacogenetic 
Research 
Not applicable. 
9.8.  Biomarkers and specify other analyses 
Not applicable. 
9.8.1. Samples for Immunogenicity Research  
Not applicable. 
9.9.  Health Economics [OR] Medical Resource Utilization and Health 
Economics 
Health Economics and Medical Resource Utilization parameters were not evaluated in this study. 
 

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10. Statistical Considerations 
10.1. Sample Size Determination 
 
The sample size for this pragmatic study was based on comparisons of the primary outcome of medication knowledge 
between the two arms (i.e., usual care vs EMC2) at the T2 interview. We expect patients in the usual care arm to score 
an average of 55.6% correct responses (SD=28.4) based on a previous study that tested comprehension of the FDA 
standard Med Guides to those to be used in this study(9). Enrolling 330 patients and estimating 90% retention at the 
T2 interview (N=300, 150 per arm, 6 per provider), we will have 80% power to detect a minimum difference of 9.4% 
between the EMC2 and the usual care arm assuming a Type I error of 5% (improving from 55.6% to 65.0% or greater). 
An intra-class correlation coefficient (ICC) of 0.001 was used; we expect clustering of physicians to have minimal 
influence on outcomes. However, even if the ICC were higher (i.e. 0.01) we could still detect a difference as small as 
9.6%.   
With the sample size set by the primary outcome, we also report minimum detectable differences for medication 
adherence measures.  We estimate 65% of the usual care arm to demonstrate proper use of their medications based on 
prior studies(1, 18).  With similar assumptions described above, a sample of 300 participants would enable us to detect 
a minimum absolute difference of 14.4% between arms with an ICC of 0.001 and 14.7% with an ICC of 0.01. We 
expect participants in the usual care arm to score an average of 27.5 (SD=7.2) on the ASK-12 based on validation 
studies(15). Retaining 300 participants (150 per arm, 6 per provider) at the T2 follow-up interview we will have 80% 
power to detect a minimum difference of 2.4 between the EMC2 and the usual care arm (improving from 27.5 to 25.1 
or less) using an ICC of 0.001 and a difference of 2.5 (improving from 27.5 to 25.0 or less) and with an ICC of 0.10.  
While no cut-off indicating non-adherence is provided, the goal would be for patients to score below 22.5, the average 
score in patients who took medications exactly as directed in the ASK-12 validation studies(15).  We could detect 
differences smaller than this with the proposed sample size. In addition, differences in subscale scores of 1.3 for 
behavior, 0.9 for health beliefs, and 1.0 for inconvenience/forgetfulness could be detected between arms assuming 
mean scores of 10.5 (SD=3.8), 8.1 (SD=2.7), and 8.9 (SD=3.0), respectively, in the usual care arm.    
 
10.2.  Populations for Analyses 
For purposes of analysis, the following populations are defined in table 5. 
Table 5 shows study population.  
 
Population 
Description 
Enrolled  
All patients who provide written consent 
Randomized 
Since this is a provider-randomized study, patients who are enrolled are 
automatically randomized. 
 
Evaluable 
Patients who had no post randomization efficacy measure for the parameter 
being analyzed will be excluded. Patients will be included in the treatment 
group they were randomized to regardless of whether the treatment is received 
as planned.   
 
10.3. Statistical Analyses 
10.3.1. General Statistical Considerations 
We will perform analyses to address each of the aims using SAS v9.4 (Cary, NC).  
The proposed trial uses a cluster-randomized design where the prescribing physician is the unit of randomization. 
We will randomize providers (i.e. attendings and fellows) to one of two intervention arms (usual care, EMC2). To 
optimize the likelihood of obtaining similar populations in each, providers will be placed into strata based on their 

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roles (attending, fellow) and historical volume of study medications dispensed (high, medium, low) for attendings. 
Providers from each strata will be randomized and identities will be revealed after randomization is complete. 
Patients enrolling in the study are assigned to the study arm of the provider signing their prescription within the 
EHR. 
Given the brief follow-up period, we anticipate ~90% retention at T2 interview. These estimates result in 330 
patients recruited with an anticipated 300 patients (150 per arm) available for primary data analysis.   
Effectiveness analyses will be conducted on the full analysis set.  This set includes all data from all randomized 
patients completing the outcomes of interest according to the treatment the patients were assigned. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise stated. 
Any change to the data analysis methods described in the protocol will require an amendment ONLY if it changes a 
principal feature of the protocol.  Any other change to the data analysis methods described in the protocol, and the 
justification for making the change, will be described in the clinical study report (CSR).  Additional exploratory 
analyses of the data will be conducted as deemed appropriate. 
10.3.2. Treatment Group Comparability 
10.3.2.1. Patient Disposition 
A detailed description of patient disposition will be provided at the end of the study.  
10.3.2.2. Patient Characteristics 
T1 assessment will include socio-demographics, social support, and health status, including number of 
comorbidities. We will also probe for medication concerns (i.e. about costs, side effects, risks) for patients who do 
not fill or are not taking their medicine.  
Health Literacy. We will assess health literacy via the Newest Vital sign or three validated screening questions that 
assess health literacy skills. 
Patient Motivation. The Consumer Health Activation Index (CHAI) assesses patients’ ‘activation’ or motivation to 
participate in healthcare decisions and actions. 
 
T1 patient characteristics will be compared by arm using t-tests and χ2 tests, as appropriate. Any significant 
differences (p < .05) across study arms will be entered as covariates in models described below. 
10.3.2.3. Concomitant Therapy  
Not applicable. 
10.3.2.4. Treatment Compliance  
Not applicable. 
10.3.3.  Efficacy Analyses 
10.3.3.1. Primary Analyses 
Aim 1. Test the effectiveness of the EMC2 Strategy, compared to usual care, to improve patient 
understanding and safe use of prescribed medications    
Medication knowledge is the primary outcome of interest, and will be analyzed as a score ranging from 0-100 
reflecting the percent of items correct for each medication. Associations between medication knowledge and 
potential confounders at the patient (socio-demographic characteristics, comorbidities, # and type of medications 
taken, new or changed prescription, previous history with side effects, literacy, and primary language) and 
medication (drug type, route of administration) levels will be examined. We intend to use generalized linear mixed 
models (GLMM) to account for the correlated nature of the data from patients prescribed medications from the same 
providers, specifying the identity link for the outcome of medication knowledge using PROC GLIMMIX in SAS 
(v.9.4). Treatment assignment will be the independent variable of primary interest and modeled as a fixed effect, and 
prescriber will be modeled as a random effect. We will also include fixed effects for any potential confounding 

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covariates noted in the descriptive studies. For all GLMM analyses, we will report point estimates and 95% 
confidence intervals, and the extent to which random effects suggest correlation of outcomes within prescribers.  
 
Additionally, we will examine rates of missing data, and determine if there are any discernible patterns using 
GLMMs with a logit link function to predict the presence of missing data. Should we find significant predictors, we 
will use multiple imputation methods and present results as secondary analyses.     
10.3.3.2. Secondary Analyses 
Aim 2. Test the effectiveness of the EMC2 Strategy, compared to usual care, to improve patient adherence to 
prescribed medications 
We will repeat all GLMM analyses described in Aim 1, but with medication adherence outcomes relevant to Aim 2. 
We will specify the logit link for binary outcomes (whether treatment was initiated (yes or no) and proper use (correct 
or incorrect)) and the identity link for continuous outcomes (time to fill and ASK-12 scores). We will collect data 
from the EHR related to the study medications (order dates, sig, quantity, type of fill, prescribing provider, etc…) 
needed to conduct the analyses.  
10.3.3.3. Tertiary/Exploratory Analyses 
Aim 3. Evaluate the fidelity of the EMC2 Strategy to promote provider counseling, deliver patient Rx 
information, and inform providers of potential harms. 
Compared to usual care, patients receiving the EMC2 strategy will: 
1)  report higher rates and quality of provider Rx counseling    
2)  report higher rates of receipt of print Rx information  
Appropriate bivariate analyses will be performed based on each outcome measure described below using t-tests, 
Wilcoxon Rank-Sum, or χ2 tests, as appropriate.   
Provider Rx Counseling. We will ask patients (yes/no) whether their provider(s) (physician/nurse) counseled them on 
their prescribed medication. We will also ask adapted questions from the Health Literacy supplemental items of the 
Consumer Assessment of Health Providers Survey (CAHPS) to evaluate the extent and quality of physician verbal 
counseling. 
Receipt of print Rx information.  All patients will be asked whether they received any print Rx information at their 
appointment.  We will further probe intervention patients to determine whether the health literate Med Guide Summary 
was specifically received and its perceived helpfulness.  Additionally, we will also collect EHR data to determine 
whether the Med Guide Summary was printed with their after-visit summaries.   
We will also examine completion rates of: 
1) the EHR portal survey by patients in the intervention arm  
2) clinic follow-up for patients identifying Rx concerns in the portal survey.  
Completion of the EHR Portal Survey. Intervention patients will be asked (yes/no) whether they received the emails 
to visit the portal and if they completed the portal questionnaire. We will also confirm this by determining if portal 
questionnaire results were populated in the EHR. 
Clinic follow-up for patients identifying Rx concerns.  At each performance site, clinical liaisons will share with the 
study team what specific medication-related concerns that are self-reported by patients via the portal assessment 
might warrant follow-up. It is at the discretion of each clinical practice to choose how they will triage the 
information provided via the feedback from the EMC2 intervention, and as part of the study we will explore the 
frequency and nature of follow-up that occurred for various medication-related concerns by self-report and in the 
EHR. 
 
 

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10.3.4. Safety Analyses 
Not applicable. 
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses 
Not applicable. 
10.3.6.  Other Analyses 
Not applicable. 
10.3.6.1.  Health Economics  
Not applicable. 
10.3.6.2. Subgroup Analyses  
Not applicable. 
10.3.7. Interim Analyses 
No interim analyses are planned for this pragmatic study as risks are minimal and even small effects on adherence 
rates may be important given the scalability and low cost to implement these interventions.  If an unplanned interim 
analysis is deemed necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol. 
  
 
 

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11. Appendices 

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Attachment 1. 
Abbreviations and Definitions 
 
Term 
Definition 
AE 
Adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
EMC2 
Electronic health record-based Medication Complete Communication  
EHR 
Electronic health record 
ASK-12 
Adherence barrier survey 
Rx 
Prescribed 
CHAI 
Consumer health activation index 
 
REMS 
 
GLMM 
 
MAR 
 
CAGOS 
 
Risk evaluation and mitigation strategy 
 
Generalized linear mixed model 
 
Missing at random 
 
Consumer assessment of health providers survey  

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Attachment 2. 
Clinical Laboratory Tests 
Not applicable. 
 

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Attachment 3. 
Regulatory and Ethical Considerations, 
Including the Informed Consent Process 
Appendix 3.1.1. 
Informed Consent 
Patients. Subjects will be informed about the nature of the pragmatic study by a CITI certified RA and asked to 
provide written informed consent in a private space. Additionally they will be notified that only those contents of 
their medical record that are necessary to evaluate of the intervention will be released to the research team at 
Northwestern and ACCESS. Finally, they will be informed about the follow-up telephone interview for the study (3 
months post baseline). They will be informed that they may withdraw from the study at any time and given contact 
information for the PI and study coordinator. These consent forms will be locked in a file cabinet only accessible to 
necessary research staff.  Participants will be given the option to receive a blank consent form for reference if they 
request it. 
 
Subjects may provide electronic or verbal consent, documented in REDCap, if they cannot complete an in-person 
interview due to COVID-19 institutional policy. Participants will be asked to complete an online consent with 
HIPPA authorization and complete the baseline interview by phone after the consent is obtained. The RC will send 
patients a link to REDCap by email or text message to be able to read through the consent. If the participant agress 
to participate, they will be asked to electronically sign and date the online consent.  
 
Participants that indicate they do not have the means to e-consent (ie. no access to internet) will be allowed to give 
verbal consent. In this event, we request a waiver of documention of informed consent and an alteration to obtain 
verbal HIPPA authorization. Due to institutional restrictions on in-person research activities at participating 
recruitment sites, research cannot practicably be conducted without this waiver or alteration. Once verbal consent 
and HIPPA authorization is obtained, the consent date and the name of the RC that obtained the consent will be 
recorded in REDCap.  
 
All forms of consent will be obtained in a process fashion. During the review of the IRB approved consent 
document, the subject will be asked to explain in his/her own words of his/her understanding of the consent. This 
will enable the research personnel to enter into a dialogue with the subject and ensure that the subject understands 
he/she is free to withdraw at any time without penalty. Additionally, subjects will be encouraged to ask questions 
prior to giving consent, and all questions/answers will be documented in REDCap. There will be no exertion of any 
overt or covert coercion. Patients who verbally consent will be emailed or mailed a blank copy of the consent 
document for their records.  
 
Providers. At Northwestern and ACCESS, we will ask providers to consent to be part of the study, which includes 
consenting to be randomized to one of the two study arms. We are asking for provider consent to allow any 
providers who are uncomfortable with the study to opt out. As noted in recruitment, providers will be informed of 
the nature and details of the study via email and a brief overview at a monthly business meeting. Providers will be 
asked to sign a written consent electronically or in-person to be a part of the study, which includes their consent to 
allow their patients to be randomized.  All providers will be told that their participation is voluntary; they can stop at 
any time, and whether they participated or not will not be disclosed to their superiors. Their participation in the 
study will be kept confidential and made anonymous in reports. If the provider does not want to participate or 
decides to stop before completing the patient enrollment period, this will not be disclosed to any superiors. At the 
secondary site, providers will be informed of the nature of the study and the details of the study via email and will be 
told that they may opt out of participating. Any providers who choose to opt out will be removed from the study.  
 
Waiver of HIPAA Authorization are requested to identify subjects (patients) prior to enrollment into the study. 
 
The investigator is responsible for ensuring: 
• 
that the patient understands the potential risks and benefits of participating in the study 

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• 
that informed consent is given by each patient or legal representative.  This includes obtaining 
the appropriate signatures and dates on the informed consent form (ICF) prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product. 
• 
answering any questions the patient may have throughout the study and sharing in a timely 
manner any new information that may be relevant to the patient willingness to continue his or 
her participation in the trial. 
A legal representative must give informed consent for a child to participate in this study.  In addition to informed 
consent given by the legal representative, the child may be required to give documented assent, if capable. 
Appendix 3.1.2. 
Ethical Review 
The investigator must give assurance that the ethical review board (ERB) was properly constituted and convened as 
required by International Conference on Harmonisation (ICH) guidelines and other applicable laws and regulations. 
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the study may begin 
at the investigative site(s).  Lilly or its representatives must approve the ICF, including any changes made by the 
ERBs, before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline on Good 
Clinical Practice (GCP). 
The study site’s ERB(s) should be provided with the following: 
• 
Study protocol and updates during the course of the study 
• 
informed consent form  
• 
relevant curricula vitae 
Appendix 3.1.3. 
Regulatory Considerations 
This study will be conducted in accordance with: 
• 
consensus ethics principles derived from international ethics guidelines, including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 
• 
applicable ICH GCP Guidelines 
• 
applicable laws and regulations 
 
Some of the obligations of the sponsor will be assigned to a third party. 
Appendix 3.1.4. 
Investigator Information 
Michael S. Wolf, PhD MPH 
Professor, Medicine and Learning Sciences  
Northwestern University 
750 N. Lake Shore Drive, 10th Floor 
Chicago, IL  60611 
Phone: (312) 503-5592 
 
Stacy Cooper Bailey, PhD MPH 
Associate Professor of Medicine  
Northwestern University 
750 N. Lake Shore Drive, 10th Floor 
Chicago, IL  60611 
Phone: (312)503-5595 
 

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Appendix 3.1.5. 
Protocol Signatures 
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best of his or her 
knowledge, the protocol accurately describes the planned design and conduct of the study. 
After reading the protocol, each principal investigator will sign the protocol signature page and send a copy of the 
signed page to a Lilly representative. 
Appendix 3.1.6. 
Final Report Signature 
The investigator will sign the final clinical study report (CSR) for this study, indicating agreement with the analyses, 
results, and conclusions of the report. 
Appendix 3.2. 
Data Quality Assurance 
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following: 
• 
provide instructional material to the study sites, as appropriate 
• 
be available for consultation and stay in contact with the study site personnel by mail, telephone, 
and/or fax 
• 
review and evaluate CRF data and use standard computer edits to detect errors in data collection 
• 
conduct a quality review of the database 
In addition, Lilly or its representatives will periodically check a sample of the patient data recorded against source 
documents at the study site.  The study may be audited by Lilly or its representatives, and/or regulatory agencies at 
any time.  Investigators will be given notice before an audit occurs. 
The investigator will keep records of all original source data.  This might include laboratory tests, medical records, 
and clinical notes.  If requested, the investigator will provide the sponsor, applicable regulatory agencies, and 
applicable ERBs with direct access to original source documents. 
Training at the Northwestern and ACCESS will begin after surveys and interview protocols have been refined and 
standardized. The training will include tailored discussion of 1) roles and responsibilities; 2) HIPAA and IRB 
mandates (completion of Human Subjects Training Program - CITI; 3) effective recruitment communication and 
interviewing with attention paid to health literacy and culture; and 4) gathering and recording data including 
administering the structured survey electronically.  Role playing will be used to fine tune training for obtaining 
informed consent and interviewing patients.  Institutional Review Board (IRB) approval will be attained at both sites 
prior to any active recruitment efforts.  All interviewers will be required to demonstrate competence in survey 
administration 
 
Appendix 3.2.1. 
Data Capture System 
Confidentiality and Data Management: 
Data collected includes patient and clinic staff consents, patient and clinic staff interview and/or online survey data. 
Only authorized personnel listed on each institutions IRB will have access to the data.  Any information that could 
allow identification of individual patients, including the master list, will be kept strictly confidential.  
Data Access.  The Data Custodian is the Principal Investigator, Dr. Michael Wolf.  Only authorized personnel listed 
on each institutions IRB will have access to the data.  Any information that could allow identification of individual 
participants, including the master list, will be kept strictly confidential. 
Local Data Storage. Patient survey data will be stored in REDCap, a secure, web-based application, and on the 
Northwestern secure server for the length of the study. The Project Lead or Data Analyst will download the data for 
both sites from REDCap periodically and save to the “Analytic” folder within the Eli Lilly EMC2 project folder on 
the FSM department servers which are located in a HIPAA compliant data center.  These data files do not contain 
any identifiable information, and are identified by project staff by an assigned study ID. All identifiable information 

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will remain in a separate database on the secure local servers at Northwestern. ACCESS participants will 
additionally be tracked in ACCESS’s EPIC EMR system and only accessible by ACCESS study personnel.   Upon 
completion of all study activities, a final de-identified dataset will be created. This dataset will be stored indefinitely 
on the GIM server for secondary analyses. Only authorized personnel will have access to the dataset. All identifiable 
information will be deleted upon completion of the study. 
Data Monitoring Plan to Ensure the Safety of Participants. This study is low risk and does not require a DSMB. We 
are testing a simple, EHR-based intervention that will help promote medication safety and help provide an additional 
mechanism for patients to reach out to their providers if they have any medication-related problems. If an individual 
patient reports a medication-related problem to research staff, we will advise them to speak to their providers or call 
911. As research staff, we will not be directly involved in their medical care or offer medical advice. We will also 
include language in the consent and in the online portal questionnaire that advises patients to speak to their provider 
or call 911 if they experience any problems with any medications they have been prescribed.  
 
Appendix 3.3. 
Study and Site Closure 
Appendix 3.3.1. 
Discontinuation of Study Sites 
Study site participation may be discontinued if  Lilly or its designee, the investigator, or the ERB of the study site 
judges it necessary for medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, and 
GCP. 
Appendix 3.3.2. 
Discontinuation of the Study 
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and GCP. 

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Attachment 1. 
References  
 
1. 
Wolf MS, Davis TC, Curtis LM, Bailey SC, Knox JP, Bergeron A, Abbet M, Shrank 
WH, Parker RM, Wood AJ. A Patient-Centered Prescription Drug Label to Promote Appropriate 
Medication Use and Adherence. J Gen Intern Med. 2016;31(12):1482-9. 
 
2. 
Wolf MS, Davis TC, Shrank W, Rapp DN, Bass PF, Connor UM, Clayman M, Parker 
RM. To err is human: patient misinterpretations of prescription drug label instructions. Patient 
Educ Couns. 2007;67(3):293-300. 
 
3. 
Davis TC, Wolf MS, Bass III PF, Thompson JA, Tilson HH, Neuberger M, Parker RM. 
Literacy and misunderstanding prescription drug labels. Ann Intern Med. 2006;145(12):887-94. 
 
4. 
Wolf MS, Davis TC, Tilson HH, Bass PF, 3rd, Parker RM. Misunderstanding of 
prescription drug warning labels among patients with low literacy. Am J Health Syst Pharm. 
2006;63(11):1048-55.  
5. 
Institute of Medicine. Standardizing Medication Labels: Confusing Patients Less: 
Workshop Summary. Hernandez LM, editor. Washington DC: National Academy Press; 2008. 
 
6. 
Institute of Medicine. Health literacy: A prescription to end confusion. Nielsen-Bohlman 
L, Panzer A, Kindig DA, editors. Washington DC: National Academy Press; 2004 
 
7. 
Svarstad BL, Bultman DC, Mount JK. Patient counseling provided in community 
pharmacies: effects of state regulation, pharmacist age, and busyness. Journal of the American 
Pharmacists Association. 2004;44(1):22-9. 
 
8. 
Tarn DM, Heritage J, Paterniti DA, Hays RD, Kravitz RL, Wenger NS. Physician 
communication when prescribing new medications. Arch Intern Med. 2006;166(17):1855-62.  
9. 
Wolf MS, Bailey SC, Serper M, Smith M, Davis TC, Russell AL, Manzoor BS, Belter L, 
Parker RM, Lambert B. Comparative effectiveness of patient-centered strategies to improve 
FDA medication guides. Med Care. 2014;52(9):781-9.  
 
10. 
Wolf MS, King J, Wilson EA, Curtis LM, Bailey SC, Duhig J, Russell A, Bergeron A, 
Daly A, Parker RM, Davis TC, Shrank WH, Lambert B. Usability of FDA-approved medication 
guides. J Gen Intern Med. 2012;27(12):1714-20.  
 
11. 
Wolf MS, Curtis LM, Waite K, Bailey SC, Hedlund LA, Davis TC, Shrank WH, Parker 
RM, Wood AJ. Helping patients simplify and safely use complex prescription regimens. Arch 
Intern Med. 2011;171(4):300-5.  

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12. 
Davis TC, Federman AD, Bass PF, Jackson RH, Middlebrooks M, Parker RM, Wolf MS. 
Improving patient understanding of prescription drug instructions. J Gen Intern Med. 
2009;24:57-62. 
 
13. 
Shrank WH, Parker R, Davis T, Pandit AU, Knox JP, Moraras P, Rademaker A, Wolf 
MS. Rationale and design of a randomized trial to evaluate an evidence-based prescription drug 
label on actual medication use. Contemp Clin Trials. 2010;31(6):564-71.  
 
14. 
Bailey SC, Chen AH, Sarkar U, Schillinger D, Wolf MS. Evaluation of Language-
Concordant, Patient-Centered Drug Label Instructions. J Gen Intern Med. 2012 
In press. 
 
15. 
Matza LS, Park J, Coyne KS, Skinner EP, Malley KG, Wolever RQ. Derivation and 
validation of the ASK-12 adherence barrier survey. The Annals of Pharmacotherapy. 
2009;43(10):1621. 
 
16. 
Morisky DE, Ang A, Krousel-Wood M, Ward HJ. Predictive validity of a medication 
adherence measure in an outpatient setting. The Journal of Clinical Hypertension. 
2008;10(5):348-54. 
 
17. 
Ware J, Jr., Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction 
of scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220-33.  
 
18. 
Wolf MS, Davis TC, Curtis LM, Webb JA, Bailey SC, Shrank WH, Lindquist L, Ruo B, 
Bocchini MV, Parker RM, Wood AJ. Effect of standardized, patient-centered label instructions 
to improve comprehension of prescription drug use. Med Care. 2011;49(1):96-100.  
 
 
 
 

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Attachment 2. Example Patient Portal Medication 
Questionnaire 
We would like to ask you a few questions about your [medication name].  
Please answer each question as best as you can. We appreciate your honesty.  
 
1. During the past week, did you have any of this medicine available for you to take?  
 
Yes  ............................................................................................................................ 1 
 
No .............................................................................................................................. 0 
 
If no, please go to the end of the survey and click on the submit button. 
 
2. During the past week, did you decide to stop taking this medicine without telling your doctor?   
 
Yes  ............................................................................................................................ 1 
 
No .............................................................................................................................. 0 
 
 
3. During the past week, did you decide to take more or less of this medicine than you were 
supposed to without telling your doctor?   
 
Yes  ............................................................................................................................ 1 
 
No .............................................................................................................................. 0 
 
4. Did you forget to take any of this medicine yesterday? 
 
Yes  ............................................................................................................................ 1 
 
No .............................................................................................................................. 0 
 
 
5. Did you forget to take any of this medicine the day before yesterday? 
 
Yes  ............................................................................................................................ 1 
 
No .............................................................................................................................. 0 
 
 
6. Did you forget to take any of this medicine 3 days ago? 
 
Yes  ............................................................................................................................ 1 
 
No .............................................................................................................................. 0 
 

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7. Are the instructions on how to take this medicine confusing to you? 
 
Yes ............................................................................................................................. 1 
 
No .............................................................................................................................. 0 
 
8. Did you have a hard time paying for this medicine the last time you bought it? 
 
Yes ............................................................................................................................. 1 
 
No .............................................................................................................................. 0 
 
9. Are you thinking about stopping this medication because of concerns about side effects? 
 
Yes ............................................................................................................................. 1 
 
No .............................................................................................................................. 0 
 
If you think you are having a serious side effect from your medicine, you should contact your doctor 
as soon as possible.  
 
 
[Insert sentence specific to information about prescribed study medication] 
 
You should talk to your doctor if you have any questions or concerns about your medicine.    
 
Please click on the submit button below. Thank you for answering our questions.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Attachment 3. Example Health Literate MedSheet 
 
 
 
 

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Attachment 4. Study Drugs 
Generic (Brand) Name 
miglitol (Glyset) 
Insulin  
acarbose (Precose) 
     U200 
  
     U300 
nateglinide (Starlix)  
     U500 
repaglinide (Prandin) 
     Glargine (Lantus)/Glargine (Basaglar) 
  
     Glargine (Toujeo Solostar, Toujeo Max          
Solostar) 
 
     Detemir (Levemir) 
pioglitazone (Actos) 
     Degludec (Tresiba) 
rosiglitazone (Avandia) 
     Lispro (Humalog) 
  
     Insulin Regular Human (Humulin) 
glipizide+metformin(Metaglip) 
  
glyburide+metformin (Glucovance) 
Sitagliptin (Januvia) 
metformin and saxagliptin(Kombiglyze XR) 
Saxagliptin (Onglyza) 
metformin+pioglitazone (Actoplus MET) 
Linagliptin (Tradjenta) 
metformin+rosiglitazone (Avandamet) 
Alogliptin (Nesina) 
metformin+sitagliptin(Janumet) 
  
  
Exenatide (Byetta, Bydureon) 
bromocriptine (Cycloset, Parlodel) 
Liraglutide (Victoza) 
  
Lixisenatide (Adlyxin, Lyxumia) 
Ixekizumba (taltz) 
Dulaglutide (Trulicity) 
  
  
teriparatide (forteo) 
Canagliflozin (Invokana) 
parathyroid hormone (natpara) 
Dapagliflozin (Farxiga) 
Abaloparatide (tymlos) 
Empagliflozin (Jardiance) 
  
  
etanercept (Enbrel) 
Glimepiride (Amaryl) 
adalimumab(Humira) 
Glyburide (DiaBeta, Micronase, Glynase) 
abatacept(Orencia) 
Glipizide (Glucotrol)/ Clipizide XL (Glucotrol 
XL) 
 
Chlorpropamide (Diabinese) 
 
  
 
Metformin (Glucophage, Glumetza, 
Glucophage XR, Glumetza XR. Riomet, 
Fortamet)