Social Norms, Messengers, and Processing Fluency to Increase Hypertension Medication Adherence
Phase: NA
Conditions: Medication Adherence, Hypertension
Sponsor: Brigham and Women's Hospital

 
 
 
CLINICAL TRIAL PROTOCOL 
 
Social norms, messengers, and processing fluency to increase hypertension 
medication adherence 
 
 
Principal Investigator: 
 Linda Chung, PharmD, MBA, BCACP 
Clinical Lead, Humana, Inc. 
 
 
Version 1.3 
July 28, 2023
 
 

 
2 
Table of Contents 
PRÉCIS ........................................................................................................................................... 4 
PARTICIPATING STUDY SITES ................................................................................................ 6 
1 
Study objectives ...................................................................................................................... 6 
1.1 
Primary Objective ........................................................................................................... 6 
1.2 
Secondary Objectives...................................................................................................... 6 
2 
BACKGROUND AND RATIONALE ................................................................................... 6 
2.1 
Background on Condition, Disease, or Other Primary Study Focus .............................. 6 
2.2 
Study Rationale 6 
3 
STUDY DESIGN.................................................................................................................... 7 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS .................................................. 9 
4.1 
Inclusion Criteria ............................................................................................................ 9 
4.2 
Exclusion Criteria ........................................................................................................... 9 
4.3 
Study Enrollment Procedures ......................................................................................... 9 
5 
STUDY INTERVENTIONS ................................................................................................ 10 
5.1 
Interventions, Administration, and Duration ................................................................ 10 
5.2 
Handling of Study Interventions ................................................................................... 11 
5.3 
Concomitant Interventions ............................................................................................ 11 
5.3.1 
Allowed Interventions ............................................................................................11 
5.3.2 
Required Interventions ...........................................................................................11 
5.3.3 
Prohibited Interventions .........................................................................................11 
5.4 
Adherence Assessment ................................................................................................. 11 
6 
STUDY PROCEDURES ...................................................................................................... 11 
6.1 
Schedule of Evaluations ................................................................................................ 11 
6.2 
Description of Evaluations ............................................................................................ 12 
6.2.1 
Screening Evaluation .............................................................................................12 
6.2.2 
Enrollment, Baseline, and/or Randomization ........................................................12 
6.2.3 
Follow-up Visits.....................................................................................................12 
6.2.4 
Completion/Final Evaluation .................................................................................12 
7 
SAFETY ASSESSMENTS ................................................................................................... 12 
7.1 
Specification of Safety Parameters ............................................................................... 12 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .... 13 
7.3 
Adverse Events and Serious Adverse Events ............................................................... 13 

 
3 
7.3.1 
Reporting Procedures .............................................................................................13 
7.3.2 
Follow-up for Adverse Events ...............................................................................13 
8 
INTERVENTION DISCONTINUATION ........................................................................... 14 
9 
STATISTICAL CONSIDERATIONS.................................................................................. 14 
9.1 
General Design Issues ................................................................................................... 14 
9.2 
Sample Size and Randomization .................................................................................. 14 
9.2.1 
Treatment Assignment Procedures ........................................................................14 
9.3 
Interim analyses and Stopping Rules ............................................................................ 15 
9.4 
Outcomes 
15 
9.4.1 
Primary outcome ....................................................................................................15 
9.4.2 
Secondary outcomes ..............................................................................................15 
9.5 
Data Analyses 15 
10 DATA COLLECTION AND QUALITY ASSURANCE .................................................... 15 
10.1 
Data Collection Forms .................................................................................................. 15 
10.2 
Data Management ......................................................................................................... 15 
10.3 
Quality Assurance ......................................................................................................... 16 
10.3.1 Training .......................................................................................................................16 
10.3.2 
Quality Control Committee....................................................................................16 
10.3.3 
Metrics ...................................................................................................................16 
10.3.4 
Protocol Deviations ................................................................................................16 
10.3.5 
Monitoring .............................................................................................................16 
11 PARTICIPANT RIGHTS AND CONFIDENTIALITY ...................................................... 16 
11.1 
Institutional Review Board (IRB) Review .................................................................... 16 
11.2 
Informed Consent Forms .............................................................................................. 16 
11.3 
Participant Confidentiality ............................................................................................ 17 
11.4 
Study Discontinuation ................................................................................................... 17 
12 ETHICAL CONSIDERATIONS .......................................................................................... 17 
13 REFERENCES ..................................................................................................................... 19 
 
 
 

 
4 
PRÉCIS 
Study Title  
Social norms, messengers, and processing fluency to increase hypertension medication adherence  
 
Objectives  
Aim 1: Test the effect of dynamic social norms, messenger effects, and processing fluency messages on 
hypertension medication adherence. The study team will identify 59,997 Medicare Advantage beneficiaries 
insured by Humana who are not fully adherent to hypertension medications and randomize them to one of 
six mailed communications to increase medication adherence or control. The primary outcome will be 
medication adherence (measured by pharmacy refill claims). 
 
Aim 2: Assess association of claims and demographic characteristics with intervention responsiveness. The 
study team will evaluate the impact of the interventions as a function of baseline levels of adherence, 
demographic characteristics, and clinical comorbidities to determine the association of patient 
characteristics with intervention responsiveness. These profiles could be used to target future message 
content and framing to specific patients most likely to respond. 
 
Design and Outcomes   
Design: randomized controlled clinical trial of patient-facing messages to test the impact of social norms, 
messengers, and processing fluency on hypertension medication adherence in individuals 65 to 79 years of 
age taking medication for hypertension with adherence levels (based on the proportion of days covered 
metric [PDC]) between 60% and 85%. 
 
The primary outcome will be the average end-of-year PDC in each arm. A secondary outcome will be the 
proportion of study participants with end-of-year PDC≥80%.  
See Figure 1 for an overview of the study design. 
 
 
 
 
 
 
 
 
 
Interventions and Duration  
Study participants will be randomly assigned to one of seven conditions: 
1. A scorecard from Humana reporting patients’ medication adherence using a “refill score” 
2. The Arm 1 scorecard plus dynamic social norms messaging (noting the proportion of Humana 
members improving their medication refill scores) 
3. The Arm 1 scorecard, coming from the trusted messenger of a Humana-identified pharmacist 
taking the same medication 
Figure 1: Overview of Study Design 
Patients taking medication for hypertension
Scorecard
Social norms
Messenger 
effects
Processing 
fluency
Usual care
Social norms 
+ Scorecard
Messenger 
effects + 
Scorecard
Processing 
fluency + 
Social norms
Processing 
fluency + 
Messenger 
effects
Assess medication adherence rates at 6 months
Determine association of demographic and clinical characteristics with intervention responsiveness
Randomized
Aim 1
Aim 2

 
5 
4. A modified scorecard increasing processing fluency through a visual metaphor of “closing the 
ring” 
5. The Arm 4 scorecard plus dynamic social norms messaging 
6. The Arm 4 scorecard, coming from the trusted messenger of a Humana-identified pharmacist 
taking the same medication 
7. No mailed message (usual care) 
Participants will participate in this study for approximately 6 months (through December 2023). 
 
Sample Size and Population  
Target population: 59,997 Humana Medicare patients 65 to 79 years of age taking hypertension 
medications with adherence level (based on the proportion of days covered metric [PDC]) between 60% and 
85%. Divided across 7 arms, there will be 8,571 participants in each arm. Randomization will be 
stratified by whether participants are on a 30-day medication refill cycle (~26% of overall study 
population) or a 90-day medication refill cycle (~74% of overall study population). 

 
6 
STUDY TEAM ROSTER  
Principal Investigator: 
Linda Chung, PharmD, MBA, BCACP 
Humana, Inc. 
500 W. Main Street 
Louisville, KY 40202 
Tel: 949-491-5242 
 
Lchung1@humana.com 
 
Main responsibilities/Key roles: Responsible for overseeing the trial execution and evaluation 
activities; oversight of activities related to the trial execution and evaluation of the effectiveness 
of the interventions; overseeing the activities of the sub-investigators and study staff. 
 
PARTICIPATING STUDY SITES  
Study participants will be selected from Humana, a large insurance provider. 
 
1 
STUDY OBJECTIVES 
1.1 Primary Objective 
Hypothesis: Messages using dynamic social norms, messenger effects, and processing 
fluency in combination will more effectively increase average end-of-year adherence 
level compared to usual care. 
1.2 Secondary Objectives 
Secondary objective: identify baseline clinical and demographic characteristics to predict 
the efficacy of each message. 
 
2 
BACKGROUND AND RATIONALE  
2.1 Background on Condition, Disease, or Other Primary Study Focus 
Hypertension substantially increases the risk of myocardial infarction and stroke,1 but 
medications that can effectively control hypertension (are not always taken as 
prescribed: adherence rates for hypertension medications range from about 40% to 
74% for most Americans.2-4 Non-adherence is therefore a potent contributor to 
preventable disability and death among middle-aged and older adults.5 There also 
exist disparities by race and ethnicity among Medicare Part D beneficiaries, Black 
and Hispanic patients are 38% and 45% more likely, respectively, to be nonadherent 
compared to white patients.6 
2.2 Study Rationale 
Interventions to improve medication adherence have had modest success;7,8 even the 
most effective interventions combining behavioral, educational, and logistical 
interventions for providers, health systems, and patients have limited effects.9-11 
Leveraging behavioral principles of social norms, messenger effects, and processing 
fluency may improve their impact. 

 
7 
Social norms describe perceptions about the behavior of others, which can influence 
one’s own behavior. Making information about others’ behavior more salient can 
encourage those behaviors when base rates are high. When they are low, dynamic 
norms, or information about how others’ behavior is changing, may be more 
impactful.12 Dynamic norms have shown impact in a range of healthy behaviors.13  
The effectiveness of a message also often depends on who is communicating it. 
Messenger impact can differ depending on factors such as how trusted they are, or 
how much they have in common with the people they are communicating with. 
Messenger effects have been successfully leveraged in HIV prevention and 
management14 and diabetes screening.15 Leveraging pharmacists in hypertension 
medication adherence interventions has shown promise, mainly in direct phone calls 
from pharmacists.16,17 Having medication-related messaging come from an insurance 
company’s pharmacist rather than the insurance company itself may increase its 
impact, especially with pharmacists who are taking the same medications, and with 
lower cost through written communication rather than a phone call. 
Processing fluency is the subjective ease with which information is understood, which 
can influence its actionability. Increasing processing fluency has been impactful for 
exercise18 and other health behaviors,19 including treatment adherence for juvenile 
idiopathic arthritis20 and cancer screening.21 Studies providing patients with summary 
information for statin medication adherence have demonstrated null22 or limited23 
results, but incorporating measures to ease processing fluency through tactics such as 
visual metaphors that emphasize goal progress and attainability may increase their 
impact, especially as low health literacy is a key barrier to medication adherence.24 
Messages may have varied effectiveness based on patients’ level of adherence and/or 
demographic factors, which are also associated with differences in adherence.4,6 
Tailoring a message based upon these factors could optimize future intervention 
effectiveness. 
Thus, the study team proposes a randomized trial to test the effects of mailed 
communication leveraging social norms, messenger effects, and processing fluency 
on hypertension medication adherence for patients who are not fully adherent, 
followed by analyses identifying intervention responsiveness by patient 
characteristics. 
 
3 
STUDY DESIGN 
Type/design of trial: randomized controlled trial 
Primary objective (hypothesis): Messages using dynamic social norms, messenger 
effects, and processing fluency in combination will more effectively increase average end-
of-year adherence level compared to usual care (no messages). 
Secondary objective: To identify baseline clinical and demographic characteristics to 
predict the efficacy of each message. 
Study population: Individuals 65 to 79 years of age taking any class of medication for 
hypertension, with adherence level between 60% and 85%. 
Study arms (7,143 individuals each):  

 
8 
1. A scorecard from Humana reporting patients’ medication adherence using a “refill 
score” 
2. The Arm 1 scorecard plus dynamic social norms messaging (noting the proportion of 
Humana members improving their medication refill scores) 
3. The Arm 1 scorecard, coming from the trusted messenger of a Humana-identified 
pharmacist taking the same medication. 
4. A modified scorecard increasing processing fluency through a visual metaphor of 
“closing the ring” 
5. The Arm 4 scorecard plus dynamic social norms messaging 
6. The Arm 4 scorecard, coming from the trusted messenger of a Humana-identified 
pharmacist taking the same medication. 
7. No mailed message (usual care) 
 
Study location: Humana 
Duration of enrollment period: Individuals will be enrolled at a single time point at 
study launch 
Duration of follow-up period: Approximately 6 months 
Description of intervention and administration: Study participants will be randomized 
into receiving one of 6 mailed messages (arms 1-6 above) informing them of their 
medication refill score, or no message. Two messages will be sent during the 
intervention: The first message will contain the baseline refill score. The second message 
will note any changes in the refill score. 
 
Description of descriptive and outcome variables from the medical, insurance, and 
pharmaceutical records:  
Medical variables: None 
 
Insurance / enrollment variables: 
• Patient enrollment in a Medicare Advantage Prescription Drug plan insured by 
Humana in plan year 2023 
• Patient age in plan year 2023 
• Patient Gender  
• Patient Race 
 
Pharmaceutical variables: 
• Current adherence on hypertension medications (PDC) as of July 2023 
• Unique prescription fills for hypertension medication use 
• Unique prescription fills for other medications 
• End-of-year adherence on hypertension medications (PDC) in 2023 (following 
intervention) 
 

 
9 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1 Inclusion Criteria  
Patients must meet all inclusion criteria to participate in this study: 
• Medicare Advantage beneficiary insured by Humana 
• Between the ages of 65 and 79 
• Having at least two unique fills of any class of hypertension medication within the 
calendar year  
• Adherence level (as measured by the proportion of days covered [PDC] metric) 
between 60% and 85% 
4.2 Exclusion Criteria  
Humana policy specifies that certain subgroups of members should not be included in 
research studies per contractual agreements, privacy policies and rules, or legal 
requirements. These excluded entities and groups should not be considered part of the 
overall Humana Research Population.  Members that meet the following criteria will be 
excluded:  
• Commercial Fully Insured Groups to be excluded from Research (These are 
actually employer groups that provide Medicare Group coverage to their retired 
employees).  Each quarter Data Offerings revises and updates the file of excluded 
Commercial Groups. 
a.       Blue Cross Blue Shield of Florida 
b.       Employees Retirement System of Texas, 
c.       Georgia Department of Community Health 
d.       Ohio Operating Engineers 
e.       Ohio Public Employees Retirement System 
f.        School Board of Broward County 
g.       Public Employees Insurance Agency, an agency of the State of West 
Virginia, 
h.       Missouri Blind Pension Program 
• Florida Medicaid members 
• Illinois MMAI members 
• Puerto Rico state of residence and from any other geographical areas that are 
outside of the 50 states (residents of the District of Columbia are not excluded).  
A few members have residence in the Virgin Islands or other US territories (i.e. 
Guam, American Samoa). They constitute a small count of patients and cannot be 
assigned to the 4 geographical areas typically reported for research. 
• Administrative Services Only (ASO) 
• All Group Medicare members 
4.3 Study Enrollment Procedures  
For this study, potential participants will be identified through Humana-based datasets. 
The interventions in this study will be integrated in the usual patient messaging 
workflow. All Medicare Advantage beneficiaries have provided addresses to Humana 

 
10 
that can be used for mailed communications. 59,997 Medicare Advantage beneficiaries 
insured by Humana who are not fully adherent to hypertension medications, defined as 
patients with adherence level (as measured by the Proportion of Days Covered metric 
[PDC)) between 60% and 85% (i.e., a “refill score” between 60% and 85%).  
Study arms include six intervention arms and a usual care arm. All interventions will 
specifically target hypertension medication adherence. All participants in the six 
intervention arms will receive two mailed letters. As with other minimal-risk, quality 
improvement studies the study team has performed that involve the use of routine clinical 
tools such as patient portals and reminder letters and where informed consent is 
impracticable, the study team is requesting a waiver of informed consent and HIPAA 
authorization. There are several reasons for this. One, the nature of this quality 
improvement intervention involves testing different framing types in patient letters using 
a similar infrastructure as used during regular insurance communications. Second, the 
ability to understand the true effect of the intervention as it is delivered in the real world 
would be difficult to ascertain if formal informed consent from patients were sought. 
Third, obtaining formal informed consent would predictably reduce the number of 
patients participating in the study, especially those from under-represented populations, 
and therefore undermine the generalizability of the study results, a foundational aspect of 
pragmatic clinical trial principles. In our prior work, the study team has received a waiver 
of informed consent from the IRB for similar interventions.  
 
5 
STUDY INTERVENTIONS  
5.1 Interventions, Administration, and Duration  
Study arms: 
1. A scorecard from Humana reporting patients’ medication adherence using a “refill 
score” 
2. The Arm 1 scorecard plus dynamic social norms messaging (noting the proportion of 
Humana members improving their medication refill scores) 
3. The Arm 1 scorecard, coming from the trusted messenger of a Humana-identified 
pharmacist taking the same medication 
4. A modified scorecard increasing processing fluency through a visual metaphor of 
“closing the ring” 
5. The Arm 4 scorecard plus dynamic social norms messaging 
6. The Arm 4 scorecard, coming from the trusted messenger of a Humana-identified 
pharmacist taking the same medication 
7. No mailed message (usual care) 
 
Study participants will be randomized into one of 7 arms. Participants in a treatment arm 
(arms 1-6 above) will receive 1 of 6 variations of a mailed message informing them of their 
medication refill score. Participants in the usual care arm will not receive a message. All 
participants in the six intervention arms will receive two mailed letters in total. The first 
message will contain the baseline refill score. The second message will be sent within 60 
days of the first message and note any changes in the refill score.  
 

 
11 
5.2 Handling of Study Interventions  
Quality control will be completed and messages will be sent by Humana’s internal 
communications teams, who have extensive experience sending similar messages and 
conducting similar studies. All messages will have similar overall design and language, 
with the exception of specific sections of the messages that contain the behavioral elements 
to be tested.  
 
5.3 Concomitant Interventions 
None. 
 
5.3.1 Allowed Interventions 
None.  
 
5.3.2 Required Interventions  
None. 
 
5.3.3 Prohibited Interventions 
None. 
 
5.4 Adherence Assessment  
Not applicable—no compliance requirements in the study. 
 
6 
STUDY PROCEDURES 
6.1 
Schedule of Evaluations 
Assessment 
Baseline, 
Enrollment,  
Randomization: 
(Day 0) 
Treatment 1 
(Day 1) 
Treatment 2 
(Day 53) 
Final 
analysis 
Identification of eligible 
patients 
X 
  
  
 
Enrollment/Randomization 
X 
  
  
 
Intervention (control and 
experimental) 
 
X 
X 
 
Outcome analysis 
  
 
 
X 

 
12 
6.2 Description of Evaluations  
6.2.1 Screening Evaluation 
Consenting Procedure 
As with other minimal-risk, quality improvement studies the study team has 
performed that involve the use of routine clinical tools such as patient portals and 
reminder letters, formal informed consent will not be sought.  
Screening   
Eligibility decisions will be decided based on age and adherence level in July 2023. 
6.2.2 Enrollment, Baseline, and/or Randomization 
Enrollment 
59,997 randomly selected study participants will be enrolled from the pool of 
Humana members who meet all study inclusion criteria and none of the study 
exclusion criteria.  
Baseline Assessments 
• Current adherence level as of July 2023. 
• Historical, and demographic patient characteristics including age, gender, 
race, clinical comorbidities and other medication use 
Randomization 
All study participants will be randomized post-screening and pre-initiation of study 
intervention. 
6.2.3 Follow-up Visits 
Not applicable (there are no follow-up visits included in this study). 
6.2.4 Completion/Final Evaluation 
Not applicable (there are no follow-up visits included in this study). 
 
7 
SAFETY ASSESSMENTS  
7.1 Specification of Safety Parameters 
The study team believes that the risks to participation for members are no more than 
minimal for several reasons. First, the interventions encourage the refill of hypertension 
medications indicated for and prescribed by patients’ physicians. Second, the study team 
will not be providing any direct care to patients, and all hypertension medication refill 
decisions will ultimately be made by the patient, who will have the option of contacting 
their medical team and/or Humana for advice or specific recommendations. To minimize 
the risks to privacy from use of patient data, the study team will safeguard any identifiable 
information and limit access to the information to study investigator actively involved in 
the research who have all undergone human subjects research training, using a study ID in 
all other circumstances.  

 
13 
In this pragmatic trial, the study team does not anticipate the occurrence of any incremental 
adverse events as a result of patients receiving information that encourages them to refill 
their prescribed hypertension medications on time. All patients involved in the study have 
been prescribed these medications, and the study team will exclude patients with refill 
scores that are already ≥85%. Any adverse events from the medications themselves will be 
handled in the course of regular clinical care, as they are currently. 
 
7.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
Not applicable due to the minimal risk profile of the proposed study.  
 
7.3 Adverse Events and Serious Adverse Events  
Adverse Event (AE): Any untoward or unfavorable medical occurrence in a human study 
participant, including any abnormal sign (e.g., abnormal physical exam or laboratory 
finding), symptom, or disease, temporally associated with the participants’ involvement in 
the research, whether or not considered related to participation in the research.  
Serious Adverse Event (SAE): Any adverse event that:  
• 
Results in death  
• 
Is life threatening, or places the participant at immediate risk of death from the event 
as it occurred  
• 
Requires or prolongs hospitalization  
• 
Causes persistent or significant disability or incapacity  
• 
Results in congenital anomalies or birth defects  
• 
Is another condition which investigators judge to represent significant hazards  
Given the minimal risk nature of the study, in which the intervention involves 
enhanced communication about hypertension medication adherence for Humana 
Medicare Advantage beneficiaries for quality improvement purposes, the study team 
does not expect any SAEs or AEs related to the messages delivered in this trial.  
7.3.1 Reporting Procedures 
No additional SAEs or AEs are expected as expected to take place as a result of 
participation in this study, as the study team will not be providing any direct care to 
members and all hypertension medication adherence decisions will ultimately be 
made by the patient, with the potential consultation of their medical team. If the study 
team becomes aware of any AEs or SAEs throughout the course of the study, the 
study team will collect this information.  
AE/SAE reporting to the IRB of record will also be completed in compliance with 
IRB reporting standards.  
7.3.2 Follow-up for Adverse Events 
No additional SAEs or AEs are expected to take place as a result of participation in 
this study, as the study team will not be providing any direct care to members and all 
hypertension medication adherence decisions will ultimately be made by the patient, 
with the potential consultation of their medical team. However, the study team will be 

 
14 
notified if patients reach out to Humana with feedback about the intervention 
messages. If the study team becomes aware of any AEs or SAEs throughout the 
course of the study, the study team will collect and document this information. All 
AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will 
be considered as baseline and not reported as an AE. However, if the study 
participant’s condition deteriorates at any time during the study, it will be recorded as 
an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
Events will be followed for outcome information until resolution or stabilization. 
 
8 
INTERVENTION DISCONTINUATION  
Not applicable—due to minimal risk of proposed study, there are no discontinuation 
criteria. 
 
9 
STATISTICAL CONSIDERATIONS  
9.1 General Design Issues  
The study team hypothesizes that messages using dynamic social norms, messenger 
effects, and processing fluency in combination will more effectively increase 
adherence compared to usual care, and can identify baseline clinical and 
demographic characteristics to predict the efficacy of each message.  
The primary outcome will be the average end-of-year adherence level in each arm, 
stratified by refill cycle. The study team will use Humana claims data for outcome 
measurement, which contains information on prescription claims from pharmacies, as 
well as patient information. Linear regression will be used to compare outcomes 
between each intervention arm versus usual care.  
9.2 Sample Size and Randomization 
The study team estimates a sample size of 59,997 (8,571 per arm) will provide 80% power 
to observe a ~1% difference in end-of-year adherence level compared to the usual care arm, 
conservatively assuming a usual care arm rate of 70% and a Holm-Bonferroni corrected 
alpha of 0.05 to adjust the familywise error rates for multiple hypotheses testing. This 
difference is significant as the focus of CMS Star ratings measure interventions and are 
comparable to improvements seen in other similar large-scale behavioral communication 
studies. In secondary analyses, the study team will compare arms against each other and 
adjust for any imbalanced baseline characteristics. 
9.2.1 Treatment Assignment Procedures 
Study participants will be randomized in a 1:1:1:1:1:1:1 ratio with a random number 
generator into one of 7 arms, stratified by whether participants are on a 30-day 

 
15 
medication refill cycle (~26% of overall study population) or a 90-day medication 
refill cycle (~74% of overall study population). 
 
9.3 Interim analyses and Stopping Rules 
Not applicable—interim analyses are not planned.  
 
9.4 Outcomes  
9.4.1 Primary outcome   
The primary outcome will be the average end-of-year adherence level in each 
arm, stratified by refill cycle and adjusting for age, sex, and race.  
9.4.2 Secondary outcomes   
The secondary outcome will be the proportion of study participants with end-of-year 
PDC≥80%.  
In secondary analyses, the study team will compare arms against each other and 
adjust for any imbalanced baseline characteristics.  
 
9.5 Data Analyses 
The study team will use Humana claims data for outcome measurement, which contains 
information on prescription claims from pharmacies, as well as patient information. 
Regular linear regression will be used to compare outcomes between each intervention arm 
versus usual care adjusting for the stratified randomized design, age, gender, and race. 
These adjustments are necessary as the baseline differences in adherence in each of these 
groups could influence their responses to our intervention. 
 
10 
DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms 
The study team will use the Humana claims data for outcome measurement, which contains 
information on prescription claims from pharmacies, as well as patient information.  
 
10.2 Data Management  
Individually identifiable data are maintained for administrative purposes at Humana and are 
needed to identify members to contact for the intervention. Without use of individual level 
data, the study team could not fulfill the study’s objectives. To protect the confidentiality of 
these data, only Humana associates with the appropriate data privileges will have access to 
personal identifiers while linking the data and constructing study variables for the trial.  

 
16 
10.3 Quality Assurance  
10.3.1 Training 
All members of the research team have completed or will complete appropriate 
human subjects research training and patient privacy training related to the Health 
Insurance Portability and Accountability Act (HIPAA). 
10.3.2 Quality Control Committee  
Not applicable—no study quality control committee. 
10.3.3 Metrics 
Quality control metrics for outcome measures will include checks that messages are 
being a) correctly received based on randomization assignment and b) correctly 
targeted to 30- vs. 90-day refill cycles. The study team will conduct random checks 
that targeting is being done correctly. 
10.3.4 Protocol Deviations 
The principal investigator will review study conduct (e.g., protocol deviations) on a 
monthly basis. The principal investigator will also ensure that all protocol deviations 
for the trials are reported to the IRB according to the applicable regulatory 
requirements.  
10.3.5 Monitoring 
The study team will be notified if patients or staff reach out to Humana with feedback 
about the intervention messages. If the study team becomes aware of any AEs or 
SAEs throughout the course of the study, the study team will collect this information. 
Any reports of deaths will be submitted to the IRB within 24 hours. Any unexpected 
SAEs will be reported to the IRB within 48 hours of the study’s knowledge of the 
SAE. All other reported SAEs and AEs received by the study team will be reported to 
the IRB quarterly.  
 
11 
PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review 
This protocol and any subsequent modifications will be reviewed and approved by the IRB 
responsible for oversight of the study.   
 
11.2 Informed Consent Forms 
As with other minimal-risk, quality improvement studies the study team has performed that 
involve the use of routine clinical tools such as patient portals and reminder letters and 
where informed consent is impracticable, the study team is requesting a waiver of informed 
consent and HIPAA authorization. There are several reasons for this. One, the nature of this 
quality improvement intervention involves testing different framing types in patient letters 
using a similar infrastructure as used during regular insurance communications. Second, the 
ability to understand the true effect of the intervention as it is delivered in the real world 

 
17 
would be difficult to ascertain if formal informed consent from patients were sought. Third, 
obtaining formal informed consent would predictably reduce the number of patients 
participating in the study, especially those from under-represented populations, 
and therefore undermine the generalizability of the study results, a foundational aspect of 
pragmatic clinical trial principles. The study team has received a waiver of informed 
consent from the IRB for similar interventions.  
 
11.3 Participant Confidentiality  
Individually identifiable data are maintained for administrative purposes at Humana and are 
needed to identify members to contact for the intervention. Without use of individual level 
data, the study team could not fulfill the study’s objectives. To protect the confidentiality of 
these data, only Humana associates with the appropriate data privileges, will have access to 
personal identifiers while linking the data and constructing study variables for the trial.  All 
data will be maintained at Humana, where the IRB-approved analyses will be performed. 
Only aggregated study results will be shared externally. All study team members are 
trained in research management. 
To protect against the risk of inappropriate disclosure of personal health information, no 
identifiable or individual level data will be shared outside of Humana and all data will be 
stored securely, as they are at present. All members of the research team have completed or 
will complete appropriate human subjects research training and patient privacy training 
related to HIPAA. 
To protect against the risk of inappropriate disclosure of personal health information, only 
Humana team members will access study data with encrypted identifiers. As described, all 
members of the research team have completed or will complete appropriate human subjects 
research training and patient privacy training related to the Health Insurance Portability and 
Accountability Act (HIPAA).  
 
11.4 Study Discontinuation  
The study may be discontinued at any time by the IRB, the OHRP, the FDA, or other 
government agencies as part of their duties to ensure that research participants are 
protected.  
 
12 
ETHICAL CONSIDERATIONS 
General oversight of the project by the principal investigator will occur throughout the 
study period, including regular contact with the study team to obtain ongoing feedback.   
The study team will not be providing any direct care to patients, and all medication 
decisions will ultimately be made by the patient, with the potential consultation of their 
medical team. Any adverse events will be handled in the course of regular clinical care. 
Given the minimal risks involved in participation in this study, the study team does not 
anticipate any unacceptable adverse events. However, our plan for data and safety 

 
18 
monitoring does include multiple mechanisms to ensure minimal risk of participation in the 
research.  
If the study team becomes aware of any AEs or SAEs throughout the course of the study, 
the study team will collect this information. Any reports of deaths will be submitted to the 
IRB within 24 hours. Any unexpected SAEs will be reported to the IRB within 48 hours of 
the study’s knowledge of the SAE. All other reported SAEs and AEs received by the study 
team will be reported to the IRB quarterly. 
 
 

 
19 
13 
REFERENCES 
1. 
Centers for Disease Control and Prevention, National Center for Health Statistics. 
About Multiple Cause of Death, 1999–2020. CDC WONDER Online Database 
website. Atlanta, GA: Centers for Disease Control and Prevention; 2022. Accessed 
March 1, 2023. 
2. 
Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. ; American 
Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart 
disease and stroke statistics — 2017 update: a report from the American Heart 
Association. Circulation 2017;135(10):e146–603. Errata in: Circulation 2017; 
7;135(10):e146-e603 and Circulation 2017;136(10):e196. 
3. 
Ritchey M, Chang A, Powers C, Loustalot F, Schieb L, Ketcham M, et al. Vital 
signs: disparities in antihypertensive medication nonadherence among Medicare Part 
D beneficiaries — United States, 2014. MMWR Morb Mortal Wkly Rep 
2016;65(36):967–76. 
4. 
Briesacher BA, Andrade SE, Fouayzi H, Chan KA. Comparison of drug adherence 
rates among patients with seven different medical conditions. Pharmacotherapy 
2008;28(4):437–43. 
5. 
Burnier M, Polychronopoulou E, Wuerzner G. Hypertension and Drug Adherence in 
the Elderly. Front Cardiovasc Med. 2020 Apr 7;7:49. doi: 
10.3389/fcvm.2020.00049. PMID: 32318584; PMCID: PMC7154079. 
6. 
Holmes HM, Luo R, Hanlon JT, Elting LS, Suarez-Almazor M, Goodwin JS. Ethnic 
disparities in adherence to antihypertensive medications of medicare part D 
beneficiaries. J Am Geriatr Soc. 2012 Jul;60(7):1298-303. doi: 10.1111/j.1532-
5415.2012.04037.x. Epub 2012 Jun 15. PMID: 22702464; PMCID: PMC3396714. 
7. 
Choudhry NK, Kronish IM, Vongpatanasin W, Ferdinand KC, Pavlik VN, Egan 
BM, Schoenthaler A, Houston Miller N, Hyman DJ; American Heart Association 
Council on Hypertension; Council on Cardiovascular and Stroke Nursing; and 
Council on Clinical Cardiology. Medication Adherence and Blood Pressure Control: 
A Scientific Statement From the American Heart Association. Hypertension. 2022 
Jan;79(1):e1-e14. doi: 10.1161/HYP.0000000000000203. Epub 2021 Oct 7. PMID: 
34615363. 
8. 
Kim SJ, Kwon OD, Han EB, Lee CM, Oh SW, Joh HK, Oh B, Kwon H, Cho B, 
Choi HC. Impact of number of medications and age on adherence to 
antihypertensive medications: A nationwide population-based study. Medicine 
(Baltimore). 2019 Dec;98(49):e17825. doi: 10.1097/MD.0000000000017825. 
PMID: 31804305; PMCID: PMC6919523. 
9. 
McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to 
medication prescriptions: scientific review. JAMA. 2002;288(22):2868–2879. 
10. Takiya LN, Peterson AM, Finley RS. Meta-analysis of interventions for medication 
adherence to antihypertensives. Ann Pharmacother. 2004;38(10):1617–1624. 

 
20 
11. Haynes RB, McDonald H, Garg AX, Montague P. Interventions for helping patients 
to follow prescriptions for medications. The Cochrane Database of Systematic 
Reviews 2002, Issue 2. Art. No.: CD000011. DOI: 10.1002/14651858.CD000011. 
12. Sparkman, G., & Walton, G. M. (2017). Dynamic norms promote sustainable 
behavior, even if it is counternormative. Psychological science, 28(11), 1663-1674. 
13. Sparkman, G., & Walton, G. M. (2019). Witnessing change: Dynamic norms help 
resolve diverse barriers to personal change. Journal of Experimental Social 
Psychology, 82, 238-252. 
14. Andrawis, A., Tapa, J., Vlaev, I., Read, D., Schmidtke, K.A., Chow, E.P., Lee, D., 
Fairley, C.K. and Ong, J.J., 2022. Applying behavioural insights to HIV prevention 
and management: a scoping review. Current HIV/AIDS Reports, 19(5), pp.358-374. 
15. Hallsworth, M., Snijders, V., Burd, H., Prestt, J., Judah, G., Huf, S., & Halpern, D. 
(2016). Applying behavioral insights: simple ways to improve health outcomes. 
World Innovation Summit for Health, Doha, Qatar, 29–30 November. 
16. Santschi, V., Chiolero, A., Colosimo, A.L., Platt, R.W., Taffé, P., Burnier, M., 
Burnand, B. and Paradis, G., 2014. Improving blood pressure control through 
pharmacist interventions: a meta‐analysis of randomized controlled trials. Journal of 
the American Heart Association, 3(2), p.e000718. 
17. Contreras-Vergara, A., Sifuentes-Franco, S., Haack, S., Graciano-Machuca, O., 
Rodriguez-Carrizalez, A.D., López-Contreras, A.K., Reyes-Pérez, I.V. and Huerta-
Olvera, S.G., 2022. Impact of pharmaceutical education on medication adherence 
and its clinical efficacy in patients with type 2 diabetes and systemic arterial 
hypertension. Patient preference and adherence, pp.1999-2007. 
18. Song, H., & Schwarz, N. (2008). If it’s hard to read, it’s hard to do: processing 
fluency affects effort prediction and motivation. Psychological Science, 19(10), 986-
988. 
19. Okuhara, T., Ishikawa, H., Okada, M., Kato, M., & Kiuchi, T. (2017). Designing 
persuasive health materials using processing fluency: a literature review. BMC 
Research Notes, 10(1), 1-10. 
20. Reiser, C., Zeltner, N. A., Rettenbacher, B., Baumgaertner, P., Huemer, M., & 
Huemer, C. (2021). Explaining juvenile idiopathic arthritis to paediatric patients 
using illustrations and easy-to-read texts: improvement of disease knowledge and 
adherence to treatment. Pediatric Rheumatology, 19, 1-10. 
21. Okuhara, T., Ishikawa, H., Goto, E., Okada, M., Kato, M., & Kiuchi, T. (2018). 
Processing fluency effect of a leaflet for breast and cervical cancer screening: A 
randomized controlled study in Japan. Psychology, Health & Medicine, 23(10), 
1250-1260. 
22. Reese, P.P., Kessler, J.B., Doshi, J.A., Friedman, J., Mussell, A.S., Carney, C., Zhu, 
J., Wang, W., Troxel, A., Young, P. and Lawnicki, V., 2016. Two randomized 
controlled pilot trials of social forces to improve statin adherence among patients 
with diabetes. Journal of general internal medicine, 31, pp.402-410. 

 
21 
23. Reddy, A., Huseman, T. L., Canamucio, A., Marcus, S. C., Asch, D. A., Volpp, K., 
& Long, J. A. (2017). Patient and partner feedback reports to improve statin 
medication adherence: a randomized control trial. Journal of General Internal 
Medicine, 32, 256-261. 
24. Ngoh, L. N. (2009). Health literacy: a barrier to pharmacist–patient communication 
and medication adherence. Journal of the American Pharmacists Association, 49(5), 
e132-e149