Improving Glaucoma Medication Adherence
Phase: NA
Conditions: Glaucoma
Sponsor: VA Office of Research and Development

1 
 
 
Principal Investigator: Kelly Muir, MD 
Protocol Title: Improve Glaucoma Medication Adherence 
Version#6 01/09/2018 
 
Purpose 
The purpose if this study is to improve glaucoma medication adherence in Veterans with 
medically-treated glaucoma. The study design is a single-site randomized controlled trial. 
 
Background and Significance 
Glaucoma is the leading cause of irreversible blindness worldwide1,,,,,2 and the leading 
cause of blindness in African Americans.3  The number of Americans with glaucoma is projected 
to increase by 50% over the next 15 years.4    Despite advancements in the diagnosis and 
treatment of glaucoma, no cure exists. The only intervention that has been proven to reduce the 
risk of progressive loss of vision from glaucoma is lowering the intraocular pressure.  Although 
surgery and laser treatment may be used to reduce intraocular pressure, the most common 
treatment for glaucoma is the prescription of topical eye drops.5   
Glaucoma eye drops are prescribed to be taken daily, often multiple times per day, 
indefinitely.  As with many other daily therapies for chronic, asymptomatic disease, patient 
adherence to the prescribed glaucoma regimen is often poor.6,,,,,7 Patients with glaucoma who 
are poorly adherent to the prescribed medication regimen are more likely to experience 
progressive visual field loss than patients who are more adherent.8 Factors associated with poor 
glaucoma medication adherence include advanced age,9 limited health literacy skills,10 and 
disabilities from comorbid conditions that make self-administration of eye drop difficult, such as  
arthritis.11  
The approach to assess and address glaucoma medication adherence is guided by the 
Health Decision Model (HDM). The HDM suggests that adherence with the prescribed 
glaucoma eye drop regimen is dependent on patient experiences, patient preferences, social 
interactions, knowledge, attitudes and beliefs (Figure 1). The educational components of the 
intervention address the potential for irreversible blindness from glaucoma and increase 
understanding that eye drops reduce the risk of blindness. The self-reported adherence and 
self-efficacy surveys create the personalized response component of the intervention, which 
incorporates patient experience and preferences regarding most convenient dosing regimen. In 
addition, personalized responses are used to increase participants’ self-efficacy with eye drop 
use. For example, participants who describe low self-efficacy with the physical task of 
administering the drop are taught simple tricks such as steadying the hand on the forehead, or 
prescribed eye drop aids to help with squeezing or aiming the bottle.  
We have found in our prior work that glaucoma patients expressing poor self-efficacy regarding 
ability to take their drops as prescribed are less adherent in the following months according to 
an electronic monitor1 so the screening questions we tested in our preliminary work target self-
efficacy.  
This study will expand upon previous work and incorporate the most current evidence-
based strategies into the design. The authors of a 2009 Cochrane review concluded that 
although there were too few studies of glaucoma medication adherence of high quality to make 
firm recommendations, interventions that include glaucoma education and individualized care 
planning are most successful.45 Boland and colleagues have shown that mnemonic aides in the 
form of automated text or voicemail messaging can improve adherence, at least in the short-
term.4 We know, however, that even experienced drop-users often cannot successfully 
administer a drop into the eye,2 and daily reminders will not alleviate this barrier to adherence.  

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
2 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
Accordingly, a more comprehensive approach is needed to improve glaucoma self- 
management.  
The long-term goal of this research program is to reduce glaucoma-related blindness in 
Veterans. The objective of this project is to test an intervention to improve medication 
adherence. The proposed intervention is novel in that it was developed through a prior pilot 
study with input from Veterans with glaucoma and with a multidisciplinary team that includes 
local and national operations partners. This collaborative approach and careful attention to cost 
will facilitate implementation of the program should the intervention prove effective. The 
screening and outcomes measures have also been studied in the Durham VA Eye Clinic as part 
of the preliminary studies leading to this proposal. 
 
Design 
The proposed study is a randomized controlled trial of an educational intervention to 
improve glaucoma medication adherence. Participants will be Veterans who are patients of the 
Durham VA Eye Clinic with medically-treated glaucoma and their companions (family or friend) 
if a companion is available (we have been approved for a Waiver of Informed Consent 
Documentation for companions). Participants will be randomized to receive either a general eye 
health educational session (control arm) or an educational intervention developed to improve 
glaucoma medication adherence (intervention arm).  All participants will be provided with a 
“smart bottle” (AdhereTech, NYC) to house one of their glaucoma medications. The smart bottle 
records the date and time that the bottle is opened. For participants in the intervention arm only, 
a reminder through AdhereTech will be activated. Participants randomized to the intervention 
will meet with the interventionist approximately 4 weeks following the enrollment visit. The 
intervention will be delivered one-on-one, in a private room at the Durham VA. Companions, if 
applicable, will accompany the Veteran in the intervention. Drop administration instruction will 
be directed toward the veteran participant or if applicable towards the companion. Veterans 
randomized to the control arm will be scheduled for a session with the interventionist 
approximately 4 weeks after the enrollment visit. The control visit will include review of a 
Powerpoint presentation on general eye health, including but not specific to glaucoma. The 
presentation will be delivered one-on-one, in a private room at the Durham VA. Companions, if 
applicable, will accompany the Veteran in the presentation. Both the intervention and the control 
session will last approximately 30-60 minutes. Participants in the control arm will receive an 
electronic medication monitor but the reminder function will not be activated. Participants will be 
brought in for a 6-month follow up visit and the 12 month follow up will be conducted over the 
telephone. 
Outcomes: 
  Specific Aim 1.  Evaluate the impact of an intervention to improve glaucoma medication 
adherence among Veterans at 6-month follow up. 
    Hypothesis 1: Veterans randomized to the intervention will have a greater proportion of 
prescribed glaucoma medication doses taken as measured by the electronic medication monitor 
in the 6 months following the intervention compared to Veterans randomized to the control arm.  
     The primary outcome for hypothesis 1A is the proportion of prescribed doses taken 
according to the electronic monitor. Participants in both arms will receive the electronic monitor 
or “smart bottle,” which wirelessly transmits the date and time of opening of the smart bottle to 
the study team. From these medication events, the proportion of prescribed doses will be 
derived, defined as the ratio of the number of times the smart bottle was opened to the required 
number of doses prescribed according to the medical record over the period of time that the 
bottle is in use. For example, if a participant is advised to take his or her glaucoma drop twice a 
day for the 180 days that the bottle is in use and the smart bottle reveals 135 openings over the 
same time period, the proportion of prescribed doses taken is 37.5%.  
    

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
3 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
   Specific Aim 2. Evaluate the impact of the intervention on intensification of glaucoma therapy 
among Veterans at 12-months post randomization. 
   Hypothesis 2: The proportion of Veterans in the intervention arm that are prescribed more 
intensive glaucoma therapy, defined as addition of adjuvant glaucoma medication or 
recommendation for laser or glaucoma surgery will be less than the proportion of Veterans in 
the control arm who are prescribed more intensive glaucoma therapy in the 12 months following 
the intervention.    
    Baseline data collection will include cataloging the current glaucoma medication regimen 
prescribed to the participant. Chart abstractions will be performed at approximately 12 months 
following the randomization and intensification of glaucoma therapy will be defined as either 1) 
the addition of another glaucoma medication to the baseline regimen, 2) recommendation for 
glaucoma laser treatment, or 3) recommendation for glaucoma surgery in the 12 months 
following randomization. We will collect these data at approximately 12 months because the 
Metrics study suggested that 55% of participants in the control arm will have intensification of 
therapy within one year. 
 
  Specific Aim 3.  Evaluate the incremental cost-effectiveness and budget and workflow 
impacts of the intervention compared to usual care. 
Hypothesis 3: The intervention will be cost-effectiveness for the following ratios: 1) cost per 
percentage improvement in medication adherence; 2) cost per blindness averted; and 3) cost 
per quality-adjusted-life years saved. 
 
A direct measurement approach will be used to estimate per-patient intervention and 
control arm costs. Glaucoma-related health care utilization costs will be derived from VA 
administrative datasets. The cost estimates will be combined with observed improvement in 
medication adherence and reduction in escalation in therapy to estimate the first two 
incremental cost effectiveness ratios. Simulation using Markov modeling will be used to 
estimate the incremental cost per blindness averted and quality-adjusted life years (QALYs) 
gained. Cost estimates and labor time data collected will be combined with glaucoma 
prevalence rates among Veterans to estimate overall budget and workload impacts to the VA 
healthcare system. 
   
Risk/Benefit Assessment 
The intervention is educational in nature and does not impose physical risks to 
participants.  The primary risks to participants are loss of time and confidentiality. Participants’ 
time was considered as an important factor in designing an intervention which is efficient yet 
hopefully effective. Actions taken to mitigate the risk of loss of confidentiality are addressed in 
the sections “Privacy and Confidentiality” and “Information Security.”  If, in the course of the 
study, any information becomes available that might influence the course of clinical care of the 
participant, this information will be communicated directly to the treating provider. The study 
offers no definitive benefit to participants but the knowledge gained may lead to improvements 
in the management of glaucoma for future patients.  
 
Selection of Subjects 
We will screen individuals until we meet the desired sample size of randomizing 200 
Veterans and enroll up to 200 of their companions (family or friend) if a companion is 
available. Enrollment of a companion will not be required for otherwise eligible Veterans to be 
included in the study.  
 
Inclusion criteria for patients at datapull:  

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
4 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
1) Diagnosis of open angle glaucoma [primary open angle glaucoma, pigment dispersion 
glaucoma, pseudoexfoliation glaucoma, combined mechanism glaucoma, low tension 
glaucoma] recorded in the medical record,  
2) Prescribed glaucoma eye drops,  
3) Visual field performed within the last 9 months. As visual field testing is standard care 
glaucoma and we wish to establish baseline glaucoma severity, we will require that subjects 
have a visual field test documented in the chart within 18months of enrollment.   
 
Exclusion criteria for patients:   
1) Intraocular surgery in the past 3 months or anticipated in the next 3 months [as prescribed 
drops may change frequently in the perioperative period],  
2) Active uveitis or eye infection [as medication regimen may vary from day to day],  
3) Visual acuity less than 20/70 in the better-seeing eye, because Veterans with low vision 
may not be able to complete the vision-dependent tasks required for study completion.  
4) Lacks proficiency in English,  
5) Lacks either a cell phone or landline phone 
 
Exclusion criteria for patients At Screener: 
“How confident are you that you always remember to use your glaucoma medications? (not at 
all confident, somewhat confident, very confident)” and “In the past 4 weeks, did you ever 
forget to take your medicine?” Veterans who respond both “very confident” and “no”, 
respectively, will be excluded. 
Inclusion criteria for companions at screener:  
1) Willing to participate in assisting the patient with glaucoma drops and  
2) Willing to accompany the patient to the intervention visit for participants in the intervention 
arm or eye health education visit for participants in the control arm.  
 
Exclusion criteria for companions: Unable or unwilling to attend baseline visit and intervention 
or control arm educational session with patient participant.  
 
Exclusion criteria for patients or companions:  
1) Lacks proficiency in English,  
2) Lacks either a cell phone or landline phone.  
 
Exclusion criteria for patients post randomization: 
1. Decision by patient and provider to cease glaucoma medication use  
2. Change in functional status such that the drops are no longer administered by the patient or 
the companion (such as nursing home care) 
 
Subject Recruitment 
Recruitment and Enrollment Process:  We will use a recruitment strategy that was very 
efficient in our pilot studies. Potential participants will be identified by a data pull of Veterans 
with upcoming appointments at the DVAMC meeting inclusion/exclusion criteria. The medical 
records of potential participants identified by the data pull will be reviewed in detail to confirm 
eligibility based on the remaining inclusion/exclusion criteria. Potential participants confirmed 
to be eligible will be mailed a letter providing study information and a phone number to call to 
opt out of further contact regarding the study. Veterans who were mailed letters and did not 
opt out will be called by the study coordinator to discuss potential participation. If the Veteran 
is interested, screening questions will be asked to identify potential participants most likely to 
be poorly adherent to their prescribed glaucoma medication regimen. Veterans who screen 
positive for poor adherence and are interested in participation will be scheduled for an 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
5 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
appointment along with a companion if a companion is involved in his or her glaucoma 
management. Written informed consent and HIPAA authorization from the Veteran will be 
obtained at that time.  
 
Recruitment Targets and Feasibility:  We plan to randomize 200 Veterans (and enroll up to 
200 companions if appropriate) over 24 months. Our pilot study identified 1533 Veterans 
meeting preliminary inclusion/exclusion criteria.  In our pilot study, we used the proposed 
recruitment strategy and enrolled 31 Veterans over 3 months.  In the proposed study, we will 
recruit 4-5 days/week, which greatly expands our ability to enroll and comfortably achieve our 
recruitment goal.   
 
Consent Process 
 
Potential participants who are eligible and express interest in the study after the 
screener phone call will meet in person with a member of the research team in a private room 
in the Durham VAMC or Hillandale clinic. The study will be described in detail and all 
questions answered.  If the patient chooses to participate they will sign and date the informed 
consent and HIPPA forms. The signed informed consent and HIPPA documents safeguarded 
under lock and key at locations managed by the Durham VA Medical Center HSR&D: Legacy 
Tower, Durham, NC floor 6 room 636. While we will go through a consent process for 
companions, we were granted a Waiver of Informed Consent Documentation and a Waiver of 
HIPAA Authorization for the companion.  
 
Study Interventions 
 
The variables and data collection schedule are presented below (Table 1). 
Baseline Data Collection: To reduce travel burden (and increase recruitment), we will strive to 
administer baseline surveys following informed consent on the day of a Veteran’s scheduled 
appointment at the Durham VAMC or Hillandale clinic. However, we will make multiple dates 
and times available to the participants; and whenever possible, we will coordinate the baseline 
with a regularly scheduled appointment. 
 
Randomization and Stratification:  Participants will be randomized at the first informational 
session in a 1:1 allocation to the intervention or to the control arm.  Randomization will be 
stratified according to if a companion is enrolled in the study with the participant. We anticipate 
20% of participants will include a companion.60 Randomization will also be stratified according 
to whether the glaucoma medication housed by the AdhereTech bottle is prescribed to be take 
once daily or more than once daily.  Randomization status will be disclosed to the participant 
at the time of the intervention or control arm eye health education visit. Neither participants nor 
staff can be masked to randomization status.  
 
Retention: To minimize participant burden and maximize their retention, screening is 
conducted over the phone. We will make multiple dates and times available to the participants; 
whenever possible, we will coordinate the baseline, education and information session and 6-
month study visit with a regularly scheduled appointment. Our study staff will call participants 
prior to the intervention visit to confirm availability and remind them of the study appointment.  
In order to maximize retention during the follow-up phase of the study, study staff will contact 
participants by telephone as needed and ask about any problems using the smart bottle. 
 
 
 
 
 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
6 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
 
 
 
Study Flow: 
 
 
 
Educational Session:  Participants will meet with the interventionist approximately 4 weeks or 
up to several months (depending on convenience for the participant) following the enrollment 
visit. We will work with participants to find the most convenient time for schedule the 
educational session. Participants will be compensated $25 for their time. The intervention will 
be delivered one-on-one in a private room in the Durham VA. At the education session visit, all 
participants will be given a “smart bottle” (AdhereTech, NYC) to house one of their glaucoma 
medications.  If a participant is prescribed more than one glaucoma medication, the 
AdhereTech bottle will house the medication that is dosed most frequently. If the participant is 
prescribed more than one glaucoma medication and all glaucoma medications are dosed at 
the same frequency, the AdhereTech bottle will house the medication that the participant has 
been prescribed for the longest period of time... The smart bottle records the date and time 
that the bottle is opened. For participants in the intervention arm only, a reminder function from 
AdhereTech will be activated. Patients will have the option of choosing up to three reminder 
methods: text message, phone call, bottle will beep. All reminder messages will comply with 
VA privacy standards. Companions, if applicable, will accompany the Veteran in the education 
session and if the companion is responsible for drop administration, drop administration 
instruction will be directed towards the companion. 
 
Interventionist: The interventionist will be an ophthalmic technician trained by Dr. Muir in the 
content and delivery of the intervention.  An ophthalmic technician is chosen as the 
interventionist because, in most eye clinics, the ophthalmic technician sees the patient before 
and sometimes after the eye care provider and is responsible for some or all of the patient 
education provided. Ophthalmic technicians are employed in most, if not all, VA Eye Clinics.  
Intervention Arm Content:  
 
1.  Video testimonial from a glaucoma patient: 
(http://www.eyecareamerica.org/news/press/,  (Don Saunders discusses his glaucoma 
diagnosis).   
 
2.  Discussion of glaucoma and the potential for blindness, facilitated by the glaucoma 
educator using a 3-dimensional model eye: 
(http://www.shopanatomical.com/ProductDetails.asp?ProductCode=ACC-
JS6513&Click=26698&gdftrk=gdfV2758_a_7c884_a_7c3471_a_7cACC_d_JS6513) and 
photographic representation of glaucomatous vision loss  
 
4.  One-one-one demonstration of eye drop instillation techniques.  The participant will 
also demonstrate for the study coordinator how he or she instills eye drops so that individualized 
feedback regarding success of instillation and possible contamination of the bottle tip can be 
discussed with the subject.  

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
7 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
 
5. Provision of a mnemonic aid which alerts the participant to missed doses. We will 
develop a library of messages which can be delivered via text or voicemail to remind 
participants to take their eye drops. The messages will be consistent with the barriers identified 
by the participant on the SASES. For example, if a participant has noted difficulty taking drops 
while a work, the reminder may include a suggestion to keep an extra eye drop bottle at work. 
 
6.  Review of the participant manual, described below. 
The educator will lead the discussion with the aid of a leadership manual, outlining the 
steps of the intervention, potential questions, and suggested responses.  Each subject will 
receive a participant manual for use in the session and at home that contains: 
a.  An illustrated brochure on glaucoma and eye drop instillation technique that 
we developed to be appropriate for patients with a 4th grade reading level.   
  
 
b.  An individualized schedule for dosing of glaucoma medications.   
Subjects will be given written instructions consisting of a simple chart of the 
name of each eye drop, the color of the top on the bottle and the number of times 
per day that each medication should be used.  
c.  Individualized suggestions for improving adherence based on the subject’s 
responses to the Self-reported Adherence and Self Efficacy Survey (SASES). 
The identification of each specific problem on the SASES will be linked to 
recommendations directed at resolving the problem. In such a way, the 
intervention will be tailored to each subject’s individual needs. 
 
Control Arm Content: The control arm is designed as an attention control that includes 
interaction with the interventionist. This will allow us to attribute observed differences to the 
content of the intervention, rather increased interaction with a provider. Veterans randomized 
to the control arm will be scheduled for a session with the interventionist approximately 4 
weeks after the enrollment visit. The information session will be delivered one-on-one in a 
private room in the Durham VA. The control visit will include review of a Powerpoint 
presentation on general eye health, including but not specific to glaucoma. The control session 
will last approximately 60 minutes, similar in length to the time spent in the intervention. 
Participants in the control arm will receive an electronic medication monitor but the reminder 
function will not be activated. Companions, if applicable, will accompany patient participants to 
the educational session. 
 
6 month Study Visit: At approximately 6 months after randomization, we will schedule a follow 
up appointment with both control and intervention arm participants. We will have participants 
bring back their Adhere Tech bottles and participants will be compensated $20. At the 6-month 
study visit we will administer the SASES survey, the NEHEP survey as well as ask about any 
intermittent life events; we will observe eye drop administration and if the companion is 
responsible for drop administration, drop administration observation will be directed towards 
the companion. 
 
12 month Study Visit: At approximately 12 months following initial intervention visit we will call 
participants and administer the SASES survey, the National Eye Institute Visual Function 
Questionnaire survey, EuroQol as well as ask about any intermittent life events. 
We may call participant and/or companion after the 12 month study visit to ask follow up 
questions on their experience in our research study. 
 
 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
8 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
 
Table 1: 
Timetable of Data Collected from Patients and Companions                                                       
 
Patient Participant Measures 
 
Baseline 
Ed 
Session 
6 
months     
12 
months 
    Demographics: Age, sex, race, 
ethnicity, education,  marital status, living 
environment, self-rated health 
X 
 
 
 
   General: Rapid Estimate of Health 
Literacy in Adults63  
X 
 
 
 
   Self-reported glaucoma medication 
adherence: Self-reported Adherence and 
Self-efficacy Survey (SASES) 
 X 
 
X 
X 
   EuroQol (EQ-5D5L)   
EuroQolEuroQol 
X 
 
 
X 
   Intermittent Events: Stressful life 
events, Changes in vision 
 
 
X 
X 
   Observation of eye drop administration 
X 
X 
X 
 
   Smart bottle data 
 
 
X 
 
  NEHEP 
X 
 
X 
 
  Travel 
X 
 
 
 
  National Eye Institute Visual Function 
Questionnaire 
X 
 
 
X 
 
Chart Abstract: 
 
 
 
 
    Ophthalmologic: Visual acuity; 
ophthalmic diagnoses, history of 
ophthalmic surgery/laser, most recent 
visual field parameters including mean 
deviation and severity 
X 
 
 
X 
    General Medical: Comorbidities, 
Medication list 
X 
 
 
X 
 
Adverse Events 
All adverse events will be reported per Durham VAMC requirements. 
 
Costs and/or Payments to Subjects 
There will be no cost to research participants for any research treatment or research 
testing done as part of this research study. Some Veterans are required to pay co-payments for 
medical care and services provided by the VA. These co-payment requirements will continue to 
apply to medical care and services provided by the VA that are not part of this study. 
Participants in the study will be offered $20 to compensate for their time. Participants are 
welcome to discontinue study activities at any time. Companions will not be compensated. 
 
Data and Safety Monitoring 
Prospective Study: The data pull for potential participants will be obtained from the Corporate Data 
Warehouse. This process is typically executed with a DART application following IRB study 
approval. All data will be collected by members of the study team managed by the Durham VA 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
9 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
Medical Center HSR&D: Legacy Tower, Durham, NC floor 6 room 636. A paper chart review 
form will be used by the study coordinator or research assistant when reviewing patient charts 
from the original data pull. This information will be entered into an Illume survey once it’s 
completed. This will allow quicker review of charts. The chart review form containing inclusion 
and exclusion criteria will have the patients study ID number, date of chart review, and name of 
study staff that completes the review. Survey responses will be collected using an Illume survey 
or with paper documents and then entered into an Illume survey.  The paper documents of the 
surveys will only be used if we are unable to access the Illume surveys due to network 
connectivity problems. Therefore, the paper documents will only serve as a backup form of data 
collection. Once data can be entered into Illume the study coordinator or research assistant will 
do so. All study files with the exception of forms that require PHI such as consent forms are 
organized by study ID number and no other identifiers. The study tracking database containing 
study ID, full names, full SSN, addresses, phone numbers, and dates of clinic appointments will 
be protected using passwords and study group policies and will be accessible only to personnel 
on current staff listing who need to contact subjects, such as the project coordinators, research 
assistants, and study clinicians.The tracking database loated at 
R:vhadurhsrdfile1\$research\distributedapps\hsrdtrackingapp will serve as a crosswalk linking 
the patient PHI to their study ID.  Only members of our DVAMC research team will have access 
to identifiers and coded data.  Coded data with direct identifiers removed (i.e., name, address, 
telephone numbers, SSN, DOB) will be placed behind the VA firewall.  DVAMC HSR&D study 
staff statisticians will have access to data through VINCI during the analysis phase of our study. 
 
The in-person intervention/control session will be audio-recorded using voice recorders 
directly connected to VA issued laptops or desktops that meet applicable regulations for 
updates, encryption and information security.  The “Sparky” USB audio recorder is a pass 
through audio recorder which does not store any data.  Software is required for this device 
which is installed and configured by VA OI&T personnel after sanctuary exemptions have been 
obtained.   Transcription of the qualitative interviews will be conducted utilizing VA approved 
software installed and configured by VA OI&T personnel after sanctuary exemptions have been 
obtained.  
 
The AdhereTech data (date and time of opening the bottle) will be sent using a FIPS 
140-2 secure algorithm for our authentication protocol to a secure server maintained by 
AdhereTech. Data will be accessed by our study staff via a secure login to AdhereTech.com. 
The data will be accessed from AdhereTech.com and downloaded directly into our study project 
folders behind the VA firewall.  A crosswalk will be made to link the patient to the specific 
AdhereTech device they used. Adhere Tech will have coded information (i.e. device identifier 
only) about participants in the control arm and identified information (i.e. phone number & 
device identifier) for participants in the intervention arm. The patient information is entered by 
research study staff on the server-side of Adhere Tech through an online secure login. 
 
Data Storage: The bottle itself contains no stored patient data whatsoever. It contains only a 
unique Bottle ID which is mapped to the patient's information in AdhereTech's secure backend 
server only. The only identifying piece of information AdhereTech stores about patients is the 
phone number they have requested to be contacted in the event of a dosage reminder event. 
Even this is optional if the participant choses to have the bottle beep as a reminder. AdhereTech 
follows all measures of the HIPAA security rule to ensure that patient data is properly secured 
and encrypted while at rest. 
 
Data Transmission: AdhereTech does not transmit any patient information over the cellular 
connection. Only encoded measurements taken from the bottle and its unique bottle ID. 
AdhereTech utilizes a FIPS 140-2 secure algorithm for our authentication protocol and 
cryptographic hashing protocol to authenticate bottle connections to the AdhereTech backend 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
10 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
server. This ensures that all bottle data received comes only from AdhereTech bottles. 
AdhereTech uses the GSM network for its cellular connectivity (AT&T in the United States), in 
order to secure our bottle connections against main-in-the-middle eavesdropping attacks. Once 
connected to the cellular network, the bottle communicates using an HTTP post. AdhereTech 
supports an additional layer of security by utilizing HTTPS for Bottle->Server communication. 
AdhereTech's infrastructure machines communicate with one another on a private access-list 
controlled intranet using TLS/SSL. The bottle does not collect, store, or transmit any PHI. The 
bottle transmits measurement data to secure servers managed by AdhereTech, where they are 
then linked to the patient. However, the patient is only denoted by the anonymized unique ID of 
our choosing.  
 
Data  used for post study analysis will come from VINCI. Once data has been extracted 
study/OI& T personnel will extract and move relevant study data files to the secure VINCI project 
space allocated to this study by VINCI. Ol&T and VINCI personnel not under the purview of the Pl 
will control the servers, network, processors, firewall and software behind the VINCI firewall, 
including access rights granted to study personnel. VINCI personnel will be responsible for 
maintaining VINCI servers where study data will be kept. It will be VINCI personnel who will move, 
backup and remove study data from VINCI servers and who will control access to data stored on 
VINCI servers.  
 
Future Data Use: Data collected during the course of the study will be maintained for use in a 
future data repository (the IRB documents for this planned repository have not yet been 
submitted). This language is included in the Informed Consent Form and HIPAA waiver to be 
signed by study participant.  
 
Privacy, Confidentiality, and Information Security 
1. Lists of Data Reviewed and/or Collected for Screening/Recruitment and Conduction 
of Study:  
 
The Personal Health Information that will be obtained, used, and/or shared for this study 
includes:   
Identifier(s) 
Source(s) of Health Information 
 Names 
 Medical history & physical exam 
information: Diagnosis list: Diagnosis of 
glaucoma, primary open angle glaucoma, 
secondary glaucoma, pigment dispersion 
glaucoma, open angle glaucoma NOS, 
glaucoma suspect. Opthamology progress 
notes: eye exams, eye procedures, active 
medications, humphry visual field exam 
including date of exam, intraocular surgeries 
including type and date, active uveitis or 
ocular infections including type and date, 
visual acuity values. Primary care progress 
notes: active medications, comorbidities. 
 All geographic subdivisions smaller than a 
State, including street address, city, county, 
precinct, and zip code.  Describe: Home 
address including house number, street, city, 
state, zip code and PO Box number. 
 Photographs, videotapes, audiotapes, or 
digital or other images – In order to ensure 
fidelity to the proposed intervention, 
approximately every 8th one-on-one session 
will be audio-recorded 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
11 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
Identifier(s) 
Source(s) of Health Information 
 All elements of dates (except year) for dates 
directly related to an individual, including birth 
date, admission date, discharge date, visit or 
treatment dates, etc.; and all ages over 89,  
Describe: Date of birth, date and time of clinic 
appointments (prior and future - primary care 
and specialty clinic visits), date of eye 
procedures, date of eye exams, date of eye 
surgeries, date of humphry visual field exam, 
date of eye pressure results, date of occular 
infections. 
 Biologic specimens (e.g., blood, tissue, 
urine, saliva). Describe: 
 Telephone numbers 
 Progress notes 
 Fax numbers 
 Diagnostic / Laboratory test results 
 Electronic mail addresses 
 Operative reports 
 Social Security Numbers 
 Imaging (x-ray, CT, MRI, etc.) 
 Medical record numbers 
 Discharge summaries 
 Health plan beneficiary numbers 
 Survey / Questionnaire responses 
 Account numbers 
 Billing records 
 Certificate and/or license numbers  
 HIV testing or infection records 
 Vehicle identifiers and serial numbers, 
including license plate numbers  
 Sickle cell anemia information 
 Device identifiers and serial numbers – of the 
Adhere Tech bottle 
 Alcoholism or alcohol use information 
 Web Universal Resource Locators (URLs) 
 Drug abuse information 
 Internet Protocol (IP) address numbers 
 Mental health (not psychotherapy) notes 
 Biometric identifiers, including finger & voice 
prints 
 Psychological test results 
 Full-face photographic images and any 
comparable images 
 Genetic testing 
 Any other unique identifying number, linked 
study ID, characteristic, or code, describe:  
Creation of a Study ID 
 Other, describe:  CAN (Care Assessment 
Need) Score 
 
All non-Veterans enrolled in this study will receive the VA Notice of Privacy Practices (NOPP) 
and are requested to sign the acknowledgment form.  The signed acknowledgment form will be 
maintained with the research records. 
 
2. Data and/or Specimen Acquisition:   
Data for this study will be collected through (check all that apply): 
  Prospective data and/or specimen collection obtained from participants.  Provide 
description of processes:  
 
The data will be captured with Illume Survey; entered by research study member: 
1. Chart Review - The medical records of potential participants identified by the data pull will 
be reviewed in detail to confirm eligibility based on the remaining inclusion/exclusion 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
12 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
criteria. Inclusion criteria for patients: Diagnosis of open angle glaucoma [primary open 
angle glaucoma, pigment dispersion glaucoma, pseudoexfoliation glaucoma, combined 
mechanism glaucoma, low tension glaucoma] recorded in the medical record, Prescribed 
glaucoma eye drops, Visual field performed within the last 9 months. As visual field testing 
is standard care glaucoma and we wish to establish baseline glaucoma severity, we will 
require that subjects have a visual field test documented in the chart within 18 months of 
enrollment. Exclusion criteria for patients:  Intraocular surgery in the past 3 months or 
anticipated in the next 3 months [as prescribed drops may change frequently in the 
perioperative period], Active uveitis or eye infection [as medication regimen may vary from 
day to day], Visual acuity less than 20/70 in the better-seeing eye, because Veterans with 
low vision may not be able to complete the vision-dependent tasks required for study 
completion. (submitting a Waiver or Alteration of Informed Consent Process and Waiver or 
Alteration of HIPAA Authorization for screening purposes).  
2. Screener call survey to asses for participant interest and poor adherence (submitting a 
Waiver or Alteration of Informed Consent Process and Waiver or Alteration of HIPAA 
Authorization for screening purposes).  
3. Baseline -  After patient has signed ICF and HIPAA Authorization: Demographics: Age, 
sex, race, ethnicity, education,  marital status, living environment, self-rated health; 
General Medical: Comorbidities, Medication list, Ophthalmologic: Visual acuity; ophthalmic 
diagnoses, history of ophthalmic surgery/laser, most recent visual field parameters 
including mean deviation and severity; General: Rapid Estimate of Health Literacy in 
Adults63 and survey of available and preferred means of communication (cell phone call or 
text, landline), mental cognition; Self-reported glaucoma medication adherence: Self-
reported Adherence and Self-efficacy Survey (SASES);  National Eye Institute Visual 
Function Questionnaire; EuroQol 5D-5L, National Eye Health Education Program 10 T/F 
questionnaire (NEHEP), Travel;  Observation of eye drop administration.  
4. 6 Month Study Visit - Self-reported glaucoma medication adherence: Self-reported 
Adherence and Self-efficacy Survey (SASES); Intermittent Events: Stressful life events, 
Changes in vision. Smart bottle data: Medication events collected from smart bottle 
device, including date and time. Wwill observe eye drop administration; NEHEP. 
5. 12 Month Study Visit -  Obtained over the telephone: Self-reported glaucoma medication 
adherence: Self-reported Adherence and Self-efficacy Survey (SASES); National Eye 
Institute Visual Function Questionnaire; EuroQol 5D-5L;  Intermittent Events: Stressful life 
events, Changes in vision; From chart abstraction: General Medical: Comorbidities, 
Medication list; Ophthalmologic: Visual acuity; ophthalmic diagnoses, history of ophthalmic 
surgery/laser, most recent visual field parameters including mean deviation and severity; 
Intensification of glaucoma therapy: addition of adjuvant medical therapy, glaucoma laser, 
or glaucoma surgery. 
 
  Retrospective data collection and/or specimens obtained from medical chart review/data 
access.  Describe how data will be obtained (e.g., fileman, CDW, etc.):  Potential participants 
will be identified by a data pull of Veterans with upcoming appointments at the DVAMC meeting 
inclusion/exclusion criteria. Data pull for potential participants will be obtained from the 
Corporate Data Warehouse. This process is typically executed with a DART application 
following IRB study approval. The medical records of potential participants identified by the data 
pull will be reviewed in detail to confirm eligibility based on the remaining inclusion/exclusion 
criteria. Data used for Aim 3 analysis  will come from VINCI. Once data has been extracted 
study/OI& T personnel will extract and move relevant study data files to the secure VINCI 
project space allocated to this study by VINCI. Ol&T and VINCI personnel not under the purview 
of the Pl will control the servers, network, processors, firewall and software behind the VINCI 
firewall, including access rights granted to study personnel.  

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
13 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
 
  Retrospective data collection and/or specimens obtained from an IRB-approved data and/or 
specimen repository.  Indicate the repository source including name, VA location, and IRB 
number:       . 
Note:  for data and/or specimens obtained from a VA approved data repository, a Data Use 
Agreement (DUA) must be executed prior to obtaining data and/or specimens.  See VHA 
Handbook 1200.12 for further information. 
3. Level of Data:   
The following level(s) of data will be acquired/maintained for this study (check all that apply): 
  Identified (e.g., names, addresses or other identifiers included)  
  Coded (direct and/or all identifiers removed, but study code/ID included)  
  De-Identified (all HIPAA 18 and study ID/code removed): 
  Verified Statistically  
 
OR 
  Verified by Absence or Removal of HIPAA 18 and study ID  
  Limited Data Set 
  Other: Describe:        
 
4. Location of Data and/or Specimens, and Data Retention Plan:  
A.  
All data will be collected by members of the study team managed by the Durham 
VA Medical Center HSR&D: Legacy Tower, Durham, NC floor 6 room 636. Electronic 
files with PHI will be stored on a password protected secure VA server located at 
P:\\vhadurhsrdfile1\$projects [P:\MAGIC].  A paper chart review form will be used by the 
study coordinator or research assistant when reviewing patient charts from the original 
data pull. This information will be entered into an Illume survey once it’s completed. This 
will allow quicker review of charts. The chart review form containing inclusion and 
exclusion criteria will have the patients study ID number, date of chart review, and name 
of study staff that completes the review. Survey responses will be collected using an 
Illume survey or with paper documents and then entered into an Illume survey.  The 
paper documents of the surveys will only be used if the VA servers go down or the 
Illume survey is not working. Any data that is collected on paper the document will be 
stored at HSR&D: Legacy Tower, Durham, NC floors 6 room 636. The signed informed 
consent and HIPPA documents safeguarded under lock and key at locations managed 
by the Durham VA Medical Center HSR&D: Legacy Tower, Durham, NC floor 6 room 
636. Electronic files with PHI will be stored on a password protected secure VA server 
located at P:\\vhadurhsrdfile1\$projects [P:\MAGIC IIRThe tracking database loated at 
R:vhadurhsrdfile1\$research\distributedapps\hsrdtrackingapp will serve as a crosswalk 
linking the patient PHI to their study ID.   
 
 
B. In order to ensure fidelity to the proposed intervention, approximately every 8th one-on-
one session will be audio-recorded and reviewed by Dr. Muir and the co-investigators 
with changes made as needed. At the start of the recording we will remind the Veteran 
and partner that the session is being recorded and that their assent will be captured on 
the recording.  We will tell them that they do not have to give their names, but just say 
"yes" to the prompt you given them (e.g, "is it ok to record the session"). The one-on-

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
14 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
one session will be audio-recorded using voice recorders directly connected to VA 
issued laptops or desktops that meet applicable regulations for updates, encryption 
and information security.  The “Sparky” USB audio recorder is a pass through audio 
recorder which does not store any data.  Software is required for this device which is 
installed and configured by VA OI&T personnel after sanctuary exemptions have been 
obtained.   Transcription of the qualitative interviews will be conducted utilizing VA 
approved software installed and configured by VA OI&T personnel after sanctuary 
exemptions have been obtained.  
 
  Data will be also be placed at the VA Informatics and Computing Interface (VINCI; 
http://vaww.vinci.med.va.gov/vincicentral/VINCIWorkspace.aspx). The VA Informatics and 
Computing Infrastructure is a partnership between the VA Office of Information Technology and 
the Veterans’ Health Administration Office of Research and Development.  Researchers and 
operations staff can use VINCI to access data and statistical analysis tools in a virtual working 
environment through a certified VHA network computer using the VA Intranet or Virtual Private 
Network (VPN).  
B. Data Retention Plan 
 Research records will be maintained and destroyed according to the National Archives and 
Records Administration, Records Schedule Number:  DAA-0015-2015-0004.  Records 
destruction, when authorized, will be accomplished using the then current requirements for the 
secure disposal of paper and electronic records.  Currently, destruction of research records (see 
DAA-0015-2015-0004, section 7.6 “Research Investigator Files” for materials included in 
research records) is scheduled for 6 years after the cut-off (the cut-off is the completion of the 
research project) and may be retained longer if required by other federal agencies.  Records will 
not be destroyed without pre-notification to the facility records manager. .   
  Other data retention plan, describe:  Data collected during the course of the study will be 
maintained for use in future studies focused around investigation of glaucoma and treatment 
adherence. 
 
5. Data Access and Data Recipients:   
 
Only members of our DVAMC research team will have access to identifiers and coded data.  
Coded data with direct identifiers removed (i.e., name, address, telephone numbers, SSN, 
DOB) will be placed behind the VA firewall.  DVAMC HSR&D study staff statisticians will have 
access to data through VINCI during the analysis phase of our study.  Adhere Tech will receive 
the phone number and study subject ID for subjects in the intervention arm if the subject agrees 
to be contacted via text as a reminder to open their medication bottle.   
 
All VA research personnel who have access to VHA records are instructed, in accordance with 
VA policy, on the requirements of Federal privacy and information laws and regulations, VA 
regulations and policies, and VHA policy. All study personnel who are VA employees working 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
15 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
within the VA system have fulfilled all required HIPAA and other VA security and privacy policy 
training requirements and have agreed to follow guidelines pertaining to the protection of patient 
data. All research staff sign VA Rules of Behavior, and all study staff are up-to-date with VHA 
Privacy Policy Training and the VA Office of Cyber and Information Security Awareness Training 
Course. The data security and privacy procedures summarized in that course include logging off 
or locking the computer when walking away from it; no sharing of access codes, verify codes or 
passwords; not allowing anyone else to use the computer under one’s password; and disposing 
of sensitive information using VA-approved methods (e.g., shredder bins). 
Access to study data will be removed for all study personnel when they are no longer part of the 
research team.  
 
6. Data and/or Specimen Transportation and/or Transmission for all data and/or 
specimens involved in the study:  
  
I. 
  Data and/or specimens will not be transported or transmitted outside of Durham 
VAMC environment. 
II. 
  Data and/or specimens will be transported BETWEEN sites that are under 
the auspices of the Durham VA Medical Center.  
a. 
 Local DVAMC memorandum “Authorization to Use, Process, Store, or 
Transmit VA Sensitive Information Outside VA Owned or Managed Facilities” 
has been pre-filled out for each study team member who may transport the 
data and/or specimens off-site.  This (these) forms are included with the IRB 
materials.   
b. 
  Containers (e.g., briefcase, bin) are labeled with the following notice (label 
placed on the outside of container): 
NOTICE!!! 
Access to these records is limited to: AUTHORIZED PERSONS ONLY. 
Information may not be disclosed from this file unless permitted by all applicable legal 
authorities, which may include the Privacy Act; 38 U.S.C. §§ 5701, 5705, 7332; the 
Health Insurance Portability and Accountability Act; and regulations implementing those 
provisions, at 38 C.F.R. §§ 1.460 – 1.599 and 45 C.F.R. Parts 160 and 164. Anyone who 
discloses information in violation of the above provisions may subject to civil and criminal 
penalties. 
 
III. 
   Data and/or specimens will be transmitted to other VA sites using the following 
method(s): 
A. Data 
  Data are de-identified and thus will be sent via unencrypted e-mail or 
unencrypted disk (encryption is optional). 
  Data are coded or contain identifiers and thus will be sent  
  Other, describe:        

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
16 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
B. Specimens 
  Specimens are de-identified and thus will be sent via standard carrier (tracking is 
optional). 
  Specimens are coded or contain identifiers and thus will be sent via VA-
authorized carrier with tracking.   
  Other, describe:        
IV. 
  Data and/or specimens will be transported non-VA/VHA sites (e.g., academic 
affiliates, laboratories, etc.) using the following method(s): 
A. Data 
  Data are de-identified and thus will be sent via unencrypted e-mail or 
unencrypted CD. 
  Data shared with Adhere Tech (study ID and potentially phone number of subjects in the 
intervention arm) is entered by research study staff on the server-side of Adhere Tech through 
an online secure login.The AdhereTech data (date and time of opening the bottle) will be sent 
using a FIPS 140-2 secure algorithm for our authentication protocol to a secure server 
maintained by AdhereTech. Data will be accessed by our study staff via a secure login to 
AdhereTech.com. The data can be accessed at AdhereTech.com and downloaded directly onto 
a VA computer.  The AdhereTech device and system does not store any PHI. A crosswalk will 
be made to link the patient to the specific AdhereTech device they used. Data Storage: The 
bottle itself contains no stored patient data whatsoever. It contains only a unique Bottle ID which 
is mapped to the patient's information in AdhereTech's secure backend server only. The only 
identifying piece of information AdhereTech stores about patients is the phone number they 
have requested to be contacted in the event of a dosage reminder event. Even this is optional. 
AdhereTech follows all measures of the HIPAA security rule to ensure that patient data is 
properly secured and encrypted while at rest. 
 
Data Transmission: AdhereTech does not transmit any patient information over the cellular 
connection. Only encoded measurements taken from the bottle and its unique bottle ID. 
AdhereTech utilizes a FIPS 140-2 secure algorithm for our authentication protocol and 
cryptographic hashing protocol to authenticate bottle connections to the AdhereTech backend 
server. This ensures that all bottle data received comes only from AdhereTech bottles. 
AdhereTech uses the GSM network for its cellular connectivity (AT&T in the United States), in 
order to secure our bottle connections against main-in-the-middle eavesdropping attacks. Once 
connected to the cellular network, the bottle communicates using an HTTP post. AdhereTech 
supports an additional layer of security by utilizing HTTPS for Bottle->Server communication. 
AdhereTech's infrastructure machines communicate with one another on a private access-list 
controlled intranet using TLS/SSL. The bottle does not collect, store, or transmit any PHI. The 
bottle transmits measurement data to our secure servers, where they are then linked to the 
patient. However, the patient is only denoted by the anonymized unique ID of your choosing. 
Thus, no PHI is required for AdhereTech. 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
17 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
For intervention arm participants (in which the reminder function is activated) we will make clear 
in the HIPAA Authorization and Informed Consent that the Adhere tech server will have contact 
information on the patient if they choose to request text messaging or phone call as their 
reminder feature. . 
  Data are coded or identified and will be uploaded to sponsor website using electronic case 
report form (eCRF)  https://www.adheretech.com/users/sign_in which uses TLS 1.2, AES with 
256 bit encryption (High); ECDH_P256 with 256 bit exchange. If the workstation is changed 
during this study we will enable any new workstation with this configuration. 
 Other, describe:       
B. Specimens N/A 
  Specimens are de-identified and thus will be sent via standard carrier (tracking is 
optional) or will be hand-delivered by research study personnel.  Specify method of 
delivery:        
  Specimens are coded and thus will be sent via VA-approved carrier with tracking 
or will be hand-delivered by research study personnel.  Specify method of delivery:  
      
In accordance with the HIPAA and the Privacy Act, for any coded or identifiable data or 
specimens released from the Durham VAMC (with the exception of Limited Data Sets), an 
Accounting of Disclosure (AOD) will be maintained (e.g., in a database or spreadsheet) that 
includes the participant’s name, date of the disclosure, description of the nature of the 
Individually Identifiable Information (III) disclosed, purpose of each disclosure, and the name 
and address of the person/agency to whom the disclosure was made. 
7. Risk Mitigation Strategies:   
  Data are fully de-identified (stripped of HIPAA 18 and study ID/code) before being shared 
outside of Durham VAMC. 
  Specimens are fully de-identified (stripped of HIPAA 18 and study ID/code before being 
shared outside of Durham VAMC. 
  Direct identifiers will be maintained separately from data and or specimens by using a code 
to “identify” subjects.  In a separate database (i.e., a “linking” or “cross-walk” database) this 
code will be linked to identifying subject information.   
  Other, specify:   
 
8. Suspected Loss of VA Information: 
Should any incident such as theft or loss of data, unauthorized access of sensitive data or non-
compliance with security controls occur it will be immediately reported according to VA policy. All 
incidents regarding information security/privacy incidents will be reported to the ISO and PO within 1 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
18 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
hour of acknowledgement of issue and done so using the VHADUR Research Events Report e-mail group 
(VHADURResearchEventReport@va.gov). 
9. Reporting of Results:   
  Reporting of results, such as in scientific papers and presentations, will never identify individual 
subjects.  Data will be presented in aggregate and individual-level data will not be published. 
  Other results reporting plan, describe:       
10. Future Use of Data: 
 
  Data will be retained for future use.  This is described elsewhere in the protocol and is noted in the 
HIPAA authorization. 
 
  Future Use of data is optional (i.e., not required by the research subject). 
  Future Use of data is required for participation in the study. 
  No future use of data is currently planned. 
11. Use of Mail Merge Technology 
  Mail merge programs will be used to generate letters and/or address labels for mailings to potential 
or already enrolled research subjects.  The study team is aware that to reduce risk of mail merge related 
privacy incidents, use of mail merge programs requires a 25% accuracy check to verify that (potential) 
research subject name and mailing address are properly “matched”.  If discrepancies are found, a 100% 
accuracy check is required before letters may be mailed.   
 
Data Analysis and Statistical Considerations 
 
Specific Analyses Planned: 
    Specific Aim 1:  Evaluate the impact of an intervention to improve glaucoma 
medication adherence among Veterans at 6-month follow up. 
      Hypothesis 1: Veterans randomized to the intervention will have a greater proportion of 
prescribed glaucoma medication doses taken as measured by the electronic medication monitor 
in the 6 months following the intervention compared to Veterans randomized to the control arm.  
 
The primary outcome measure is each patient’s proportion of prescribed doses taken in the 6 
months after the intervention according to the electronic monitor.  We will use general linear 
regression models to test for a between-group difference in mean proportion of prescribed 
doses over 6 months.  This regression model can be written as: Yi = 0 + INTi*1 + FREQi*2 + 
COMi*3 , where Yi represents the proportion of prescribed doses that patient i has taken 
through the 6-month follow-up. In this model, INTi is the intervention group indicator; therefore, 
1 represents the mean difference in proportion of prescribed doses in the INT group as 
compared to the control group. We will formally evaluate the intervention effect by testing that 1 
differs from zero and report the mean difference and corresponding 95% confidence interval. A 
mean difference significantly greater than 0 provides evidence that INT group patients have a 
greater mean proportion of prescribed doses taken. The model will also include stratification 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
19 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
variables (frequency of glaucoma medication dosing (once vs more than once daily, FREQ) ), 
companion (COM)) as recommended in the CPMP guidelines.66   
 
In addition to the preceding model, mean adherence will also be separated into six 30-day 
intervals and incorporated into a longitudinal model. This will allow us to understand trends of 
adherence over the course of the 6-month follow up period (e.g. initial improvements following 
the intervention followed by stability or decline).  Non-linearity of these changes over time can 
be evaluated and contrasted between groups using SAS PROC MIXED.  The richness of this 
adherence data will also enable us to explore particular patterns of nonadherence often 
associated with clinical progression of disease.  For example, in exploratory analyses, we will 
examine whether intensification of therapy may be associated with running out of drops before 
the next available refill and missing the last week of dosing each month versus rationing drops 
such that drops are used only every 2-3 days.  
 
  Specific Aim 2: Evaluate the impact of the intervention on intensification of glaucoma 
therapy among Veterans at 12-month follow-up. 
    Hypothesis 2: The proportion of Veterans in the intervention arm that are prescribed more 
intensive glaucoma therapy, defined as addition of adjuvant glaucoma medication or 
recommendation for laser or glaucoma surgery will be less than the proportion of Veterans in 
the control arm who are prescribed more intensive glaucoma therapy in the 12 months following 
the intervention.   
We will use logistic regression to test for a between-group difference in rates of therapy 
intensification at 12 months.  This logistic regression model can be written as: Logit(pi) = 0 + 
INTi*1 + LITiFREQiLITi*2 + COMi*3, where pi represents the probability that patient i has 
intensified therapy by the 12-month follow-up. Similar to above, INTi is the intervention group 
indicator; therefore, 1 represents the log-odds ratio of therapy intensification in the intervention 
group as compared to the control group.  We will formally evaluate the intervention effect by 
testing that 1 differs from zero and report the odds ratio (exp(1)) and 95% CI of the odds ratio. 
We will formally evaluate the intervention effect by testing that 1 differs from zero and report the 
odds ratio (exp(1)) and 95% CI of the odds ratio. In this case, however, an odds ratio 
significantly less than 1.0 provides evidence that intervention group patients have lower rates of 
intensification of glaucoma therapy.  Again, the model will also include the randomization 
stratification variables (healthdaily dosing frequency (FREQhealth literacy (LIT), companion 
(COM)).  
 
Specific Aim 3:  Evaluate the incremental cost-effectiveness and budget and workflow 
impacts of the intervention compared to control. 
 
The economic analysis will be conducted in the base-case from the VA’s perspective. 
However, we will also collect patient costs, and thus taken together, will approximate a societal 
perspective. The time horizon for analysis of the first two incremental cost-effectiveness ratios 
will be the 6-months following intervention; for blindness averted and QALYs saved, we will 
adopt a lifetime time horizon. Future costs will be inflated at a 2% annual rate and future costs 
and benefits will be discounted at 3% annually in the base-case. We will use a range of 0-5% for 
these parameters in sensitivity analysis. 
 
Direct Intervention Arm Cost. The main intervention costs are labor inputs, consisting of the 
one-time fixed labor cost of training and the variable labor cost of conducting the adherence 
intervention. To calculate training cost, we will multiply Dr. Muir’s and the ophthalmic 
technician’s respective wage rates, including fringe benefits cost, by the 3 hours needed for 
training.  Training cost will be applied in the base-case analysis, but because training cost 
attenuates over time as more patients are treated, it will be excluded in sensitivity analysis. For 
each one-on-one session and monthly booster phone calls with the patient/companion, the 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
20 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
interventionist will log the session and phone call times. These times will be multiplied by the 
technician’s wage rate to estimate intervention variable labor cost. The non-labor cost inputs 
will consist of the smart bottles and eye drop aids provided to patients. The fixed training, 
variable intervention labor and non-labor inputs will be aggregated and then divided by the 
number of patients in the intervention arm to derive per-patient intervention cost. 
 
Direct Control Arm Cost. Time of each one-on-one session with the patient/companion will be 
logged and multiplied by the technician’s wage rate to estimate per-control patient cost. 
 
Indirect cost. The VA healthcare system also incurs costs, such as administration, utilities, and 
custodial services that cannot be directly attributed to a given health care service but 
nonetheless should be included in the cost analysis. We will collect direct and indirect costs 
observed for ophthalmology clinic stop codes in the VA Decision Support System (DSS) 
extract for the Durham VA Medical Center. These will be used to calculate a direct-to-indirect 
cost multiplier. This multiplier will be applied to the estimated direct intervention and control 
arm costs to estimate their respective total costs. For both intervention and control arm costs, 
we will only account for costs that are likely to be incurred in “real world” clinical care; study-
driven costs will be excluded. For example, the education session provided to control arm 
patients isn’t likely to occur in usual clinical care and will not be included in the cost estimate.  
 
Resource utilization. Expenditures are impacted not only by the cost of the intervention itself 
but also on other ophthalmology goods and services utilized. Therefore, we will collect 
glaucoma medication data from the VA Decision Support System Pharmacy extract. Using eye 
clinic stop codes and glaucoma diagnosis codes, we will collect outpatient costs incurred 
during the study period from DSS outpatient extracts.  
 
Patient costs. Attendance of the one-on-one sessions will require the patients and/or 
companion to incur travel cost and may require that he/she miss work in order to attend the 
session. We will account for these indirect costs by asking the patients and companions to 
self-report how far they traveled round trip to attend the one-on-one session and whether they 
or their companion had to take time off from work to attend the session, and if so, how much 
time they took off. We will estimate travel cost by self-report  and multiply the number of miles 
traveled by the deduction allowed by the Internal Revenue Service for medical-related travel. 
We will multiply time missed from work by an average hourly wage rate. The indirect costs 
reported in each arm will be aggregated and then divided by the respective group samples to 
estimate per-patient indirect cost.  
 
Cost-Effectiveness. The 3 cost-effectiveness ratios that we will measure are: 1) cost per 
percentage improvement in medication adherence; 2) cost per blindness averted; and 3) cost 
per QALYs saved. We will consider the intervention to be cost-effective if the incremental cost-
effectiveness ratio is ≤ $100,000 per QALY saved or $150,000 per QALY saved, as recently 
recommended.67 The estimation of these ratios are provided in the Data Analysis section 
below. 
 
Data Analysis for Cost. The analysis will begin with standard descriptive statistics of the cost 
and effectiveness variables. We will then conduct bivariate analyses to assess statistical 
significance of group mean differences. If the main outcome is significantly different between 
the two groups, the first incremental cost-effectiveness ratio will be based on cost and 
improvement in medication adherence during the study period. However, incremental cost per 
blindness averted and QALYs saved will require simulating costs and outcomes among a 
larger hypothetical population and a time horizon beyond the study period. We will estimate 

Principal Investigator: Kelly Muir, MD 
 
 
 
 
 
 
21 
Protocol Title: Improve Glaucoma Medication Adherence Version#6 
Version#6 01/09/2018 
 
these ratios by replicating the Markov model developed by the Centre for Eye Research 
Australia.68 We will use 2nd order Monte Carlo simulation to incorporate probabilistic sensitivity 
analysis into the base-case estimates and to estimate confidence intervals of the incremental 
cost-effectiveness ratios. We will also conduct extensive parameter and model sensitivity 
analyses to assess the robustness of the base-case results.  If the main outcome is not 
statistically significant between the two groups, then the economic analysis will focus on 
differences in intervention costs and health care costs between the two groups during the 
study period. 
 
 
Budget and Workflow Impact. For planning purposes it will be helpful for VA administrators to 
know what impacts implementing this adherence intervention will have on budget and 
workflow. We will use US glaucoma prevalence information available in the literature69 to 
extrapolate the number of Veterans that are likely to be affected by glaucoma annually. We will 
multiply this target patient population by the intervention and health care resource utilization 
costs observed first by the treatment arm patients and then by the control arm patients. The 
difference between these 2 estimates will be the incremental budget impact of the intervention.  
Similarly, we will multiply this target patient population by the amount of per-patient time 
required to conduct the intervention in the treatment and control arms and the incremental time 
will be the workflow impact. We will convert the incremental workflow impact to full-time 
equivalents (FTEs). 
 
 
1. 
Kingman S. Glaucoma is second leading cause of blindness globally. Bulletin of the World Health 
Organization 2004;82:887-8. 
2. 
Resnikoff S, Pascolini D, Etya'ale D, et al. Global data on visual impairment in the year 2002. 
Bulletin of the World Health Organization 2004;82:844-51. 
3. 
Congdon N, O'Colmain B, Klaver CC, et al. Causes and prevalence of visual impairment among 
adults in the United States. Arch Ophthalmol 2004;122:477-85. 
4. 
Friedman DS, Wolfs RC, O'Colmain BJ, et al. Prevalence of open-angle glaucoma among adults in 
the United States. Arch Ophthalmol 2004;122:532-8. 
5. 
Johnstone MA, Shingleton BJ, Crandall AS, Brown RH, Robin AL. Glaucoma surgery treatment 
patterns of ASCRS members--2000 survey. J Cataract Refract Surg 2001;27:1864-71. 
6. 
Friedman DS, Quigley HA, Gelb L, et al. Using pharmacy claims data to study adherence to 
glaucoma medications: methodology and findings of the Glaucoma Adherence and Persistency Study 
(GAPS). Investigative ophthalmology & visual science 2007;48:5052-7. 
7. 
Gurwitz JH, Glynn RJ, Monane M, et al. Treatment for glaucoma: adherence by the elderly. Am J 
Public Health 1993;83:711-6. 
8. 
Rossi GC, Pasinetti GM, Scudeller L, Radaelli R, Bianchi PE. Do adherence rates and 
glaucomatous visual field progression correlate? Eur J Ophthalmol 2011;21:410-4. 
9. 
Dreer LE, Girkin C, Mansberger SL. Determinants of medication adherence to topical glaucoma 
therapy. J Glaucoma 2012;21:234-40. 
10. 
Muir KW, Santiago-Turla C, Stinnett SS, et al. Health literacy and adherence to glaucoma 
therapy. Am J Ophthalmol 2006;142:223-6. 
11. 
Winfield AJ, Jessiman D, Williams A, Esakowitz L. A study of the causes of non-compliance by 
patients prescribed eyedrops. Br J Ophthalmol 1990;74:477-80.