Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes (TARGIT-DM)
Phase: NA
Conditions: Diabetes
Sponsor: Brigham and Women's Hospital

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy 
for Patients With Diabetes (TARGIT-DM) 
NCT02846779 
10/04/2018 
 
 
 
 
 
 
 
 
 
Table of Contents 
Initial protocol .............................................................................................................................................. 2 
Final protocol ............................................................................................................................................. 15 
Summary of changes to protocol .............................................................................................................. 27 
Original analysis plan ................................................................................................................................. 28 
Final analysis plan ...................................................................................................................................... 32 
Summary of changes to the analysis plan ................................................................................................. 34 
 
 
 
 
 
 
 
 
 
 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
Initial protocol 
 
Targeted Adherence Intervention to Reach Glycemic Control with Insulin Therapy for patients with 
Diabetes (TARGIT-DIABETES) 
 
 
OBJECTIVES 
 
Primary aim: To evaluate the impact of three intervention strategies of equivalent cost but which vary by 
degree of targeting and intervention intensity, on insulin persistence (primary outcome) and HbA1c level 
(secondary outcome) at 12 months. 
 
Secondary aim: To compare rates of healthcare utilization and spending between treatment groups, 
including diabetes-specific clinic visits, and emergency room visits. 
 
 
BACKGROUND AND SIGNIFICANCE 
 
With over 25 million Americans affected and annual costs upwards of $174 billion, diabetes remains a 
national public health priority.1 Effective medications to control blood glucose and reduce the morbidity 
associated with this condition are widely available and uptake in the past decade has been encouragingly 
high. In 2011, the age-adjusted percentage of adults with diagnosed diabetes who reported taking oral 
hypoglycemic therapy, insulin, or both was nearly 81%.2 
 
Unfortunately, non-adherence to these evidence-based therapies is extremely common and is a central 
contributor to poor diabetic outcomes, including cardiovascular decline, kidney, eye, and nerve disease 
complications.3  Non-adherence to oral hypoglycemic medications, typically the first line of therapy after 
diagnosis, remains around 50%, while self-reported non-adherence to insulin is as low as 30%.4,5 Among 
diabetic patients initiating basal insulin, treatment persistence, defined as remaining on the initial prescribed 
insulin without switching or discontinuation, at 12 months is 65%.6 
 
To date, research to characterize non-adherence to insulin and evaluate interventions to improve uptake 
and promote appropriate and consistent use remains sparse. Given the growing numbers of patients on 
insulin and the significant barriers to adherence among patients on insulin, including inconvenience, 
embarrassment, lifestyle restriction, negative social stigma, and poor self-efficacy, more research in this 
domain is urgently needed.  
 
Successful interventions must be multi-faceted and thus are often complex. When considering large-scale 
system-wide interventions, complexity is not a virtue. Moreover, there may be significant inefficiencies to 
providing adherence interventions to patients who may not need or benefit from them. To improve the 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
likelihood that interventions will be feasible on a large scale and can be transferred between sites, multi-
faceted yet targeted interventions are warranted. 
 
The primary aim of this study is to compare three equivalently priced strategies for improving insulin 
persistence and glycosylated hemoglobin [HbA1c] control among diabetic patients on insulin. The three 
study arms will use interventions that differ both with regard to which patients are targeted and the intensity 
of the engagement strategy that will be used (see Figure 1). The low intensity intervention in study arm 1 will 
be deployed to all subjects randomized to that arm while a moderate intensity intervention will be deployed 
to focused populations within study arm 2 and a high intensity intervention will be deployed to an even more 
focused population in study arm 3. The targeted population will be defined through poor disease control 
and/or predicted risk of non-adherence. We will evaluate differences in rates medication persistence 
measures and changes in HbA1c between the study arms using routinely collected data.  
 
The study population for this trial will consist of members enrolled in commercial insurance provided by 
Horizon Blue Cross Blue Shield of New Jersey (Horizon), one of the largest health insurers in New Jersey. 
Horizon has demonstrated a strong commitment to quality improvement interventions for patients with 
chronic diseases and has previously worked with Dr. Choudhry and his colleagues to recruit members to 
participate in pragmatic clinical trials.  
 
Horizon has an internal Privacy Board whose mandate is to review the risks and anticipated benefits to 
Horizon members of any proposed research project and to assure that research projects guarantee the 
privacy of members and confidentiality of data. For the current study, the Privacy Board has reviewed and 
approved the proposed trial as described herein and has provided a waiver of HIPAA authorization to use 
Horizon data for subject identification.   
 
Figure 1: Overall Study Design 
 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
 
 
 
 
 
STUDY DESIGN 
 
The proposed three-arm pragmatic trial will employ quality improvement interventions currently in use by 
Horizon but which, for the purposes of this study, will differ both with regard to which patients are targeted 
and the intensity of the engagement strategy that will be used. Because the cost of each arm is equivalent, 
arms without targeting will provide a lower cost, less intensive intervention to a greater number of patients, 
whereas arms with patient targeting will be able to provide a more intensive intervention to fewer patients 
who are deemed to be at risk. Please see Figure 1 for a schematic of the three study arms. 
 
ARM 1: Non-Targeted Low Intensity Intervention 
All patients in this arm will receive a low intensity, telephonic clinical pharmacist-lead adherence 
intervention, as described in the following section. The intervention will be offered to all patients regardless 
of adherence risk prediction or disease control. Because the intervention will be deployed to all subjects in 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
the arm, the nature of the intervention will be less intense, such that the number of phone calls will be 
limited and the resources offered will occur primarily at the beginning of the intervention period. 
 
ARM 2: Adherence Risk-Targeted Moderate Intensity Intervention 
Patients who are at moderate risk of insulin non-adherence at the start of the study, as determined by an 
external data analytics company that currently works with Horizon, RxAnte, will receive a moderate intensity 
adherence intervention. Sixty percent of patients will be targeted (hereafter referred to as “high-value” 
targeting) and receive the intervention. Patients predicted to have a very high or very low risk of non-
adherence (low-value targeting) will receive usual care. Because the intervention will be deployed to fewer 
subjects in the arm, the nature of the intervention will be more intense. Not only will patients be able to 
receive more pharmacist phone calls, the clinical pharmacist will be able to offer more resources to assist 
with adherence and will also provide limited feedback as necessary to the patient’s providers, including the 
prescribing physician and/or pharmacist. 
 
ARM 3: Adherence Risk and Glycemic Control-Targeted High Intensity Intervention 
 
This arm uses both adherence risk assessment as well as glycemic control, as assessed by baseline levels 
of HbA1c, to determine which patients are targeted and which intervention they receive. Patients will be 
targeted if they have a) moderate risk of non-adherence and b) poor disease control (HbA1c ≥ 8%) or 
unknown control (missing HbA1c). Overall, 40% of patients will be targeted (high-value targeting) and 
receive the intervention; the rest will receive usual care. 
 
Because the number of patients receiving the intervention is less than in arm 2, the nature of the 
intervention will be even more intense. Patients will receive more telephone calls and the clinical pharmacist 
will be able to offer much more outreach to the patient’s prescribing physician and/or pharmacist. 
 
 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
Table: Type of targeting and intervention assignment in each arm 
Targeting 
Approach 
Arm 1 
Arm 2 
Arm 3 
Sample size 
2000 
2000 
2000 
Targeting rate 
100% 
60% 
40% 
Number targeted 
2000 
1200 
800 
Type of targeting 
None 
Adherence risk only 
Adherence risk and 
Glycemic control 
Intervention 
Low intensity 
Moderate intensity for 
patients with moderate 
adherence risk 
High intensity for patients with 
moderate adherence risk AND 
high/unknown HbA1c 
 
Adherence risk prediction 
 
Adherence risk will be determined at the start of the study in partnership with RxAnte, whose analytics 
platform uses standard insurer enrollment and claims data to predict future medication use. RxAnte has a 
pre-existing relationship with Horizon and performs adherence risk prediction analytics for patients with 
chronic diseases such as hypertension and diabetes. 
 
The company’s algorithm assigns patient-level scores to reflect adherence predictions and has previously 
been validated to predict non-persistence to insulin. RxAnte will create a validation cohort with the Horizon 
claims data from 2013-2015 and will prospectively apply this model to the 2016 Horizon enrollment data. For 
the purpose of this study, our goal is to intervene on 60% patients in arm 2 and 40% patients in arm 3. 
Therefore we will assign a clinically-meaningful threshold within which we will target patients.  
 
Patients who are assessed to have a very high or very low risk of non-adherence (the highest and lowest 
risk scores) will be considered to be low-value targets. Our hypothesis is that these patients are unlikely to 
benefit from an adherence intervention due to ongoing very poor or very good adherence, respectively. This 
reflects current clinical practice of who is targeted with quality improvement interventions at the level of large 
insurers. Patients who are assessed to have a moderate risk of non-adherence will be considered to be 
high-value targets. These are patients with an adherence risk score of 0.2 and higher (20% probability or 
higher of being adherent to insulin at 12 months).  
 
INTERVENTION COMPONENTS 
 
The interventions for each of the study arms will be delivered by Magellan, a pharmacy benefit management 
company that provides telephonic disease management services to numerous large insurers, including 
Horizon. The specific interventions have been designed by the investigative team in conjunction with 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
Magellan and will offer an approach tailored to increasing levels of patient engagement and support in 
attaining higher levels of insulin persistence.  
 
The intervention components increase in frequency and type of contact across the three study arms and are 
cumulative (each arm includes all intervention components included in previous arm). Each patient will 
receive an introductory mailing that describes the pharmacist consultation and a pillbox. The components 
are summarized in the table below and described in more detail in Appendix B. 
 
Table: Summary of intervention components 
Intervention Components 
Arm 1 
Arm 2 
Arm 3 
Outreach Population (n) 
2000 
1200 
800 
Introductory mailing with pillbox 
X 
X 
X 
Telephonic intervention focus 
Adherence 
Adherence and 
Glycemic Control  
Adherence and 
Glycemic Control 
Max number of calls to patient 
4 
6 
12 
Type of provider and/or pharmacy 
outreach 
Obtain contact 
information 
Obtain contact 
information; limited 
f/u from 
techs/CCAs for 
certain clinical 
scenarios  
Obtain contact 
information; full f/u 
from techs/CCAs/ 
PharmDs for all 
clinical scenarios 
Max number of calls to 
provider/pharmacist 
1 
2 
12 
Quarterly educational mailings 
 
X 
X 
Text messaging (TM) service 
None  
Moderate intensity 
High  
intensity 
 
ARM 1: Non-Targeted Low Intensity Intervention 
 
Patients will receive an adherence outreach delivered by Magellan clinical staff, including pharmacists  with 
or without advanced training (e.g. certification in Medication Therapy Management), nurses, technicians, 
customer care associates, and 4th year PharmD candidates. Patients will be contacted by telephone and 
during these calls, the Magellan staff will: 
1. Confirm current treatment regimen and reason(s) for treatment 
2. Guide member-specific discussion focused on identifying potential barriers to medication adherence 
including cost, side effects, complexity of regimen, education, and expectations of treatment 
3. Conduct motivational interviewing and educational reinforcement regarding disease state, 
importance of adherence, and strategies for success/improvement. 
 
This telephonic consultation may be repeated up to 2 times (3 calls total) and will focus on identifying and 
overcoming barriers to adherence. The follow-up calls may be limited to the beginning of the outreach and 
will not necessarily be distributed throughout the duration of follow-up. 
 
 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
ARM 2: Adherence Risk-Targeted Moderate Intensity Intervention 
 
Patients will receive an adherence and glycemic control outreach delivered by Magellan clinical staff. Only 
members with a telephone number available in the Horizon member files will be assigned to the moderate 
intensity intervention. Patients will be contacted by telephone and during these calls, in addition to the topics 
discussed in arm 1, the Magellan staff will: 
1. Assess the adequacy of the patient’s regimen. Staff will not suggest any changes to the patient’s 
regimen but instead educate and encourage patient to communicate to provider. 
2. Guide member-specific discussion focused on identifying potential barriers to glycemic control 
including availability of glucose monitoring equipment, side effects, barriers to diet and lifestyle 
recommendations, and education 
3. Conduct motivational interviewing and educational reinforcement regarding disease state, 
importance of adherence, and strategies for success/improvement 
 
In addition to the pharmacist intervention described in arm 1, this arm will include: 
- 
Up to 6 calls total by Magellan clinical staff. If 6 calls are not deemed necessary by patient and 
pharmacist, the pharmacist will at the very least try to provide follow-up at 3, 6, and 9 months after 
randomization, where appropriate. 
- 
One outreach call to provider or pharmacist, as needed, to update clinical status and resolve 
potential barrier to adherence 
- 
Referral to a moderate intensity text messaging (TM) service as needed. The content of the TMs 
have been created by the BWH investigators and the TMs themselves will be delivered by the 
investigators to a Magellan subcontractor, Mobile Commons, which provides a service for patients 
to provide their cell phone numbers to receive weekly text messages in a way that is confidential.  
Patients will be asked to opt in. 
- 
Quarterly follow-up letters at 3, 6, and 9 months that include information about importance of 
glycemic control and adherence. The schedule of mailings is listed in the table below and copies of 
the actual mailings are attached. 
Table: Mailings schedule 
Month 
Arm 1 
Arms 2 and 3 
0 
Intro letter and 
postcard + pillbox 
Intro letter and postcard + pillbox 
Intro letter and postcard + pillbox 
 
 
Previously reached by Magellan 
pharmacist 
Previously not reached by Magellan 
pharmacist 
3 
 
• 
Follow-up letter: previously 
reached member 
• 
Handout: “Understanding my 
insulin treatment” 
• 
Follow-up letter: previously not 
reached member 
• 
Handout: “Understanding my 
insulin treatment” 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
6 
 
• 
Follow-up letter: previously 
reached member 
• 
Handout: “Remembering to 
take my medicines” 
• 
Follow-up letter:  previously not 
reached member 
• 
Handout: “Remembering to take 
my medicines” 
9 
 
• 
Follow-up letter: previously 
reached member 
• 
Handout: “Maintaining my 
treatment plan” 
• 
Follow-up letter: previously not 
reached member 
• 
Handout: “Maintaining my 
treatment plan” 
 
ARM 3: Adherence Risk and Glycemic Control-Targeted High Intensity Intervention 
 
Patients will receive the same adherence and glycemic control outreach delivered by Magellan clinical staff 
as described in Arm 2. Only members with a telephone number available in the Horizon member files will be 
assigned to the high intensity intervention. 
 
In addition to the pharmacist interventions described in arm 2, this arm will include the following changes: 
- 
Up to 12 calls total by Magellan clinical staff, instead of 6 calls total. 
- 
Up to 12 outreach calls to provider or pharmacist, as needed, to update clinical status and resolve 
potential barrier to adherence, instead of 1 outreach call. In this scenario, the pharmacist may 
discuss potential insulin dose titration with prescribing physician and communicate these changes 
back to the patient with the provider’s permission. 
- 
Referral to a high intensity text messaging (TM) service as needed, instead of referral to only a 
moderate TM service. The moderate intensity TM service includes weekly texts whereas the high 
intensity TM service includes daily texts. Patients will have the option to enroll in either frequency, if 
interested. If the patient elects into receiving daily texts, they will have the option of switching into 
weekly texts or no texts at any point during the intervention. 
 
 
STUDY POPULATION 
 
Patients who are potentially eligible for inclusion will be identified from the cohort of patients currently 
receiving health insurance from Horizon. In order to maintain generalizability, exclusion criteria will be 
minimal. Patients meeting the following inclusion/exclusion criteria will be selected for participation: 
 
Inclusion criteria: 
a) Commercially-insured individuals who receive medical and pharmacy health insurance benefits 
administered by Horizon Blue Shield Blue Cross of New Jersey 
b) Age  ≥ 18 years as of January 1, 2016 
c) ≥ 3 months of continuous enrollment prior to randomization 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
d) ≥ 1 prescription for basal insulin during the 6 months prior to randomization 
e) Members with type 2 diabetes, as determined by medical claims or prior prescription of an oral anti-
diabetic medication (OAD) 
 
Exclusion criteria: 
a) Patients whose primary insurance is Medicaid or Medicare 
 
Baseline HbA1c will not be an inclusion criterion. However patients with baseline HbA1c (within 6 months of 
randomization) will be flagged and later stratified during randomization.  
 
 
RECRUITMENT PROCEDURE 
Patients will be recruited into the study by a review of Horizon medical and pharmacy claims and risk 
scoring performed by RxAnte. After randomization, patients will be assigned to an intervention group or 
usual care depending on study arm, adherence risk score, and baseline HbA1c value. 
 
Once a patient is reached, the Magellan pharmacist will explain the purpose of the consultation and ask the 
patient if he/she would like to participate. If a patient agrees, this will be considered implicit consent. If a 
patient wishes to not participate and wishes to not receive further contact, this will be noted and the patient 
will not be contacted again.  
 
Data on all patients will be analyzed according to whichever group the patient was randomized to, 
regardless of whether the patient was reached or agreed to participate. 
 
RANDOMIZATION 
 
There are multiple partners who are working together to identify eligible patients and deliver the intervention. 
Our goal is to use the minimal amount of clinical data necessary at each step in order to implement the 
intervention. Because of the large number of patients who will be contacted by Magellan pharmacists, 
patient selection, randomization, and recruitment will occur over the first 4 months of the trial. This will 
require the following steps: 
 
• 
Horizon analytics team will send claims data on all insulin users from 2013 to 2015 to RxAnte to perform 
validation of insulin adherence risk scores. Before the study starts, Horizon will send updated enrollment 
files. 
• 
RxAnte will assign risk scores on all insulin users and send risk scores to Horizon 
• 
Horizon will apply inclusion and exclusion criteria and select patients eligible for randomization. They will 
flag patients with baseline HbA1c values, claims-based diabetes diagnosis (in contrast to OAD-based 
diabetes diagnosis, and telephone number availability).  

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
• 
Horizon will randomize 1,500 patients meeting criteria above. Randomization will be stratified by HbA1c 
availability, claims-based diabetes diagnosis, and telephone number availability.  
• 
Horizon will send the following aggregated and de-identified data to Brigham: distribution of risk scores 
and HbA1c values in arms 2 and 3. Brigham investigators will choose risk score and HbA1c cut-offs that 
will result in appropriate targeting levels. 
• 
Brigham will send these cut-offs to Horizon. The Horizon analytics team will apply these thresholds to 
make intervention assignments within each randomized group. 
• 
Horizon will send the necessary data on all patients assigned to receive an intervention to Magellan. 
• 
The process above will be repeated monthly 3 additional times so that randomized and recruitment is 
staggered over the course of 4 months. 
 
Randomization will occur in a 1:1:1 ratio conducted on the patient level. In order to have adequate power to 
study our secondary outcome, change in HbA1c, our randomization will be stratified on patients with 
baseline HbA1c lab availability within the 6 months prior to randomization.  
 
This randomization will occur using a random number generator at Horizon Analytics. Randomization codes 
will be assigned strictly sequentially as patients become eligible. The randomization key will be maintained 
at Horizon Analytics as well as the allocation of patients to the intervention arms. 
 
Data Sources 
 
The data that will be used for patient selection and analysis includes medical and pharmacy claims and lab 
data from Horizon. Complete paid pharmacy and medical services claims data will be combined into a 
database consisting of all filled prescription, procedures, inpatient and outpatient physician encounters, 
hospitalizations, long-term care admissions and deaths for all patients studied.  
 
In addition to the Horizon claims data, both vendors will provide de-identified aggregate data on risk 
prediction and patient contact to Brigham investigators. Specifically, RxAnte will provide aggregate risk 
prediction scores from their initial scoring. These scores will be linked to an anonymous patient ID (the link 
between patient ID and medical record number will be kept by Horizon analytics). Magellan will provide a 
monthly report of how many patients were reached and the type of contact (e.g. number of patients who 
were engaged on the telephone, the number of providers who were contacted). 
 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
 
 
REFERENCES 
 
1. 
CDC. National Diabetes Fact Sheet, 2011. 2011; 
http://www.cdc.gov/DIABETES/pubs/pdf/ndfs_2011.pdf. Accessed April 12, 2014. 
2. 
CDC. Crude and Age-Adjusted Percentage of Adults with Diabetes Using Any Diabetes Medication. 
2011; ://www.cdc.gov/diabetes/statistics/meduse/fig3.htm. Accessed April 12, 2014. 
3. 
Aikens JE, Piette JD. Longitudinal association between medication adherence and glycaemic 
control in Type 2 diabetes. Diabet Med. Mar 2013;30(3):338-344. 
4. 
Bryson CL, Au DH, Maciejewski ML, et al. Wide clinic-level variation in adherence to oral diabetes 
medications in the VA. J Gen Intern Med. May 2013;28(5):698-705. 
5. 
Farsaei S, Radfar M, Heydari Z, Abbasi F, Qorbani M. Insulin adherence in patients with diabetes: 
Risk factors for injection omission. Prim Care Diabetes. Apr 7 2014. 
6. 
Abu Hassan H, Tohid H, Mohd Amin R, Long Bidin MB, Muthupalaniappen L, Omar K. Factors 
influencing insulin acceptance among type 2 diabetes mellitus patients in a primary care clinic: a 
qualitative exploration. BMC Fam Pract. 2013;14:164. 
7. 
Avorn J, Monette J, Lacour A, et al. Persistence of use of lipid-lowering medications: a cross-
national study. JAMA : the journal of the American Medical Association. May 13 1998;279(18):1458-
1462. 
8. 
Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J. Long-term persistence in 
use of statin therapy in elderly patients. JAMA : the journal of the American Medical Association. Jul 
24-31 2002;288(4):455-461. 
9. 
Choudhry NK, Setoguchi S, Levin R, Winkelmayer WC, Shrank WH. Trends in adherence to 
secondary prevention medications in elderly post-myocardial infarction patients. 
Pharmacoepidemiology and drug safety. Dec 2008;17(12):1189-1196. 
10. 
Cutrona SL, Choudhry NK, Fischer MA, et al. Targeting cardiovascular medication adherence 
interventions. J Am Pharm Assoc (2003). May-Jun 2012;52(3):381-397. 
11. 
Solomon DH, Iversen MD, Avorn J, et al. Osteoporosis telephonic intervention to improve 
medication regimen adherence: a large, pragmatic, randomized controlled trial. Arch Intern Med. 
Mar 26 2012;172(6):477-483. 
12. 
Wei W, Pan C, Xie L, Baser O. Real-world insulin treatment persistence among patients with type 2 
diabetes. Endocr Pract. Jan-Feb 2014;20(1):52-61. 
 
 
 
 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
Appendix B: Study Workflow 
 
 
 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
 
 
 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
Final protocol 
 
Targeted Adherence Intervention to Reach Glycemic Control with Insulin Therapy for patients with 
Diabetes (TARGIT-DIABETES) 
 
 
OBJECTIVES 
 
Primary aim: To evaluate the impact of three intervention strategies of equivalent cost but which vary by 
degree of targeting and intervention intensity, on insulin persistence (primary outcome) and HbA1c level 
(secondary outcome) at 12 months. 
 
Secondary aim: To compare rates of healthcare utilization and spending between treatment groups, 
including diabetes-specific clinic visits, and emergency room visits. 
 
 
BACKGROUND AND SIGNIFICANCE 
 
With over 25 million Americans affected and annual costs upwards of $174 billion, diabetes remains a 
national public health priority.1 Effective medications to control blood glucose and reduce the morbidity 
associated with this condition are widely available and uptake in the past decade has been encouragingly 
high. In 2011, the age-adjusted percentage of adults with diagnosed diabetes who reported taking oral 
hypoglycemic therapy, insulin, or both was nearly 81%.2 
 
Unfortunately, non-adherence to these evidence-based therapies is extremely common and is a central 
contributor to poor diabetic outcomes, including cardiovascular decline, kidney, eye, and nerve disease 
complications.3  Non-adherence to oral hypoglycemic medications, typically the first line of therapy after 
diagnosis, remains around 50%, while self-reported non-adherence to insulin is as low as 30%.4,5 Among 
diabetic patients initiating basal insulin, treatment persistence, defined as remaining on the initial prescribed 
insulin without switching or discontinuation, at 12 months is 65%.6 
 
To date, research to characterize non-adherence to insulin and evaluate interventions to improve uptake 
and promote appropriate and consistent use remains sparse. Given the growing numbers of patients on 
insulin and the significant barriers to adherence among patients on insulin, including inconvenience, 
embarrassment, lifestyle restriction, negative social stigma, and poor self-efficacy, more research in this 
domain is urgently needed.  
 
Successful interventions must be multi-faceted and thus are often complex. When considering large-scale 
system-wide interventions, complexity is not a virtue. Moreover, there may be significant inefficiencies to 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
providing adherence interventions to patients who may not need or benefit from them. To improve the 
likelihood that interventions will be feasible on a large scale and can be transferred between sites, multi-
faceted yet targeted interventions are warranted. 
 
The primary aim of this study is to compare three equivalently priced strategies for improving insulin 
persistence and glycosylated hemoglobin [HbA1c] control among diabetic patients on insulin. The three 
study arms will use interventions that differ both with regard to which patients are targeted and the intensity 
of the engagement strategy that will be used (see Figure 1). The low intensity intervention in study arm 1 will 
be deployed to all subjects randomized to that arm while a moderate intensity intervention will be deployed 
to focused populations within study arm 2 and a high intensity intervention will be deployed to an even more 
focused population in study arm 3. The targeted population will be defined through poor disease control 
and/or predicted risk of non-adherence. We will evaluate differences in rates medication persistence 
measures and changes in HbA1c between the study arms using routinely collected data.  
 
The study population for this trial will consist of members enrolled in commercial insurance provided by 
Horizon Blue Cross Blue Shield of New Jersey (Horizon), one of the largest health insurers in New Jersey. 
Horizon has demonstrated a strong commitment to quality improvement interventions for patients with 
chronic diseases and has previously worked with Dr. Choudhry and his colleagues to recruit members to 
participate in pragmatic clinical trials.  
 
Horizon has an internal Privacy Board whose mandate is to review the risks and anticipated benefits to 
Horizon members of any proposed research project and to assure that research projects guarantee the 
privacy of members and confidentiality of data. For the current study, the Privacy Board has reviewed and 
approved the proposed trial as described herein and has provided a waiver of HIPAA authorization to use 
Horizon data for subject identification.   
 
 
 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
Figure 1: Overall Study Design 
 
 
 
 
 
 
STUDY DESIGN 
 
The three-arm pragmatic trial will employ quality improvement interventions currently in use by Horizon but 
which, for the purposes of this study, will differ both with regard to which patients are targeted and the 
intensity of the engagement strategy that will be used. Because the cost of each arm is equivalent, arms 
without targeting will provide a lower cost, less intensive intervention to a greater number of patients, 
whereas arms with patient targeting will be able to provide a more intensive intervention to fewer patients 
who are deemed to be at risk. Please see Figure 1 for a schematic of the three study arms. 
 
ARM 1: Non-Targeted Low Intensity Intervention 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
All patients in this arm will receive a low intensity, telephonic clinical pharmacist-lead adherence 
intervention, as described in the following section. The intervention will be offered to all patients regardless 
of adherence risk prediction or disease control. Because the intervention will be deployed to all subjects in 
the arm, the nature of the intervention will be less intense, such that the number of phone calls will be 
limited and the resources offered will occur primarily at the beginning of the intervention period. 
 
ARM 2: Adherence Risk-Targeted Moderate Intensity Intervention 
Patients who are at moderate risk of insulin non-adherence at the start of the study, as determined by an 
external data analytics company that currently works with Horizon, RxAnte, will receive a moderate intensity 
adherence intervention. Sixty percent of patients will be targeted (hereafter referred to as “high-value” 
targeting) and receive the intervention. Patients predicted to have a very high or very low risk of non-
adherence (low-value targeting) will receive usual care. Because the intervention will be deployed to fewer 
subjects in the arm, the nature of the intervention will be more intense. Not only will patients be able to 
receive more pharmacist phone calls, the clinical pharmacist will be able to offer more resources to assist 
with adherence and will also provide limited feedback as necessary to the patient’s providers, including the 
prescribing physician and/or pharmacist. 
 
ARM 3: Adherence Risk and Glycemic Control-Targeted High Intensity Intervention 
 
This arm uses both adherence risk assessment as well as glycemic control, as assessed by baseline levels 
of HbA1c, to determine which patients are targeted and which intervention they receive. Patients will be 
targeted if they have a) moderate risk of non-adherence and b) poor disease control (HbA1c ≥ 8%) or 
unknown control (missing HbA1c). Overall, 40% of patients will be targeted (high-value targeting) and 
receive the intervention; the rest will receive usual care. 
 
Because the number of patients receiving the intervention is less than in arm 2, the nature of the 
intervention will be even more intense. Patients will receive more telephone calls and the clinical pharmacist 
will be able to offer much more outreach to the patient’s prescribing physician and/or pharmacist. 
 
 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
Table: Type of targeting and intervention assignment in each arm 
Targeting 
Approach 
Arm 1 
Arm 2 
Arm 3 
Sample size 
2000 
2000 
2000 
Targeting rate 
100% 
60% 
40% 
Number targeted 
2000 
1200 
800 
Type of targeting 
None 
Adherence risk only 
Adherence risk and 
Glycemic control 
Intervention 
Low intensity 
Moderate intensity for 
patients with moderate 
adherence risk 
High intensity for patients with 
moderate adherence risk AND 
high/unknown HbA1c 
 
Adherence risk prediction 
 
Adherence risk will be determined at the start of the study in partnership with RxAnte, whose analytics 
platform uses standard insurer enrollment and claims data to predict future medication use. RxAnte has a 
pre-existing relationship with Horizon and performs adherence risk prediction analytics for patients with 
chronic diseases such as hypertension and diabetes. 
 
The company’s algorithm assigns patient-level scores to reflect adherence predictions and has previously 
been validated to predict non-persistence to insulin. RxAnte will create a validation cohort with the Horizon 
claims data from 2013-2015 and will prospectively apply this model to the 2016 Horizon enrollment data. For 
the purpose of this study, our goal is to intervene on 60% patients in arm 2 and 40% patients in arm 3. 
Therefore we will assign a clinically-meaningful threshold within which we will target patients.  
 
Patients who are assessed to have a very high or very low risk of non-adherence (the highest and lowest 
risk scores) will be considered to be low-value targets. Our hypothesis is that these patients are unlikely to 
benefit from an adherence intervention due to ongoing very poor or very good adherence, respectively. This 
reflects current clinical practice of who is targeted with quality improvement interventions at the level of large 
insurers. Patients who are assessed to have a moderate risk of non-adherence will be considered to be 
high-value targets. These are patients with an adherence risk score of 0.1 and higher (10% probability or 
higher of being adherent to insulin at 12 months).  
 
Once RxAnte calculates baseline risk scores on the entire population, we will look at the distribution of risk 
scores in arms 2 and 3 to make intervention assignments. In arm 2, we will assign the moderate intensity 
intervention to all patients with a telephone number with a risk score of 0.1 up until the point where we reach 
60% of the population (1200 patients). All other patients in arm 2 will receive usual care. In arm 3, we will 
assign the high intensity intervention to all patients with a telephone number with a HbA1c greater than or 
equal to 8% or missing HbA1c who have a risk score of 0.2 or greater, up until the point where we reach 
40% of the population (800 patients). All other patients in arm 3 will receive usual care. 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
 
 
INTERVENTION COMPONENTS 
 
The interventions for each of the study arms will be delivered by Magellan, a pharmacy benefit management 
company that provides telephonic disease management services to numerous large insurers, including 
Horizon. The specific interventions have been designed by the investigative team in conjunction with 
Magellan and will offer an approach tailored to increasing levels of patient engagement and support in 
attaining higher levels of insulin persistence.  
 
The intervention components increase in frequency and type of contact across the three study arms and are 
cumulative (each arm includes all intervention components included in previous arm). Each patient will 
receive an introductory mailing that describes the pharmacist consultation and a pillbox. The components 
are summarized in the table below and described in more detail in Appendix B. 
 
Table: Summary of intervention components 
Intervention Components 
Arm 1 
Arm 2 
Arm 3 
Outreach Population (n) 
2000 
1200 
800 
Introductory mailing with pillbox 
X 
X 
X 
Telephonic intervention focus 
Adherence 
Adherence and 
Glycemic Control  
Adherence and 
Glycemic Control 
Outreach based on telephone 
number availability 
All members 
Only members with 
phone number 
Only members with 
phone number 
Max number of attempts to engage 
patient 
3 
4 
4 
Max number of calls to engaged 
patient 
3 
6 
12 
Type of provider and/or pharmacy 
outreach 
Obtain contact 
information 
Obtain contact 
information; limited 
f/u from 
techs/CCAs for 
certain clinical 
scenarios  
Obtain contact 
information; full f/u 
from techs/CCAs/ 
PharmDs for all 
clinical scenarios 
Max number of calls to 
provider/pharmacy for contact info 
2 
2 
2 
Max number of pharmacy/provider 
clinical follow-up 
0 
1 
12 
Quarterly educational mailings 
None 
X 
X 
Text messaging (TM) service 
None  
Moderate intensity 
High  
intensity 
Adverse event reporting 
X 
X 
X 
 
ARM 1: Non-Targeted Low Intensity Intervention 
 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
NCT02846779 
Patients will receive an adherence outreach delivered by Magellan clinical staff, including pharmacists, 
nurses, technicians, customer care associates, and 4th year PharmD candidates. Patients will be contacted 
by telephone and during these calls, the Magellan staff will: 
4. Confirm current treatment regimen and reason(s) for treatment 
5. Guide member-specific discussion focused on identifying potential barriers to medication adherence 
including cost, side effects, complexity of regimen, education, and expectations of treatment 
6. Conduct motivational interviewing and educational reinforcement regarding disease state, 
importance of adherence, and strategies for success/improvement. 
 
This telephonic consultation may be repeated up to 2 times (3 calls total) and will focus on identifying and 
overcoming barriers to adherence. The follow-up calls may be limited to the beginning of the outreach and 
will not necessarily be distributed throughout the duration of follow-up. 
 
Magellan staff will attempt to reach all members in arm 1, regardless of whether a telephone number is 
available within the Horizon member files. Therefore, Magellan staff will contact the pharmacy and/or 
provider office to obtain phone numbers on all members. Therefore the number of attempts made to engage 
a member is fewer than in other arms. 
 
 
ARM 2: Adherence Risk-Targeted Moderate Intensity Intervention 
 
Patients will receive an adherence and glycemic control outreach delivered by Magellan clinical staff. Only 
members with a telephone number available in the Horizon member files will be assigned to the moderate 
intensity intervention. Patients will be contacted by telephone and during these calls, in addition to the topics 
discussed in arm 1, the Magellan staff will: 
4. Assess the adequacy of the patient’s regimen. Staff will not suggest any changes to the patient’s 
regimen but instead educate and encourage patient to communicate to provider. 
5. Guide member-specific discussion focused on identifying potential barriers to glycemic control 
including availability of glucose monitoring equipment, side effects, barriers to diet and lifestyle 
recommendations, and education 
6. Conduct motivational interviewing and educational reinforcement regarding disease state, 
importance of adherence, and strategies for success/improvement 
 
In addition to the pharmacist intervention described in arm 1, this arm will include: 
- 
Up to 6 calls total by Magellan clinical staff. If 6 calls are not deemed necessary by patient and 
pharmacist, the pharmacist will at the very least try to provide follow-up at 3, 6, and 9 months after 
randomization, where appropriate. 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
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- 
One outreach call to provider or pharmacist, as needed, to update clinical status and resolve 
potential barrier to adherence 
- 
Referral to a moderate intensity text messaging (TM) service as needed. The content of the TMs 
have been created by the BWH investigators and the TMs themselves will be delivered by the 
investigators to a Magellan subcontractor, Mobile Commons, which provides a service for patients 
to provide their cell phone numbers to receive weekly text messages in a way that is confidential.  
Patients will be asked to opt in. 
- 
Quarterly follow-up letters at 3, 6, and 9 months that include information about importance of 
glycemic control and adherence. The schedule of mailings is listed in the table below and copies of 
the actual mailings are attached. 
Table: Mailings schedule 
Month 
Arm 1 
Arms 2 and 3 
0 
Intro letter and 
postcard + pillbox 
Intro letter and postcard + pillbox 
Intro letter and postcard + pillbox 
 
 
Previously reached by Magellan 
pharmacist 
Previously not reached by Magellan 
pharmacist 
3 
 
• 
Follow-up letter: previously 
reached member 
• 
Handout: “Understanding my 
insulin treatment” 
• 
Follow-up letter: previously not 
reached member 
• 
Handout: “Understanding my 
insulin treatment” 
6 
 
• 
Follow-up letter: previously 
reached member 
• 
Handout: “Remembering to 
take my medicines” 
• 
Follow-up letter:  previously not 
reached member 
• 
Handout: “Remembering to take 
my medicines” 
9 
 
• 
Follow-up letter: previously 
reached member 
• 
Handout: “Maintaining my 
treatment plan” 
• 
Follow-up letter: previously not 
reached member 
• 
Handout: “Maintaining my 
treatment plan” 
 
ARM 3: Adherence Risk and Glycemic Control-Targeted High Intensity Intervention 
 
Patients will receive the same adherence and glycemic control outreach delivered by Magellan clinical staff 
as described in Arm 2. Only members with a telephone number available in the Horizon member files will be 
assigned to the high intensity intervention. 
 
In addition to the pharmacist interventions described in arm 2, this arm will include the following changes: 
- 
Up to 12 calls total by Magellan clinical staff, instead of 6 calls total. 
- 
Up to 12 outreach calls to provider or pharmacist, as needed, to update clinical status and resolve 
potential barrier to adherence, instead of 1 outreach call. In this scenario, the pharmacist may 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
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discuss potential insulin dose titration with prescribing physician and communicate these changes 
back to the patient with the provider’s permission. 
- 
Referral to a high intensity text messaging (TM) service as needed, instead of referral to only a 
moderate TM service. The moderate intensity TM service includes weekly texts whereas the high 
intensity TM service includes daily texts. Patients will have the option to enroll in either frequency, if 
interested. If the patient elects into receiving daily texts, they will have the option of switching into 
weekly texts or no texts at any point during the intervention. 
 
 
STUDY POPULATION 
 
Patients who are potentially eligible for inclusion will be identified from the cohort of patients currently 
receiving health insurance from Horizon. In order to maintain generalizability, exclusion criteria will be 
minimal. Patients meeting the following inclusion/exclusion criteria will be selected for participation: 
 
Inclusion criteria: 
f) 
Commercially-insured individuals who receive medical and pharmacy health insurance benefits 
administered by Horizon Blue Shield Blue Cross of New Jersey 
g) Age  ≥ 18 years as of January 1, 2016 
h) ≥ 3 months of continuous enrollment prior to randomization 
i) 
≥ 1 prescription for basal insulin during the 6 months prior to randomization 
j) 
Members with type 2 diabetes, as determined by medical claims or prior prescription of an oral anti-
diabetic medication (OAD) 
 
Exclusion criteria: 
b) Patients whose primary insurance is Medicaid or Medicare 
 
Baseline HbA1c will not be an inclusion criterion. However patients with baseline HbA1c (within 6 months of 
randomization) will be flagged and later stratified during randomization.  
 
 
RECRUITMENT PROCEDURE 
Patients will be recruited into the study by a review of Horizon medical and pharmacy claims and risk 
scoring performed by RxAnte. After randomization, patients will be assigned to an intervention group or 
usual care depending on study arm, adherence risk score, and baseline HbA1c value. 
 
All patients assigned to an intervention group will receive an introductory mailing that includes a letter 
introducing the pharmacist consultation and a pillbox. This letter will provide information about how to 
schedule a pharmacist call. In addition, patients will receive a phone call that provides the patient with an 
automated message explaining that they will be contacted by a pharmacist. Patient may receive up to one of 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
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these interactive voice response (IVR) messages at the beginning of enrollment. A Magellan technician will 
attempt to reach the patient by phone up to 3 times in arm 1 and up to 4 times in arms 2 and 3. For patients 
who are not reached by phone, the Magellan team will reach out to the physician office or pharmacy to 
confirm current contact information.  
 
Once a patient is reached, the Magellan pharmacist will explain the purpose of the consultation and ask the 
patient if he/she would like to participate. If a patient agrees, this will be considered implicit consent. If a 
patient wishes to not participate and wishes to not receive further contact, this will be noted and the patient 
will not be contacted again.  
 
If a patient is not reached by phone with the above strategies, the patient will receive the quarterly mailing 
as outlined for arms 2 and 3. Data on all patients will be analyzed according to whichever group the patient 
was randomized to, regardless of whether the patient was reached or agreed to participate. 
 
RANDOMIZATION 
 
There are multiple partners who are working together to identify eligible patients and deliver the intervention. 
Our goal is to use the minimal amount of clinical data necessary at each step in order to implement the 
intervention. Because of the large number of patients who will be contacted by Magellan pharmacists, 
patient selection, randomization, and recruitment will occur over the first 4 months of the trial. This will 
require the following steps: 
 
• 
Horizon analytics team will send claims data on all insulin users from 2013 to 2015 to RxAnte to perform 
validation of insulin adherence risk scores. Before the study starts, Horizon will send updated enrollment 
files. 
• 
RxAnte will assign risk scores on all insulin users and send risk scores to Horizon 
• 
Horizon will apply inclusion and exclusion criteria and select patients eligible for randomization. They will 
flag patients with baseline HbA1c values, claims-based diabetes diagnosis (in contrast to OAD-based 
diabetes diagnosis, and telephone number availability).  
• 
Horizon will randomize 1,500 patients meeting criteria above. Randomization will be stratified by HbA1c 
availability, claims-based diabetes diagnosis, and telephone number availability.  
• 
Horizon will send the following aggregated and de-identified data to Brigham: distribution of risk scores 
and HbA1c values in arms 2 and 3. Brigham investigators will choose risk score and HbA1c cut-offs that 
will result in appropriate targeting levels. 
• 
Brigham will send these cut-offs to Horizon. The Horizon analytics team will apply these thresholds to 
make intervention assignments within each randomized group. 
• 
Horizon will send the necessary data on all patients assigned to receive an intervention to Magellan. 
• 
The process above will be repeated monthly 3 additional times so that randomized and recruitment is 
staggered over the course of 4 months. 
 
Randomization will occur in a 1:1:1 ratio conducted on the patient level. In order to have adequate power to 
study our secondary outcome, change in HbA1c, our randomization will be stratified on patients with 
baseline HbA1c lab availability within the 6 months prior to randomization.  

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
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This randomization will occur using a random number generator at Horizon Analytics. Randomization codes 
will be assigned strictly sequentially as patients become eligible. The randomization key will be maintained 
at Horizon Analytics as well as the allocation of patients to the intervention arms. 
 
 
Data Sources 
 
The data that will be used for patient selection and analysis includes medical and pharmacy claims and lab 
data from Horizon. Complete paid pharmacy and medical services claims data will be combined into a 
database consisting of all filled prescription, procedures, inpatient and outpatient physician encounters, 
hospitalizations, long-term care admissions and deaths for all patients studied.  
 
In addition to the Horizon claims data, both vendors will provide de-identified aggregate data on risk 
prediction and patient contact to Brigham investigators. Specifically, RxAnte will provide aggregate risk 
prediction scores from their initial scoring. These scores will be linked to an anonymous patient ID (the link 
between patient ID and medical record number will be kept by Horizon analytics). Magellan will provide a 
monthly report of how many patients were reached and the type of contact (e.g. number of patients who 
were engaged on the telephone, the number of providers who were contacted). 
 
 

 
 
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26 
 
 
 
REFERENCES 
 
1. 
CDC. National Diabetes Fact Sheet, 2011. 2011; 
http://www.cdc.gov/DIABETES/pubs/pdf/ndfs_2011.pdf. Accessed April 12, 2014. 
2. 
CDC. Crude and Age-Adjusted Percentage of Adults with Diabetes Using Any Diabetes 
Medication. 2011; ://www.cdc.gov/diabetes/statistics/meduse/fig3.htm. Accessed April 12, 2014. 
3. 
Aikens JE, Piette JD. Longitudinal association between medication adherence and glycaemic 
control in Type 2 diabetes. Diabet Med. Mar 2013;30(3):338-344. 
4. 
Bryson CL, Au DH, Maciejewski ML, et al. Wide clinic-level variation in adherence to oral diabetes 
medications in the VA. J Gen Intern Med. May 2013;28(5):698-705. 
5. 
Farsaei S, Radfar M, Heydari Z, Abbasi F, Qorbani M. Insulin adherence in patients with 
diabetes: Risk factors for injection omission. Prim Care Diabetes. Apr 7 2014. 
6. 
Abu Hassan H, Tohid H, Mohd Amin R, Long Bidin MB, Muthupalaniappen L, Omar K. Factors 
influencing insulin acceptance among type 2 diabetes mellitus patients in a primary care clinic: a 
qualitative exploration. BMC Fam Pract. 2013;14:164. 
7. 
Avorn J, Monette J, Lacour A, et al. Persistence of use of lipid-lowering medications: a cross-
national study. JAMA : the journal of the American Medical Association. May 13 
1998;279(18):1458-1462. 
8. 
Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J. Long-term persistence in 
use of statin therapy in elderly patients. JAMA : the journal of the American Medical Association. 
Jul 24-31 2002;288(4):455-461. 
9. 
Choudhry NK, Setoguchi S, Levin R, Winkelmayer WC, Shrank WH. Trends in adherence to 
secondary prevention medications in elderly post-myocardial infarction patients. 
Pharmacoepidemiology and drug safety. Dec 2008;17(12):1189-1196. 
10. 
Cutrona SL, Choudhry NK, Fischer MA, et al. Targeting cardiovascular medication adherence 
interventions. J Am Pharm Assoc (2003). May-Jun 2012;52(3):381-397. 
11. 
Solomon DH, Iversen MD, Avorn J, et al. Osteoporosis telephonic intervention to improve 
medication regimen adherence: a large, pragmatic, randomized controlled trial. Arch Intern Med. 
Mar 26 2012;172(6):477-483. 
12. 
Wei W, Pan C, Xie L, Baser O. Real-world insulin treatment persistence among patients with type 
2 diabetes. Endocr Pract. Jan-Feb 2014;20(1):52-61. 
 
 
 
 

 
 
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Appendix B: Study Workflow 
 
 
 

 
 
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Summary of changes to protocol 
 
Date of 
submission 
Description of modification 
Rationale for modification 
Approval 
date 
Original IRB 
submission 
- 
- 
4/29/2016 
8/22/2016 
Small adjustments were made in terms of how 
to assign patients to specific interventions in 
each arm based upon whether the patient had 
an available phone number or not.  
We received pilot data from 
Horizon about the proportion 
of eligible subjects with 
missing telephone numbers to 
adjust the intervention 
deployment,  
9/12/2016 
 
 
 
 

 
 
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Original analysis plan 
 
OUTCOME MEASURES 
Primary outcome: insulin persistence at 12 months 
Insulin persistence: this is a binary outcome that labels the patient as persistent or non-persistent to 
insulin at 12 months. The patient will be categorized as being persistent if a refill is observed within the 
expected time of medication coverage for stratum of metric quantity dispensed, defined as the 90th 
percentile of time, between the first and second fills among patients with at least one refill. The 90th 
percentile of time will be determined based on the model building cohort using historical Horizon data and 
will be measured using Horizon pharmacy claims. 
 
Secondary outcomes 
Mean change in HbA1c: change in HbA1c from baseline to follow-up, averaged over the study arm. 
HbA1c values obtained 6-12 months after randomization will be used for follow-up. If multiple HbA1c 
values are present, the value closest to 12 months will be used. HbA1c values will be assessed using lab 
data provided to Horizon.  
Health care spending: This will be calculated from allowed amounts appearing in Horizon’s claims data 
for prescription medications, nondrug medical services, and the combination of these two factors after the 
assignment of the patient to a study group. 
Rates of healthcare utilization: Rates of medical follow-up including physician visits, emergency room 
visits, hospitalization will be calculated based on Horizon’s claims data for nondrug medical services.  
Alternative measures of insulin persistence: these measures include defining persistence as having a gap 
between insulin prescriptions < 90 days and refilling within 30 or 60 days of after date of previous fill plus 
days supply.   
 
Statistical analyses 
All analyses will be performed based on intention-to-treat principles. Rates of insulin persistence and time 
to non-persistence will be compared using Kaplan-Meier estimates and Cox proportional hazards models. 
If there are differences in baseline characteristics between study groups that are believed to be 
confounders of the intervention–outcome association, we will repeat our analyses after adjusting for these 
covariates. Patients will be censored at time of non-persistence, loss of insurance eligibility, or end of 
follow-up, whichever occurs first. Mean change in HbA1c will be compared using Student’s t-test or 
Wilcoxon rank sum test. Analysis of healthcare utilization and healthcare cost will be performed using 
generalized estimating equations. An additional per protocol analysis will be conducted to compare rates 
of insulin persistence and mean change in HbA1c among patients intervened upon.  
 
Sample size calculation 
Based on prior work by Wei et al.12, the proportion of patients persistent to insulin after 12 months in a 
commercially insured population is 65%. Assuming that 40% of targeted individuals are reached by 

 
 
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Magellan in each of the three arms and that less than 10% of subjects are lost to follow-up, randomizing 
2,000 patients into each arm would give us more than 80% power at an alpha threshold of 0.05 to detect 
at least a 9% increase in the proportion of patients who are persistent with insulin between study arms 2 
and 1 and at least an 11% increase between study arms 3 and 1. We believe this is a clinically 
meaningful difference and is feasible given the sample size estimates we calculated with the assistance 
of the Horizon analytics team using their 2014 enrollment data. Under these same assumptions but 
assuming a reach rate of 30% by Magellan, we would have 80% power at an alpha threshold of 0.05 to 
detect an 11% increase in the proportion of patients who are persistent with insulin between study arms 2 
and 1 and a 13% increase between arms 3 and 1. 
 
 
 

 
 
Targeted Adherence Intervention to Reach Glycemic Control With Insulin Therapy for Patients With Diabetes 
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Final analysis plan 
 
OUTCOME MEASURES 
Primary outcome: insulin persistence at 12 months 
Insulin persistence: this is a binary outcome that labels the patient as persistent or non-persistent to 
insulin at 12 months. The patient will be categorized as being persistent if a refill is observed within the 
expected time of medication coverage for stratum of metric quantity dispensed, defined as the 90th 
percentile of time, between the first and second fills among patients with at least one refill. The 90th 
percentile of time will be determined based on the model building cohort using historical Horizon data and 
will be measured using Horizon pharmacy claims. This threshold is formally defined as the 90th percentile 
of the time between the first insulin fill after follow-up and the second insulin fill, adjusting for insulin type 
and quantity dispensed. For example, 90% of Horizon members refilled their prescription for insulin 
glargine (15 units) within 141 days of their first prescription in 2012-2015. We will prospectively apply this 
90th percentile cut-off based on historical data to patients in this study.  This process will be repeated to 
define 90th percentile thresholds for the time between the second and third refill, the third and fourth refill 
and so on, and patients will be considered non-persistent if they fail to refill before any of these threshold 
times has elapsed. 
 Patients will be considered persistent if they fill a prescription for the same or a different basal insulin. If 
the patient switches basal insulins, we will apply the appropriate threshold for the 90th percentile of time.  
Patients who have 1 or fewer insulin fills (i.e. no “refills”) during follow-up will be considered non-
persistent on the day of the 90th percentile threshold.  Patients who are censored before their 90th 
percentile non-persistence threshold date will be considered persistent. 
 
 
Secondary outcomes 
Mean change in HbA1c: Glycemic control will be measured as mean change in HbA1c from baseline to 
follow-up among those patients with baseline HbA1c available. Because clinical data will not be explicitly 
collected as part of this pragmatic study, laboratory values will be assessed using data provided to 
Horizon as part of routine quality monitoring.  The HbA1c result recorded closest to the 12-month end of 
follow-up, up to 15 months after randomization, will be used in the analysis. We will impute missing follow-
up HbA1c values for those patients with an available baseline result availability but a missing follow-up 
result using multiple imputation. Changes in HbA1c without imputed values will also be reported as a 
sensitivity analysis. 
Health care spending: This will be calculated from allowed amounts appearing in Horizon’s claims data 
for prescription medications, nondrug medical services, and the combination of these two factors after the 
assignment of the patient to a study group. 
Rates of healthcare utilization: Rates of medical follow-up including physician visits, emergency room 
visits, hospitalization will be calculated based on Horizon’s claims data for nondrug medical services.  
 
Statistical analyses 
All analyses will be performed based on intention-to-treat principles.  

 
 
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Because of the time required for data processing and transfers, follow-up measurements will begin 1 
month after randomization, which is the earliest time patients could receive the intervention.  
 
In the primary analysis, the relative risk of insulin non-persistence between treatment arms will be 
compared for each insulin fill in the follow-up period using modified Poisson regression with robust error 
variance. For this analysis, we will use generalized estimating equations with a log link function, Poisson-
distributed errors, and account for correlations in the repeated measurements among patients over time. 
The primary models will adjust for the stratified randomized design.  If there are differences in baseline 
characteristics between study groups that are believed to be confounders of the intervention–outcome 
association, we will repeat our analyses after adjusting for these covariates. Patients will be censored at 
time of non-persistence, loss of insurance eligibility, or end of follow-up, whichever occurs first.  
 
We will conduct a subgroup analysis among patients with at least 2 insulin fills after the follow-up period 
begins. Sensitivity analyses will include applying alternative methods of measuring insulin use as defined 
in the literature, such as gap-based measures and medication possession ratio based on days of insulin 
supplied in each prescription. Rates of insulin persistence and time to non-persistence will be compared 
using Cox proportional hazards models in secondary analyses. If there are differences in baseline 
characteristics between study groups that are believed to be confounders of the intervention–outcome 
association, we will repeat our analyses after adjusting for these covariates. Subgroup analyses will be 
conducted to assess whether the impact of the intervention varies according to key patient 
characteristics. 
 
Change in mean HbA1c will be analyzed using generalized estimating equations with an identity link 
function and normally distributed errors, also adjusting for the stratification of randomization. Analysis of 
healthcare utilization and healthcare cost will be performed using generalized estimating equations using 
a log link with Poisson distributed errors. 
 
Sample size calculation 
Based on prior work by Wei et al.12, the proportion of patients persistent to insulin after 12 months in a 
commercially insured population is 65%. Assuming that 40% of targeted individuals are reached by 
Magellan in each of the three arms and that less than 10% of subjects are lost to follow-up, randomizing 
2,000 patients into each arm would give us more than 80% power at an alpha threshold of 0.05 to detect 
at least a 9% increase in the proportion of patients who are persistent with insulin between study arms 2 
and 1 and at least an 11% increase between study arms 3 and 1. We believe this is a clinically 
meaningful difference and is feasible given the sample size estimates we calculated with the assistance 
of the Horizon analytics team using their 2014 enrollment data. Under these same assumptions but 
assuming a reach rate of 30% by Magellan, we would have 80% power at an alpha threshold of 0.05 to 
detect an 11% increase in the proportion of patients who are persistent with insulin between study arms 2 
and 1 and a 13% increase between arms 3 and 1. 
 
 

 
 
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Summary of changes to the analysis plan 
The primary and secondary outcomes are now further clarified along with the specific analytic strategy 
for these outcomes.