A Randomized Study to Evaluate the Efficacy of Insulclock® in Patients With Uncontrolled Type 2 Diabetes
Phase: NA
Conditions: Diabetes
Sponsor: Emory University

Insulclock Proposal, 06/01/2018 
 
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IRB00094393 
 
NCT03224234 
 
A Randomized Study to Evaluate the Efficacy of Insulclock® in  
Patients with Uncontrolled Type 2 Diabetes 
 
 
Principal Investigator: 
 
Guillermo E. Umpierrez, M.D. 
 
06/01/2018 
 

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Title:   
 
A Randomized Study to Evaluate the Efficacy of Insulclock® in Patients with Uncontrolled Type 2 
Diabetes  
 
 
Principal Investigator: 
 
 
Guillermo E. Umpierrez, M.D. 
Professor of Medicine  
Emory University School of Medicine 
Director, Diabetes and Endocrinology Section 
 
 
 
 
Grady Health System 
 
Co-Principal Investigators: 
 
 
 
 
Francisco J Pasquel, MD, MPH 
Assistant Professor of Medicine, Endocrinology  
Emory University School of Medicine 
 
Rodolfo J Galindo, MD 
Assistant Professor of Medicine, Endocrinology  
Emory University School of Medicine 
 
 
 
Investigators: 
Emory University, Atlanta 
  Priyathama Vellanki, MD 
  Maya Fayfman, MD 
  Sonya Haw, MD 
  David Reyes-Umpierrez 
  Georgia Davis 
  Alexandra Migdal 
 
 
 

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Research Objectives and Specific Aims: 
Diabetes is arguably the most urgent healthcare challenge of the 21st century. An estimated that 1 in 11 adults 
have diabetes with an estimated 415 million individuals with diabetes worlwide.1  In the United States, 21 
million persons have been diagnosed with diabetes, with approximately 90–95% of cases due to type 2 
diabetes (T2D).2 Diabetes is a leading cause of cardiovascular disorders, blindness, end-stage renal failure, and 
non-traumatic amputations.2 Extensive evidence from epidemiological and randomized control studies have 
shown that improved glycemic control decreases the risk of diabetic complications, and is likely to be of 
benefit in preventing long-term cardiovascular complications.3 However, despite the availability of a large 
variety of antidiabetic drugs, insulin formulations, and clinical guidelines, only one-third of patients on basal 
insulin and one-fourth of those on basal insulin and oral antidiabetes drugs achieved target A1C <7.0%.3-5  
Poor adherence to insulin regimens is common and reported in up to two-third of patients with diabetes.6-8The 
most common barriers with insulin injections are socio-economic factors, complexity of treatment and 
adherence to prescribed dosing time, which lead to frequent insulin omissions, as reported in more than half of 
patients with diabetes.9 The frequency of insulin injection irregularities (omission, mistiming and dosing) are 
similar for patients using basal insulin alone versus those using basal with bolus  insulin regimens.7 Thus it is 
important to identify patients at risk and to develop strategies and tools to increase adherence to prescribed 
insulin regimens. Recent advances in this field include the availability of electronic reminders, mobile 
communication technology such as phone short message services, 10 smartphones and wrist-worn smartwatch, 
11 and a variety of insulin pens with memory functions and electronic display.12-14 However, current devices 
are designed for specific insulin brands, are not interchangeable among available insulin pens, and they lack 
alarm systems to notify patients and caretakers about insulin delays and missing doses.  
Insulclock®15 is a small electronic device easily plugged to any brand of insulin pen devices 
to help track date, time and dosage of the last injection, type of insulin used and temperature. 
Insulclock has an alarm system with visual and sound alerts to prevent insulin omissions and 
mistiming. Via Bluetooth and smart-phone technology, information is stored and readily 
available for data analysis by patients, caregivers and healthcare professionals. The 
Insulclock’s real time memory and alert system are likely to improve treatment adherence, 
patient's satisfaction, and quality of life measures, which may improve glycemic control in 
insulin treated patients with T2D.   
 
Study Aims: 
Aim 1.  To determine whether the Insulclock system results in improved treatment adherence and 
reductions in treatment irregularities (insulin omission, mistiming and dosing) compared to 
conventional insulin pen device.  Patients with inadequately controlled T2D treated with oral antidiabetic 
agents and basal insulin (NPH, glargine or detemir) will be randomized to Group A: Insulclock device with 
feedback or to Group B:  Insulclock without feedback.  All patients will use the Insulclock device attached to 
glargine U100 insulin pens (SoloStar®) during the study period. Participants in Group A will receive daily 
information on their smartphone on insulin administration (time and dosing) as well as reminders in the event 
of missing doses. Participants in Group B, will use the Insulclock, but will not receive feedback on insulin 
administration.  Differences in insulin injection irregularities (omission, mistiming and dosing) will be 
compared at each clinic visit during the study period.  
Hypothesis: The Insulclock device will improve adherence reducing insulin omission, mistiming and dosing 
errors compared to standard pen device.  
 
Aim 2.  To determine whether the Insulclock system yields higher treatment satisfaction scores in 
poorly controlled patients with T2D compared to a conventional insulin pen device. Patients with 
inadequately controlled T2D (HbA1c ≥ 7.0%) treated with oral antidiabetic agents and basal insulin once daily 
(NPH, glargine or detemir) will be enrolled in a 24 week randomized, cross-over clinical trial comparing the 

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use of Insulclock device system vs standard insulin pen. Treatment satisfaction will be assessed with the 
Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) 16,17 to be administered at baseline (week 0) 
and at weeks 12 and 24 to assess relative changes in the DTSQ between interventions.  The amplitude of the 
score on the DTSQc gives the degree of change in satisfaction while the direction (positive or negative) will 
provide guidance on the preference of therapy.   
Hypothesis: The Insulclock device will improve treatment satisfaction compared to standard insulin pen 
device.  
 
Aim 3.  To explore whether changes in adherence with the Insulclock improves glycemic control, as 
measure by change in HbA1c from baseline, when compared to conventional insulin pen device. HbA1c 
will be measured at week 0 and at weeks 12 and 24 to assess differences in glycemic control between groups. 
Hypothesis: The Insulclock device by improving treatment adherence may improve glycemic control 
compared to standard pen device.  
 
II. 
BACKGROUND AND STATUS OF WORK IN THE FIELD. 
Basal Insulin therapy in Type 2 Diabetes   
Insulin is the oldest and the most potent agent for the treatment of diabetes. Insulin therapy is the treatment of 
choice for patients with severely elevated HbA1c and symptoms of hyperglycemia, 18,19 and in patients with 
inadequate glycemic control despite treatment with OADs and non-insulin injectables.18,19 Clinical guidelines 
recommend the use of basal insulin, given once (glargine, detemir, degludec) or twice daily (neutral protamine 
Hagedorn [NPH], detemir) as add-on to non-insulin agents. Basal insulin analogs are preferred over NPH 
insulin because a single basal dose provides a relatively flat serum insulin concentration for up to 24 hours. 
Newer basal insulin formulations – glargine U300 and degludec- have more prolonged and stable 
pharmacokinetic (PK) and pharmacodynamic (PD) characteristics than glargine U100 and detemir.18,20 Despite 
of the multiple basal insulin formulations, a systematic review of 218 randomized clinical trials found that 
only 39% of patients with T2D treated with basal insulin achieve an HbA1c <7%.5 Moreover, a recent study 
reported no overall improvements in glycemic control among patients with T2D during the past decade.21  
Insulin Non-Adherence 
Poor adherence to medical treatment is a significant contributor to negative outcomes and increased risk of 
morbidity in patients with diabetes.22,23 Insulin non-adherence has been reported in up to two-thirds of 
patients,6-8with approximately one-third reporting an average of three episodes of insulin omission/non-
adherence within the previous month.7,24 Regimen complexity, in terms of the number of the treatments and 
frequency of administration, is known to have a negative impact on adherence.25-27 Brod et al 7 reported that 
most missed or mistimed doses were unintentional (~80%).  The most common barriers with insulin injections 
are socio-economic factors, complexity of treatment and adherence to prescribed dosing time, which lead to 
frequent insulin omission reported in more than half of patients with diabetes.9 The insulin tracking and alert 
system will address the issue of nonadherence by reminding patients about insulin dosing and avoiding 
missing insulin injections.  The alarm system can be programmed at any time(s) of the day alerting patients 
and caretakers on delayed injections, which may reduce missing doses.  
 
Use of Insulin Pens and Patient Satisfaction   
Multiple studies have reported that insulin pen devices are associated with greater treatment satisfaction and 
patient preference as well as improved dose accuracy compared to the traditional vial/syringe.28-37 
Standardized assessments of treatment satisfaction, including the Diabetes Treatment Satisfaction 
Questionnaires (DTSQs and DTSQc) and the Insulin Delivery System Rating Questionnaire (IDSRQ), have 
been validated and tested for reliability.16,17,38,39 Some insulin pen studies have evaluated patient satisfaction 
with these tools.28,30 Improving treatment satisfaction can lead to improvements in quality of life.40 
Improvements in quality of life are often cited as leading to greater adherence to treatment protocols and 
insulin administration.41 

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Advances in Insulin Treatment  
Like most areas of medicine, treatment of diabetes has changed considerably over the past decade because of 
technological advances including glucose monitoring and insulin delivery options. Major advances to improve 
adherence in diabetes include the availability of mobile communication technology such as phone short 
message services, 10 electronic reminders, smartphones and wrist-worn smartwatches, 11 and a variety of 
insulin pens with memory functions and electronic display.12-14   
Examples of smart pens commercially available or in development:  
Easylog, a compact add-on module designed to fit pen injectors. Smart sensors collect injection data directly 
from disposable or reusable pen and connect to smartphones via Bluetooth.  
Datapen, a Smart reusable injector pen connected to a mobile app. Each injection can be tracked and 
Bluetooth technology to allow access treatment data from mobile phone. 
Smartplus Insulin Pen, an injection delivery compatible with insulin pen needle device that supports insulin 
cartridges from Eli Lilly and Sanofi-Aventis insulin formulations. The pen stores and displays 195 injection 
doses, including the date and time of the injection.  
KiCoPen captures dose delivered and sends the information to an associated smartphone app.  
Human Pen Memoir® (Eli Lilly & Co) and NovoPen5® (Novo Nordisk) durable insulin pens with the 
addition of a memory function that records the dose of and hours passed since the last injection. 
Insulclock®15 is a small electronic device which is plugged to all pen devices allowing tracking information 
on date, time, dose of the last injection, remaining insulin in the pen device, as well as type of insulin used and 
temperature. Insulclock has an alarm/reminder system with visual and acoustic alerts to reduce insulin 
omissions and mistiming. Via Bluetooth and smart-phone technology, information is store and readably 
available for data analysis by patients, caregivers and healthcare professionals.  
  
 

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Significance and Innovation:  In the US, all patients with type 1 diabetes are treated with basal insulin alone 
and about 30% of patients with type 2 diabetes are treated with basal insulin alone or in combination with oral 
agents to achieve and maintain glycemic control.3 About 30.3% of patients on basal insulin and 24.2% of 
those on basal insulin and oral antidiabetes drugs achieved target A1C <7.0%.3 A systematic review of 218 
randomized trials reported that 39% of patients with T2D treated with basal insulin achieve an HbA1c <7%.5 
Insulin non-adherence is reported in up to two-thirds of patients,6-8with one-third reporting an average of three 
episodes of insulin omission/non-adherence within the previous month.7,24  
Recent devices have become available to improve adherence to insulin therapy in diabetes include the 
availability of mobile communication technology such as phone short message services,10 electronic 
reminders, smartphones and wrist-worn smartwatch,11 and a variety of insulin pens with memory functions 
and electronic display.12-14  However, these devices are not interchangeable among different insulin pens and 
they do not have the alarm systems to notify patients and caretakers about insulin delays and missing doses.  
The insulin tracking and alert system may be of great help in reminding patients about insulin dosing and 
avoiding missing insulin injections.  In addition, the Insulclock will also allow us to assess treatment 
nonadherence. Differences in treatment adherence before and after the crossed over will provide objective 
evidence of compliance and treatment adherence.  
  
III. Research Design and Methods 
 
Study Aims: 
Aim 1.  To determine whether the Insulclock system results in improved treatment adherence and 
reductions in treatment irregularities (insulin omission, mistiming and dosing) compared to 
conventional insulin pen device.   
Aim 2.  To determine whether the Insulclock system yields higher treatment satisfaction scores in 
poorly controlled patients with T2D compared to a conventional insulin pen device.  
Aim 3.  To explore whether changes in adherence with the Insulclock system results in improved 
glycemic control, as measure by change in HbA1c from baseline, when compared to conventional 
insulin pen device. 
Study Rationale. Poor adherence to medical treatment is common and is associated with increased risk of 
morbidity in patients with diabetes.22,23 Insulin non-adherence has been reported in up to two-thirds of 
patients,6-8with approximately one-third reporting an average of three episodes of insulin omission/non-
adherence within the previous month.7,24 Regimen complexity, in terms of the number of the treatments and 
frequency of administration, is known to have a negative impact on adherence.25-27 Patients with irregular 
mealtime and active social-work schedule were more likely to have insulin irregularities, many of them 
intentional omissions. In patients with T1D, poor adherence is the main cause of hyperglycemic crises 
accounting for more than half of admissions with hyperglycemic crises.42,43 Several devices have been 
designed to improve insulin adherence including new delivery options like smart pens with memory functions 
and electronic display;12-14 however they have significant limitations and their efficacy in improving treatment 
adherence or in improving glycemic control have not been tested in rigorous randomized clinical trials. The 
Insulclock device allows to record date, time, dose of the last injection, as well as type of insulin used, and 
remaining insulin volume in the pen device. A major advance of Insulclock over available smart pens is its 
ability to send visual and acoustic alert message directly from the device or via text to patients and caretakers 
in the event of insulin omissions and mistiming. In addition, the large volume data storage will allow patients 
and healthcare providers to download information on insulin patterns and omissions over a long period, 
allowing for a better understanding of insulin adherence. The present study will test whether the Insulclock 
improves adherence, quality of life, treatment satisfaction, and glycemic control compared to the standard pen 
device.      

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Study Objectives: 
Primary Objective.   
To demonstrate the superiority of Insulclock in treatment adherence (insulin omission, mistiming and dosing) 
over conventional insulin injection pen devices.   
 
Secondary Objectives: 
To demonstrate non-inferiority of Insulclock compared with standard insulin pen device on: 
 Treatment satisfaction -Diabetes Treatment Satisfaction Questionnaire Status (DTSQs)16,17  
 Diabetes Related Quality of Life (DRQoL) 
 Adherence:  
o Frequency of insulin irregularities (omission, mistiming and dosing)  
 Glycemic control: 
o Glycemic control, as measure by change in mean HbA1c from baseline 
o Frequency of hypoglycemia 
o 7-point SMBG profile 
o Daily fasting glucose profile 
 
Methods: 
 
This will be a randomized (1:1), controlled, 26-week cross-over clinical trial in patients with inadequately 
controlled T2D (HbA1c ≥ 7.0% to ≤ 12.0 %) while treated with oral antidiabetic agents and basal insulin 
(NPH, glargine or detemir).  Participants will be randomized to use the Insulclock device (Group 1) and 
standard of care using an insulin pen device (Group 2).  All patients will use the Insulclock device attached to 
glargine U100 insulin pens (SoloStar®) during the study period. During the study period. Participants in 
Group 1 will receive daily information on their smartphone on insulin administration (time and dosing) as well 
as reminders in the event of missing doses. Participants in Group 2, will use the Insulclock, but will not 
receive feedback on insulin treatment or alerts.   
 
Randomization will be stratified by:  
 HbA1c at Screening (≤8.0%, >8.0%)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*
T
*
T
*
T
*
T
*
T
*
T
*
T
*
T
Insulclock
Standard	Pen	
Device	
Screening	
(Week	-2)
Randomization
(Week	0)
Interim	Visit
(Week	6)
Interim	Visit
(Week	18)
Crossover
Termination
(Week	24)
Group	1
Group	2
*
T =		Telephone	Visit

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Study Visits 
Screening (Visit 1) 
Approximately 1-2 weeks prior to the start of the study, all potential study patients will be screened to check 
their eligibility after signing the informed consent form (ICF) and assigned a patient identification number. 
Medical history, physical examination, height, weight, vital signs, pre-existing conditions, and concomitant 
medications will be recorded during this visit. Laboratory assessments performed at Visit 1 to determine 
eligibility for the study include pregnancy tests for females, and HbA1c, serum chemistry, assays.  Patients 
who do not meet all the inclusion criteria at Visit 1 will be considered screen failures and will not be 
randomized to participate in the study. 
Eligible patients will be trained on the use of the glucometer to monitor their BG levels. Patients will be given 
diabetes diaries and associated training to record all glucose levels, insulin doses, and episodes of 
hypoglycemia. 
Insulin administration technique will be reviewed prior to randomization to ensure good technique.  
Reinforcement will be provided as needed during the follow-up visits.   
Only eligible patients treated with a once daily insulin dose of NPH, detemir, glargine insulin will be switched 
to SoloSTAR pen (glargine U100) at a total dose (TDD). 
Antidiabetic agents will be continued at the same dose, except insulin secretagogues which can be stopped if 
HbA1c is <8% or reduced by half if HbA1c is >8%.   
Patients will be instructed in performing glucose testing at home before meals, with a minimum of 2 out of the 
4 pre-meal and bedtime glucose measurements per day.  In addition, patients must perform a 7-point SMBG 
(fasting, before meals, 2 hours after meals, and bedtime) done between 3 to 5 days prior to Visit 2.   
One week after screening and before randomization, eligible participants will receive an Insulclock device. 
They will be properly trained on how to use it, charge and connect Insulclock to their mobile devices. 
Insulcloud will make smartphone available for subjects, who do not own a smartphone, during the course of 
the study. Technique skills such as the ability to navigate the app, press the button for 5 seconds while giving 
insulin injection44, and how to connect the device to their phones will be explained. They will be asked to use 
the Insulclock with their insulin pen, to get familiarized with it. An assessment will be done after the week of 
using the device in order to review quality and understanding of the technology. Those subjects that fail to use 
the device properly will be deemed Screen Failures.  
 
Instructions to be provided to Patients in Preparation for Visit 2 (Randomization visit) 
 All patients will be instructed to provide daily glucose records.  In addition, they will perform a 7-point 
SMBG done between 3 to 5 days prior to Visit 2.   
 Insulclock usage, compliance, and technique will be reviewed. 
 
Patients who complied with the 7-point glucose testing (fasting, before meals, 2 hours after meals, and 
bedtime) and fulfill the eligibility criteria at Visit 2 will be randomized to participate in the study.   
 
Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) 
 
 
Randomization (Visit 2) 
 Patients will receive detailed instruction on the use of Insulclock system according to randomization 
group.  
 Study diaries will be collected and reviewed for BG levels, episodes of hypoglycemia, insulin self-
administration 
 Dose of glargine insulin will be adjusted as needed (page 8). 

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 
Patients will be instructed in performing glucose testing at home before meals, with a minimum of 2 
out of the 4 pre-meal and bedtime glucose measurements per day.  
Telephone Visits (visit 3, 4, 6, 7, 9, 10, 12, 13) 
 Between each office visit, patients will have a telephone visit with the investigator at 2 week intervals 
after randomization (Visit 2) and interim office visits (visits 5 and 11). 
Interim Visits (visit 5 and 11) 
The following activities occur during interim visits: 
 Patients will receive detailed instruction on the use of the Insulclock system  
 Study diaries will be collected and reviewed for BG levels, episodes of hypoglycemia, insulin self-
administration 
 Dose of glargine insulin will be adjusted as needed (page 8). 
 
Patients will be instructed in performing glucose testing at home before meals, with a minimum of 2 
out of the 4 pre-meal and bedtime glucose measurements per day. 
Crossover visit (Visit 8, week 14) 
The following activities occur during crossover visit: 
 At midpoint (week 12), patients will be converted to the alternate treatment Arm (cross-over design).   
 Patients will receive detailed instruction on the use of the Insulclock system  
 Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) 
 Blood sampling for HbA1c assessment to determine efficacy of treatment 
 Study diaries collected and reviewed for BG levels, episodes of hypoglycemia, insulin self-
administration 
 Dose of glargine insulin will be adjusted as needed (page 8). 
Visit 14 (End of Study) 
 Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) 
 Blood sampling for HbA1c assessment to determine efficacy of treatment 
 Study diaries collected and reviewed for BG levels, episodes of hypoglycemia, insulin self-
administration 
 
During each visit, participants will have their insulin dose titrated to achieve a fasting glucose <130 mg/dL as 
detailed in the glargine titration algorithm.  Once the fasting glucose 3-day average is <130 mg/dL, insulin 
doses will be kept constant, unless the participant experiences recurrent hypoglycemia or severe 
hyperglycemia.   
 
Insulin Glargine Titration Schedule.  Make adjustment every 3 days after the subject has been on insulin 
U100 as follows: 
 
Mean 3 day consecutive Fasting SMBG 
Glargine U100 Dose Adjustment 
>180 mg/dL  
Increase glargine dose by 4 IU 
130 – ≤ 180 mg/dL 
Increase glargine dose by 2 IU 
71 – ≤ 130 mg/dL 
No change 
≤ 70 mg/dL 
Decrease insulin glargine dose by 10% 
≤ 40 mg/dL 
Decrease insulin glargine dose by 20-30% 
 
Upward titration should be stopped for one week after a case of hypoglycemia confirmed by a SMBG reading 
< 70 mg/dL unless there is an adequate explanation (e.g. omission of a meal) for the event. The study staff 
should instruct the subject to contact the site for any questions on the insulin dose adjustments. 
 

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Treatment satisfaction will be assessed with the Diabetes Treatment Satisfaction Questionnaire Status 
(DTSQs) 16,17 to be administered at baseline (week 0) and at weeks 12 and 24 to assess relative changes in the 
DTSQ between interventions.  The amplitude of the score on the DTSQc gives the degree of change in 
satisfaction while the direction (positive or negative) will provide guidance on the preference of one device 
over the other.   
 
Concomitant Medications:  
During the study treatment period, the following medications are prohibited:  
 Initiation of any antidiabetic agents, including oral or injectable antihyperglycemic agents  
 Systemic use of glucocorticoids for more than 10 consecutive days.  
 Initiation of any weight loss drugs  
 For patients in both groups, background metformin should be maintained throughout the study unless 
down-titration is required for safety reasons.  
Assessment of Results: 
The primary outcome of treatment adherence with the use of Insulclock with feedback or no feedback 
information (blinded) will be determined by the percentage of patients and number of insulin omission, 
mistiming and dosing.  Number insulin irregularities will be registered on the Insulclock device and data will 
be retrieved during each clinic visit.  
For treatment satisfaction, subjects’ responses to questions 1, 7 and 8 of the DTSQc will be used.  A 
comparison of the score on the DTSQs from week 12 to week 24 as well as using the score on the other 
questions of the DTSQc, which would overcome the ceiling limitation of using the DTSQs by itself, will also 
be used to assess treatment satisfaction 16,17.  The Diabetes Treatment Satisfaction Questionnaire Status 
(DTSQs) form will be administered at weeks 0, 12 and 24.   
Questionnaires will be given at week 0 for standardization purposes.  The amplitude of the score on the 
DTSQc gives the degree of change in satisfaction while the direction (positive or negative) will provide 
guidance on the preference of one device over the other (i.e., if we predict that patients greatly prefer alarm 
reminders over nothing and he/she started the group 1 with daily reminders then transitioned to group 2 
without the daily reminders, his/her score would be ‘-3’, whereas if he/she was initially not getting the daily 
reminders followed by the daily reminders then the score would be ‘+3’).  
Quality of life will be assessed at baseline and again at weeks 12 and 24 in order to determine the impact of 
the type of therapy on this outcome.  Patients will be given the Diabetes Quality of Life Clinical Trial 
Questionnaire-Revised (DQLCTQ-R), the Problem Areas In Diabetes scale (PAID) and the Elderly Diabetes 
Burden Scale (EDBS) at baseline, weeks 12 and 24 to assess their quality of life and any potential impact of 
the treatment regimen 45-47. 
Glycemic Control will be assessed via HbA1c at weeks -1, 12 and 24 and via fasting blood glucose averages 
at weeks 0, 12 and 24 from point of care testing during the preceding week. 
 
Duration of study 
The duration of this study will include a 26-week treatment phase and a safety clinic or telephone follow-up 
visit at week 28. 
 
Interim analysis 
There will be no planned interim analysis of the data. 
 
Selection of Patients 
Number of subjects planned.  The total number of patients with T2D to be included in this pilot study is 150. 
We anticipate a dropout rate of 10% - 20% through week 24 so that each arm will have 32 subjects at week 
32. 
 

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Inclusion criteria: 
Subjects meeting all the following criteria will be considered for enrollment into the study: 
1. Age: 18 to 80 years 
2. Diagnosis of T2D 
3. Screening HbA1c ≥ 7.0% to ≤ 12.0% 
4. Continuous treatment with one or more oral antidiabetic agents, for at least 2 months and/or 
5. Continuous treatment with daily basal insulin (NPH, glargine U100 or detemir), for at least 2 months, 
(insulin dose ≤0.5U/Kg/day).  
6. If patients are on combination therapy of basal insulin and GLP1-RA, the dose of GLP-1 RA should be 
stable for the past three months.   
7. Owns a smartphone compatible with the device  
8. Signed, informed consent and HIPAA documentation 
9. Subjects’ ability to self-administer insulin, use the device and complete subject reported outcomes 
instruments 
10. Subjects’ ability & willingness to adhere to and be compliant with study protocol 
 
Exclusion criteria 
1. Refusal or inability to give informed consent to participate in the study 
2. Subject is currently taking or was treated with glargine U300 insulin, degludec, insulin dose greater than 0.5 
U/kg/day during the previous three months  
3. Subject treated with prandial insulin during the previous three months  
4. Impaired renal function as shown by, but not limited to, eGFR < 30 ml/min.  
5. Muscle weakness or hemiparesis related to previous stroke or myelopathy resulting in incoordination, 
muscle weakness and inability to use pen device for insulin administration  
6. History of diabetic ketoacidosis during the previous 6 months 
7. Clinical evidence of active liver disease, or serum alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) 3 times the upper limit of the normal range 
8. History of hypoglycemia unawareness 
9. Pregnancy or lactation 
10. Known hypersensitivity to insulin glargine or any of the components 
11. Any malignancy within the last 5 years, except for adequately treated basal or squamous cell carcinoma of 
the skin or adequately treated cervical carcinoma in situ 
12. Current drug addiction or current alcohol abuse, or history of substance or alcohol abuse within the last 2 
years 
13. Diagnosis of dementia 
14. Severe gastrointestinal diseases including gastroparesis 
15. Cardiac status NYHA III-IV 
16. Acute infection 
17. Patients on or planning to receive long term oral or injectable steroid treatment for greater than 10 days 
18. Patient schedule to undergo general surgery during the next 6 months 
19. Any disease or condition that in the opinion of the investigator and/or sponsor may interfere with the 
completion of the study 
 
Potential Risks to the Subjects: 
There are no major risks associated with the intervention.   
 
Hypoglycemia.    It is possible that following the proposed protocol, patients receiving basal glargine and 
metformin may develop hypoglycemia. For this analysis, symptomatic hypoglycemia is defined as an event 
with typical symptoms (i.e., sweating, palpitation, and feeling of hunger) with or without confirmation by 
plasma glucose <54 mg/dl (3.9 mmol/L).  

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Severe hypoglycemia is defined as episodes necessitating assistance and associated with measured plasma 
glucose < 40 mg/dl (2.2 mmol/L) or with prompt recovery after administration of carbohydrates, glucagon, or 
other resuscitative actions.  
Protection against Risks: 
 
We will follow safeguards to minimize the risk to our subjects: a) we will carefully monitor response to 
medical treatment every 2 weeks by telephone contact and during clinic visits, b) women of reproductive age 
who are sexually active will undergo a urine pregnancy tests prior to participation in the study, c) female 
subjects whom are pregnant, breast-feeding, or not willing to use appropriate contraception at time of 
enrollment will not be included in the study, d) patients with significant comorbidities such as chronic kidney 
disease > stage III, liver cirrhosis, gastroparesis, and pancreatic disorders will be excluded from the study.  
Patients will receive diabetes education prior to discharge and will be instructed on hypoglycemia 
sign/symptoms and treatment.  Patients will be asked to call the diabetes center and/or PCP in the event of 
hypoglycemia. If a patient develops hypoglycemia, the dose of insulin will be reduced (see treatment 
algorithm).     
Statistical Analysis: 
This pilot study will compare treatment irregularities (insulin omission, mistiming and dosing) between 
Insulclock versus conventional insulin injection pen device.  We will also compare differences in glycemic 
control, as measured by change in mean HbA1c from baseline, number of hypoglycemic events, percentage of 
subjects maintaining therapy, 7-point SMBG profile, fasting plasma (FPG) profile, and HRQoL assessments 
(Patient reported outcomes) between groups. 
 
Analysis of Primary Endpoint: 
The primary outcome of treatment adherence with the use of Insulclock with feedback or no information 
(blinded) is whether a patient has a good adherent to the treatment regimen (assessed based on insulin 
omission, mistiming, and dosing). Given the 2 by 2 cross-over design, the superiority of the Insulclock system 
over the conventional insulin pen device will be determined by comparing the percent of patients showing a 
good treatment adherence with Insulclock but a poor treatment adherence with the conventional device to the 
percent of patients showing a poor treatment adherence with Insulclock but a good treatment adherence with 
the conventional device. We will perform this comparison based on McNemar’s test assuming the period 
effect is negligible. We will further conduct logistic regression to accommodate potential period effect and 
adjust for other potential confounders. We will apply standard model selection and model checking procedures 
(such as the Hosmer-Lemeshow tests) to decide and evaluate the final model. A p value of <0.05 will be 
considered significant.   
 
Analysis of Secondary Endpoints: 
Secondary endpoints in this study include patient satisfaction (assessed by subjects’ responses to questions 1, 
7 and 8 of the DTSQc), quality of life score, insulin dose, rate of hypoglycemia, number of episodes of severe 
hyperglycemia and hypoglycemia. For a continuous secondary outcome (e.g. quality of life score), our 
analysis will be focused on determining whether the outcome difference between period after crossover (i.e. 
period 2) versus the period before crossover (i.e. period 1) in the Insulclock group is similar to  that in the 
conventional device group. We will perform the analysis based on paired t-tests. Linear mixed models will be 
conducted to assess the study group difference while accounting for potential confounders. Appropriate 
transformations may be applied to make data better meet normality assumption. Standard model selection and 
checking procedures will be applied to determine the final linear models. For binary secondary outcomes, we 
will follow the analysis plan proposed for the primary endpoint.  
 
Power Considerations  
This is a pilot study and we plan to recruit 40 subjects for each study group. Our power calculation is mainly 
based on the binary primary outcome. We assume no more than 15% attrition rate, and assume no period 

Insulclock Proposal, 06/01/2018 
 
13
effect. In the following table, we give the power for detecting the superiority of Insulclock based on Exact 
Test for Binomial proportion with alpha=0.05, under different projections for the proportion of subjects 
showing treatment preference (i.e. adherent under one treatment but not under the other), denoted by Ptp, and 
projections for the probability of preference to Insulclock given showing treatment preference, denoted by p. 
 
 
Power 
Ptp 
 
90% 
80% 
70% 
60% 
50% 
p 
0.6 31.2% 28.2% 21.5% 17.8% 13.9% 
0.7 87.9% 83.7% 74.9% 66.5% 55.4% 
0.8 >99% 
>99% 
>99% 
97.6% 93.8% 
0.9 >99% 
>99% 
>99% 
>99% 
>99% 
Regarding the secondary outcomes, the power calculations can be made conservatively based on superiority 
hypotheses without specifying the equivalent margins. For continuous secondary outcomes, we would have 
over 80% power to detect outcome difference of 0.41 times the standard deviation based on paired t tests, with 
alpha=0.05, assuming equal outcome standard deviations for Insulclock and the conventional device, and 
within subject correlation equal to 0.3. 
Data Handing and Record Keeping: 
Data collection records with personal identifiers will be stored in locked file cabinets.  Presentation of the 
study results at regional or scientific meetings or in publications will not identify subjects.  Access to research 
and confidential records will be limited to clinical investigators, research coordinators, and the IRB at Emory 
University. 
Ethics: 
Informed Consent.  
After identification of eligible patients these individuals will be provided basic information regarding the 
study and, if interested, a member of the research staff using inclusion/exclusion criteria delineated elsewhere 
in the protocol will enroll patients.  Informed consent will be obtained before any trial related procedures 
including screening procedures. The consent form, potential risks and benefits, and the rights of research 
participants will be explained to the participant by the investigators or research coordinator.  Individuals will 
be asked if they have questions, and a member of the research staff will answer questions.  The principal 
investigator will also be available always to answer questions that participants may have during the consent 
procedure or during the time a participant is enrolled in the study.  The consent form will be completed in 
accordance with the IRB guidelines of Emory University.  A signed copy of the consent form will be provided 
to the participant and a copy will be placed in the file that is maintained for each participant in the study 
office.   
Informed consent will follow the procedure of Emory University Institutional Review Board.   Every potential 
participant will be informed in writing and verbally with the important and key points of the study.   One of 
the investigators or research coordinators will obtain a witnessed informed consent prior to inclusion of a 
patient into the study.   
The study will be conducted in accordance with the Declaration of Helsinki and will be conducted in 
accordance with the ICH GCP guidelines. The sponsor-investigator will comply with all applicable regulatory 
and legal requirements, ICH GCP guidelines and the Declaration of Helsinki in obtaining and documenting the 
informed consent. 
 
STUDY SCHEDULE: 

Insulclock Proposal, 06/01/2018 
 
14
FIRST PATIENT IN 
2017 NOVEMBER 
SCREENING 
~200 
RANDOMIZED 
80 
LAST PATIENT RECRUITED 
2018  
LAST PATIENT IN (COMPLETED) 
2018 DECEMBER 
DATA ANALYSIS 
JUNE 2019- FEBRUARY 2019 
SUBMISSION TO CONGRESS OR 
JOURNAL 
ADA 2020 MAJOR MEDICINE JOURNAL 
AND/OR DIABETES CARE 
 
 

Insulclock Proposal, 06/01/2018 
 
15
Payment for Participation: 
Participation in this study is voluntary.  Patients will receive seventy- five dollars ($75, 00) after each clinic 
visit. Total compensation will be four hundred and fifty dollars ($450). 
 
 
 

Insulclock Proposal, 06/01/2018 
 
16
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