Assessment of Participant Adherence and Glucose Control While Using a Connected Insulin Management Platform
Phase: NA
Conditions: Type 1 Diabetes, Type 2 Diabetes, Type 2 Diabetes Treated With Insulin
Sponsor: Eli Lilly and Company

Protocol Addendum F3Z-MC-IORW(f) 
Assessment of Participant Adherence and Glucose Control While Using a Connected Insulin 
Management Platform  
NCT05893797 
Approval Date: 06-Sep-2023 

F3Z-MC-IORW (f) Clinical Protocol (Version 7.0) 
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Protocol F3Z-MC-IORW(f) 
Assessment of Participant Adherence and Glucose Control 
While Using a Connected Insulin Management Platform  
Confidential Information 
The information contained in this document is confidential and is intended for the use of 
clinical investigators. It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
the Tempo Pen and Tempo Smart Button (LY8888AX), unless such persons are bound by 
a confidentiality agreement with Eli Lilly and Company or its subsidiaries. 
Note to Regulatory Authorities: This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries. 
Tempo Pen and Tempo Smart Button LY8888AX 
in support of Humalog (insulin lispro) LY275585 
Sponsor: Eli Lilly Cork Limited, a company incorporated under the laws of the Republic of Ireland with company 
registration number 615384, having a registered office at Island House, Eastgate Road, Eastgate 
Business Park, Little Island, Co. Cork Ireland, serves as the “Legal Representative” for all clinical 
investigations sponsored by Eli Lilly and Company conducted within the EU pursuant to the Medical 
Device Regulation (EU 2017/745) and applicable country legislation. 
Jennal Lynn Johnson 
Clinical Director Connected Care 
+1 317-565-9511
johnson_jennal@lilly.com 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
Protocol (Version 1) Electronically Signed and Approved by Lilly on 23 January 2023. 
Amendment (a; Version 2) Electronically Signed and Approved by Lilly on 14 April 2023. 
Amendment (b; Version 3) Electronically Signed and Approved by Lilly on 28 April 2023. 
Amendment (c; Version 4) Electronically Signed and Approved by Lilly on 10 May 2023. 
Amendment (d; Version 5) Electronically Signed and Approved by Lilly on 17 May 2023. 
Amendment (e; Version 6) Electronically Signed and Approved by Lilly on 29 June 2023. 
Amendment (f; Version 7) Electronically Signed and Approved by Lilly on date provided below 
Document ID: VV-CLIN-110605. 
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Protocol Amendment Summary of Changes 
This amendment is considered to be non-substantial. 
Changes made in this protocol amendment reflect the change from ‘up to 10 sites’ to the specific 
number of sites in France.   
Section Number and Name 
Description of Change 
1. Protocol Summary

Text for number of sites amended to state 9 sites in France.
4.1 Overall Design 

Text for Number of Sites amended to state that the study will
include 9 sites in France.
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Table of Contents 
Section 
Page 
Protocol F3Z-MC-IORW(f)  Assessment of Participant Adherence and 
Glucose Control While Using a Connected Insulin Management 
Platform ...................................................................................................................................1
Protocol Amendment Summary of Changes....................................................................................2
Table of Contents .............................................................................................................................3
1.
Protocol Summary ...................................................................................................................9
1.1.
Synopsis ..............................................................................................................................9
1.2.
Schema .............................................................................................................................11
1.3.
Schedule of Activities.......................................................................................................12
2.
Introduction ...........................................................................................................................16
2.1.
Study Rationale ................................................................................................................16
2.1.1.
Insulin Management for People with Diabetes ........................................................16
2.1.2.
Challenges with Insulin Management ......................................................................16
2.1.3.
Use of Connected Devices for Insulin Management ...............................................17
2.1.4.
Purpose of Study ......................................................................................................17
2.2. 
Components of Study Platform ........................................................................................18
2.3. 
Description of Devices .....................................................................................................20
2.3.1.
Commercial Devices and Products ..........................................................................20
2.3.1.1.
Tempo Smart Button ..........................................................................................20
2.3.1.2.
Humalog Tempo Pen ..........................................................................................21
2.3.1.3.
Dexcom G6 Continuous Glucose Monitor .........................................................22
2.3.1.4.
Glooko Medical Device Software ......................................................................23
2.3.1.4.1. 
Glooko research mobile application .............................................................23
2.3.1.4.2. 
Glooko HCP Platform ..................................................................................24
2.3.1.4.3. 
Glooko cloud data storage ............................................................................24
2.4. 
Benefit/Risk Assessment ..................................................................................................24
2.4.1.
Clinical Benefit ........................................................................................................25
2.4.2.
Potential Risks ..........................................................................................................25
2.4.3.
Methods to Minimise Risks .....................................................................................28
2.4.3.1. 
Hypoglycaemia ...................................................................................................28
2.5. 
Adverse Events, Serious Adverse Events, and Device Deficiencies ................................29
2.5.1.
Adverse Events ........................................................................................................32
2.5.2.
Serious Adverse Events ...........................................................................................33
2.5.2.1. 
Severe Hypoglycaemia .......................................................................................33
2.5.2.2. 
Pregnancy ...........................................................................................................33
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2.5.2.2.1. 
Female study participants who become pregnant ........................................33 
2.5.2.2.2. 
Partners of male study participants who become 
pregnant ........................................................................................................34 
2.5.3. 
Device Deficiency ....................................................................................................34 
2.6. 
Unanticipated Adverse Device Effects .............................................................................35 
3. 
Objectives and Endpoints ......................................................................................................36 
4. 
Study Design .........................................................................................................................38 
4.1. 
Overall Design ..................................................................................................................38 
4.1.1. 
Study Period 1 (Run-in) – Weeks 1 to 6 (Baseline) .................................................38 
4.1.2. 
Study Period 2 (Intervention) – Weeks 7 to 18 ........................................................39 
4.1.3. 
Safety Follow-up ......................................................................................................39 
4.2. 
Visit Overview..................................................................................................................39 
4.2.1. 
Administration of HCP Questionnaires ...................................................................39 
4.2.2. 
Visit 1 – Participant Screening and Enrolment ........................................................39 
4.2.2.1. 
Screening ............................................................................................................40 
4.2.2.2. 
Enrolment ...........................................................................................................40 
4.2.3. 
Visit 2 – Remote Check-in 1 ....................................................................................41 
4.2.4. 
Visit 3 – In-Person Check-in 1 .................................................................................41 
4.2.5. 
Visit 4 – Remote Check-in 2 ....................................................................................42 
4.2.6. 
Visit 5 and 6 – Remote Check-in 3 & 4 ...................................................................43 
4.2.7. 
Visit 7 – In-Person Check-in 2 .................................................................................43 
4.2.8. 
Visit 8 – Safety Follow-up and Study Exit ..............................................................44 
4.2.9. 
Unscheduled Visits ..................................................................................................44 
4.3. 
Early Discontinuation Visits .............................................................................................45 
4.4. 
Scientific Rationale for Study Design ..............................................................................46 
4.4.1. 
Rationale for Investigation of Missed Bolus Dose ..................................................46 
4.4.2. 
Rationale for Single-Arm Study ..............................................................................46 
4.4.3. 
Rationale for Inclusion of Predominately Participants with 
Type 1 Diabetes .......................................................................................................46 
4.5. 
End-of-Study Definition ...................................................................................................47 
4.6. 
Travel Restriction Flexibilities .........................................................................................47 
5. 
Study Population ...................................................................................................................48 
5.1. 
Inclusion Criteria ..............................................................................................................48 
5.2. 
Exclusion Criteria .............................................................................................................49 
5.3. 
Lifestyle Restrictions ........................................................................................................50 
5.4. 
Screen Failures .................................................................................................................50 
6. 
Study Intervention and Concomitant Therapy ......................................................................51 
6.1. 
Study Intervention(s) Administered .................................................................................51 
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6.2. 
Preparation, Handling, Storage, Labelling and Accountability ........................................52 
6.3. 
Measures to Minimise Bias ..............................................................................................53 
6.4. 
Continued Access to Study Intervention After the End of the 
Study .................................................................................................................................53 
6.5. 
Treatment of Overdose .....................................................................................................54 
6.6. 
Concomitant Therapy .......................................................................................................54 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ..................................................................................................56 
7.1. 
Discontinuation of the Study Intervention .......................................................................56 
7.2. 
Participant Discontinuation/Withdrawal from the Study .................................................56 
7.2.1. 
Participant Withdrawal ............................................................................................56 
7.2.2. 
Participant Discontinuation ......................................................................................56 
7.2.3. 
Lost to Follow-Up ....................................................................................................57 
8. 
Study Assessments and Procedures .......................................................................................58 
8.1. 
Effectiveness Assessments ...............................................................................................58 
8.1.1. 
Primary Assessments ...............................................................................................58 
8.1.2. 
Secondary Assessments ...........................................................................................59 
8.1.3. 
Exploratory Assessments .........................................................................................59 
8.2. 
Safety Assessments ..........................................................................................................59 
9. 
Statistical Considerations ......................................................................................................60 
9.1. 
Statistical Hypotheses .......................................................................................................60 
9.2. 
Analyses Sets ....................................................................................................................60 
9.2.1. 
Main Analysis Set ....................................................................................................60 
9.2.2. 
Sensitivity Analysis Set ...........................................................................................60 
9.3. 
Statistical Analyses ...........................................................................................................61 
9.3.1. 
Primary Endpoint .....................................................................................................62 
9.3.2. 
Secondary Endpoints ................................................................................................62 
9.3.3. 
Safety Analyses ........................................................................................................63 
9.3.4. 
Other Analyses .........................................................................................................63 
9.3.5. 
Subgroup Analyses ..................................................................................................63 
9.3.6. 
Sensitivity Analyses .................................................................................................63 
9.4. 
Sample Size Determination ..............................................................................................63 
9.5. 
Interim Analyses ...............................................................................................................64 
10. Appendices ............................................................................................................................65 
11. References .............................................................................................................................84 
11.1. Literature Cited .................................................................................................................84 
11.2. Previous Investigations of the Humalog Tempo pen and Tempo 
Smart Button .....................................................................................................................86 
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List of Tables 
Table 
Page 
Table 1.1. 
Schedule of Activities for Study F3Z-MC-IORW ............................................12 
Table 2.1. 
Event Collection ................................................................................................31 
Table 3.1. 
Objectives and Endpoints ..................................................................................36 
Table 6.1. 
Study Platform Components that Contact the Body .........................................51 
Table 6.2. 
Treatment Regimens for Each Study Period .....................................................52 
Table 6.3. 
Summary of Concomitant Therapies that Are Permitted and Not 
Permitted during the Study ................................................................................54 
Table 9.1. 
Sample Sizes of Evaluable Participants Needed to Detect at Least a 
Mean Difference of 0.323 Missed Bolus Doses Per Day (Alpha=0.05, 
Power=80%) ......................................................................................................64 
 
 
 
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List of Figures 
Figure 
Page 
Figure 1.1. 
Schema for Study IORW. ..................................................................................11 
Figure 2.1. 
Components of study platform. .........................................................................19 
Figure 2.2. 
Tempo Smart Button. ........................................................................................20 
Figure 2.3. 
Humalog Tempo Pen. ........................................................................................22 
Figure 2.4. 
Components of Dexcom G6 CGM System. ......................................................23 
Figure 8.1. 
Illustration of missed bolus dose and mistimed bolus. ......................................58 
 
 
 
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List of Appendices 
Appendix 
Page 
Appendix 1. 
Regulatory, Ethical, and Study Oversight Considerations ................................66 
Appendix 2. 
Adverse Events and Serious Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting ...................71 
Appendix 3. 
Contraceptive and Barrier Guidance .................................................................76 
Appendix 4. 
Provisions for Changes in Study Conduct 
During Exceptional Circumstances ...................................................................78 
Appendix 5. 
Abbreviations ....................................................................................................81 
Appendix 6. 
Protocol Amendment History ............................................................................83 
 
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1. 
Protocol Summary  
1.1. Synopsis  
Study Title: 
Assessment of Participant Adherence and Glucose Control While Using a Connected 
Insulin Management Platform 
Study Funding: 
Eli Lilly and Company 
Study Description: 
18-week, 1 country, multicentre, open-label, controlled, single-arm, pragmatic 
outpatient study to assess participant adherence and glucose control while using a 
connected insulin management platform 
Participant 
Population: 
≥18 years old diagnosed with type 1 diabetes (T1D) or type 2 diabetes (T2D) on basal 
bolus therapy with a glycated haemoglobin (HbA1c) ≥8% 
Sample Size 
Approximately 50 total study participants  
Number of Sites 
9 sites in France 
Study Duration 
Approximately 16 months 
Participant Duration  
Approximately 18 weeks 
Study Platform 
Description 
Conformité Européenne (CE) marked devices: 
 
Lilly Tempo Smart Button™, attached to the Tempo Pen™, will be used to 
detect and transmit 
 data 
 
 to the Glooko Research Mobile Application (RMA). 
 
Dexcom® G6 continuous glucose monitoring (CGM) will be used to monitor 
interstitial glucose throughout the study. 
 
The study is divided in 2 periods; (1) Masked 
 Data (run 
in): first 6 weeks and (2) Unmasked 
 Data (intervention): 
Week 7 to 18. 
CE-marked medical device software (MDSW): 
 
The Glooko RMA for people with diabetes (PwD), will be used to receive 
 data from the Tempo Smart Button and CGM to track insulin dosing 
history and interstitial glucose values and share them with healthcare 
professionals (HCPs). 
 
Glooko platform for HCPs, will be used to share and consolidate participants’ 
data from Glooko RMA with HCPs. 
Approved Medicinal Product: 
 
Lilly Tempo Pen will be used to subcutaneously administer Humalog® insulin 
to treat adults with T1D or T2D on basal bolus therapy. 
Objectives and 
Endpoints 
Primary Objective: To compare the 
number of missed bolus doses (MBDs) 
during the Study Period 2 (Weeks 15 to 
18), compared to the Study Period 1 
(Weeks 5 and 6) in participants using 
the 
Primary Endpoint: 
Difference in the average number of 
MBDs per week in the masked versus 
unmasked portions of the study. 
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CCI
CCI
CCI
CCI
CCI

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 
Tempo Pen 
 
Tempo Smart Button 
 
Glooko RMA, and 
 
Dexcom G6 CGM. 
Missed bolus dose is defined as no insulin 
dose from 1 hour prior to through 1 hour 
after the start of a glucose excursion 
(meal), where a glucose excursion was 
defined as a >70 mg/dL (>3.9 mmol/L) 
rise within 2 hours, not preceded by a 
value <70 mg/dL (<3.9 mmol/L). 
Secondary Objectives: 
1) To evaluate difference in participant 
CGM time-in-range (TIR) (≥70 to 
180 mg/dL) in the Study Period 1 
versus Study Period 2. 
2) To evaluate difference in participant 
CGM time above range (TAR) 
(>180 mg/dL and >250 mg/dL) in 
the Study Period 1 versus Study 
Period 2. 
3) To evaluate difference in participant 
CGM time below range (TBR) 
(54 mg/dL ≤ TBR < 70 mg/dL and 
< 54 mg/dL) in the Study Period 1 
versus Study Period 2. 
4) To evaluate Coefficient of Variation 
and mean sensor glucose from 
CGM values 
5) To examine occurrence and change 
of mistimed boluses between Study 
Period 1 versus Study Period 2. 
6) To evaluate the change in total 
insulin doses (basal, mealtime per 
meal type, correction bolus) Study 
Period 1 versus Study Period 2 
7) To evaluate occurrence, change, and 
Study Period 1 versus Study Period 
2 change in correction boluses 
8) To examine the association between 
MBD and TIR, TAR, TBR, HbA1c 
9) To examine the association between 
mistimed bolus and TIR, TAR, 
TBR, HbA1c 
10) To assess device preference, 
satisfaction, convenience, and ease 
of use  
Secondary Endpoints: 
 
 
 
 
1) CGM TIR (≥70 to 180 mg/dL) in the 
masked versus unmasked portions of 
the study. 
2) CGM TAR (>180 mg/dL and >250 
mg/dL) in the masked versus 
unmasked portions of the study. 
3) CGM TBR (54 mg/dL ≤ TBR 
< 70 mg/dL and < 54 mg/dL) in the 
masked versus unmasked portions of 
the study. 
4) Coefficient of variation and mean 
sensor glucose from CGM data 
collected from each participant 
5) Occurrence and change of mistimed 
boluses 
6) Total insulin dose per day, basal dose 
and insulin dose per type of meal 
(breakfast [B], lunch [L], snacks, and 
dinner [D]) as well as corrections 
doses. 
7) Occurrence, change, and masked 
versus unmasked change in 
correction boluses 
8) CGM curves integrated with data 
received from the Tempo Pen 
9) CGM curves integrated with data 
received from the Tempo Pen 
10) Participant and HCP questionnaires  
 
 
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1.2. Schema  
Figure 1.1 gives an outline of the study schema. 
 
Figure 1.1. 
Schema for Study IORW.  
 
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1.3. Schedule of Activities  
Table 1.1 summarises the Schedule of Activities (SoA) for the study. 
Table 1.1. 
Schedule of Activities for Study F3Z-MC-IORW  
 
Study Period 1 (Masked) 
Study Period 2 (Unmasked) 
Follow-up 
UNS 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 or 
ET(Exit) 
 
 
Visit Type 
On-site 
Remote 
On-site 
Remote 
Remote 
Remote 
On-site 
Remote 
 
 
Time from previous visit 
(weeks or days) 
N/A 
1 W 
5 W 
1 W 
3 W 
4 W 
4 W 
3D 
N/A 
N/A 
Visit window (days) 
N/A 
+/-3 
+7 
+/-3 
+/-3 
+/-3 
+7 
+/-1 
N/A 
N/A 
Study Logistics 
Informed Consent signed 
X 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
Reviewed 
X 
 
 
 
 
 
 
 
 
 
Enrolment 
X 
 
 
 
 
 
 
 
 
 
Install and set-up Glooko 
RMA 
X 
 
 
 
 
 
 
 
 
 
Pair the Tempo Smart 
Button 
X 
 
 
 
 
 
 
 
 
 
Study CGM device user 
training provided 
X 
 
 
 
 
 
 
 
 
 
Study phone user training 
provided 
X 
 
 
 
 
 
 
 
 
 
Complete Participant 
Training 
X 
 
 
 
 
 
 
 
 
 
Participant brings mobile 
device with RMA and 
Tempo Pen with Tempo 
Smart Button  
 
 
X 
 
 
 
X 
 
 
X 
Confirm Tempo Smart 
Button transfer onto 
Glooko RMA 
 
 
X1 
 
X1 
X1 
X1 
 
X1 
X1 
Review the functioning, 
understanding, and use of 
the study platform 
components 
X 
X 
X 
X 
X2 
X2 
 
 
X2 
 
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Study Period 1 (Masked) 
Study Period 2 (Unmasked) 
Follow-up 
UNS 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 or 
ET(Exit) 
 
 
Visit Type 
On-site 
Remote 
On-site 
Remote 
Remote 
Remote 
On-site 
Remote 
 
 
Time from previous visit 
(weeks or days) 
N/A 
1 W 
5 W 
1 W 
3 W 
4 W 
4 W 
3D 
N/A 
N/A 
Visit window (days) 
N/A 
+/-3 
+7 
+/-3 
+/-3 
+/-3 
+7 
+/-1 
N/A 
N/A 
Unmask Tempo Pen data in 
Glooko RMA 
 
 
X 
 
 
 
 
 
 
 
Clinical Assessment and Diabetes Management 
Medical History (including 
pre-existing conditions) 
X 
 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
Height and Weight 
X 
 
X3 
 
 
 
X3 
 
 
X3 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
Urine PoC Pregnancy Test 
(WOCBP only) 
X 
 
 
 
 
 
 
 
 
 
HbA1c PoC Test 
X 
 
 
 
 
 
X 
 
 
X 
Vital Signs 
X 
 
 
 
 
 
 
 
 
 
Hypoglycaemia 
management and training 
X 
 
X4 
 
X4 
X4 
 
 
X4 
QR 
Review concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review Device Deficiencies 
(DD)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of glucose values 
and insulin regimen with 
participant (adjust if 
appropriate) 
X 
 
X5 
 
X5 
X5 
X5 
 
 
X5 
Document any educational 
activities  
 
 
X6 
 
X6 
X6 
X6 
 
 
X6 
Study Material Management 
Dispense Tempo Smart 
Button 
X 
 
 
 
 
 
 
 
X4 
 
Dispense Humalog Tempo 
Pens  
X 
 
X 
 
 
 
 
 
X4 
 
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Study Period 1 (Masked) 
Study Period 2 (Unmasked) 
Follow-up 
UNS 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 or 
ET(Exit) 
 
 
Visit Type 
On-site 
Remote 
On-site 
Remote 
Remote 
Remote 
On-site 
Remote 
 
 
Time from previous visit 
(weeks or days) 
N/A 
1 W 
5 W 
1 W 
3 W 
4 W 
4 W 
3D 
N/A 
N/A 
Visit window (days) 
N/A 
+/-3 
+7 
+/-3 
+/-3 
+/-3 
+7 
+/-1 
N/A 
N/A 
Check Dexcom data 
transfer  
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Dispense Study CGM 
device and receiver 
X 
 
X 
 
 
 
 
 
X 
 
Review usage of Humalog 
Tempo Pen & Tempo 
Smart Button 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Supply Collection (as per 
Sponsor’s instructions) 
 
 
 
 
 
 
X 
 
 
X 
Study Questionnaires 
IORW Participant Visit 1 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
IORW Participant Visit 3 
Questionnaire 
 
 
X 
 
 
 
 
 
 
X7 
IORW Participant Visit 7 
Questionnaire 
 
 
 
 
 
 
X 
 
 
X 
HFS-SF Questionnaire 
X 
 
X 
 
 
 
X 
 
 
X 
IORW Initial HCP 
Questionnaire 
X8 
 
 
 
 
 
 
 
 
 
IORW End-of-study HCP 
Questionnaire 
 
 
 
 
 
 
 
X9 
N/A 
N/A 
Abbreviations:  CGM = continuous glucose monitoring; D = day; ET = early termination; HbA1c = glycated haemoglobin; HCP = healthcare professional; 
HFS-SF = Hypoglycaemia Fear Survey – Short Form (Adult Low Blood Sugar Survey); N/A = not applicable; RMA = research mobile application; DD = 
device deficiency; PoC = point-of-care; UNS = unscheduled visit; V = visit; W = week; WOCBP = women of childbearing potential. 
1 
Using Glooko HCP platform. 
2 
If deemed necessary based on a previous visit. 
3 
Weight only. 
4 
If required. 
5 
Using the Glooko HCP platform. 
6 
Recommendations that resulted from the review of the Glooko report with the participant. 
7 
If the Early Termination visit takes place before Visit 3. 
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8 
Initial HCP Questionnaire should be completed prior to site’s First Participant Visit (FPV). 
9 
End-of-study HCP Questionnaire should be completed after site’s Last Participant Visit (LPV). 
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2. 
Introduction  
2.1. Study Rationale  
2.1.1. Insulin Management for People with Diabetes  
PwD face many challenges throughout their diabetes journey to reach and maintain their 
treatment goals. They are required to strictly manage numerous facets of their lives, such as: 
 meal planning 
 lifestyle considerations, and 
 medical management of their condition, including: 
o appropriately adjusted insulin dosing 
o multiple medications with different dosing regimens (mainly for those with type 2 
diabetes [T2D]) 
o frequent glucose levels monitoring, and 
o record keeping for insulin injections timing and dosage on paper logbooks or 
apps. 
2.1.2. Challenges with Insulin Management  
People with diabetes on basal bolus insulin therapy regimen require multiple daily injections: 
 mealtime (bolus) insulin once before every meal, and 
 a long-acting insulin (basal insulin) once or twice daily. 
 
Adherence to insulin therapy is important for optimal glycaemic control. The most immediate 
consequence of missing insulin doses at mealtime is a lack of control on post-meal glucose 
excursions which has deleterious effect on time-in-range as measured by CGM, but also on 
intermediate measures such as glycated haemoglobin (HbA1c) and long term micro- and macro-
vascular complications (Andrade et al. 2017; Munshi et al. 2013; Nathan et al. 2005; Randløv 
and Pulsen 2008; Spaans et al. 2018). 
Multiple daily insulin injections can be burdensome for PwD and, therefore, adherence 
challenges including missing dose opportunities to insulin therapy is frequent, both in type 1 
diabetes [T1D] and T2D (Peyrot et al. 2012a) for reasons such as: 
 lifestyle burden, 
 difficulty with injection or the insulin regimen, and 
 certain psychosocial and behavioural factors (Peyrot et al. 2012b). 
 
HCPs and diabetes educators rely on PwD to keep paper logs or diaries of these activities to gain 
insights and discern patterns to make insulin therapy adjustments or provide education and 
training. For PwD, keeping treatment logs can be burdensome and can result in inaccurate and 
incomplete information for the PwD and their HCP (Kompala and Neinstein 2021). 
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2.1.3. Use of Connected Devices for Insulin Management  
Smart insulin pens can provide the missing data to allow HCPs and PwD to inform optimised 
insulin treatment decisions (Adolfsson et al. 2020; Heinemann et al. 2021; Klonoff and Kerr 2018; 
Kompala and Neinstein 2021; Munshi et al. 2019, Sy et al. 2022). Recent American Association 
of Clinical Endocrinology (AACE) guidelines recommend that the use of connected pens may 
help patients with diabetes and clinicians: 
 optimise insulin regimens, and 
 avoid stacking of rapid acting insulin, which may lead to hypoglycaemia (Grunberger et 
al. 2021). 
Studies with connected insulin pens have allowed HCPs to identify more precisely the frequency 
of MBDs in groups of people with T1D and T2D on CGM (Edwards et al. 2021; Adolfsson et al. 
2020; Munschi et al. 2019, Gomez-Peralta et al. 2023). 
Adolfsson et al. (2020) evaluated the use of a reusable insulin connected pen in the setting of a 
prospective multicentre observational study in Sweden, in 94 people with T1D using CGM. 
During the “baseline” observation period with blinded CGM, at least 25% of meals had a missed 
dose on average, assuming 3 meals per day. This amounted to 5 meals with a missed dose per 
week on average. Over an average period of 7 months, the authors could show an improvement 
of almost 2 hours in TIR (70-180 mg/dL), mainly due to a reduction of time above range (TAR) 
(>180 mg/dL). This happened thanks to an improvement of adherence to insulin therapy with 
43% fewer MBDs (N = 14 patients). 
Despite the low sample size, this suggests that evaluating past dosing data together with HCPs 
may have helped participants to remember and administer their mealtime doses, or to improve 
the timing of the dose, relative to the meal. The data is consistent with the hypothesis that 
connected pens may support people with the management of their insulin treatment regimens and 
help reduce missed and mistimed bolus doses. 
2.1.4. Purpose of Study  
Eli Lilly and Company (Lilly) has introduced a reusable 
 data transmission module 
(Tempo Smart Button) which can be attached to a compatible disposable single-use prefilled 
insulin pen (Tempo Pen). 
The Tempo Pen/Smart Button facilitates an automated collection 
 
 that can be put in relation with glycaemic values measured either in the 
capillary blood with fingersticks (self-monitored blood glucose [SMBG]) or with a CGM 
through a Glooko RMA. 
In this study, Lilly intends to provide further and more reliable clinical evidence to confirm what 
was observed in the Adolfsson study, focusing on showing a reduction of MBDs in a controlled 
single-arm study enrolling people with uncontrolled diabetes (HbA1c ≥8%), both T1D and T2D 
on basal bolus therapy. Patients with T2D were not included in the Adolfsson study and it is 
believed that T2D patients on basal bolus therapy could also benefit from a connected insulin 
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management platform (Grunberger et al. 2021). Study F3Z-MC-IORW (IORW) seeks to 
understand the relationship between the use of a connected insulin platform and people’s own 
daily diabetes management such as: 
 adherence to insulin regimen (MBD) 
 timing of injection (mistimed bolus) 
 daily insulin dose adjustment, and 
 glycaemic outcomes. 
 
Study IORW will assess the number of MBDs during the Study Period 2 (Weeks 15 to 18), 
compared to the Study Period 1 (Weeks 5 and 6) in participants using the: 
 Humalog Tempo Pen 
 Tempo Smart Button 
 Glooko RMA, and 
 Dexcom G6 CGM. 
 
Study IORW will be an open-label, single arm, pragmatic study, conducted with participants in 
an outpatient setting with study interventions representative of standard clinical practices, to 
minimise bias associated with participation in a clinical trial. By utilising insulin dosing and 
interstitial glucose data, this study should allow Lilly to assess the impact of connected platforms 
on diabetes management. 
2.2. Components of Study Platform  
The study platform to be used (Figure 2.1) is comprised of the following components: 
Conformité Européenne- (CE-) marked devices: 
 Tempo Smart Button (Lilly), and 
 Dexcom G6 (Dexcom) CGM. 
Approved Medicinal Product: 
 Humalog® Tempo Pen (Lilly). 
CE-marked MDSW: 
 Glooko MDSW (Glooko Inc.) installed on the study-provided Android smartphone, 
consisting of: 
o Glooko RMA for PwD 
o Glooko HCP platform 
Data from the Glooko MDSW will be stored in cloud data storage through which the data is 
shared between PwD and HCPs. 
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Abbreviations: HCP = healthcare professional; RMA = research mobile application. 
Figure 2.1. 
Components of study platform.  
 
 data from the Tempo Pen/Smart Button are wirelessly transmitted to the Glooko 
RMA via Bluetooth. Interstitial glucose values from the Dexcom G6 CGM are transmitted 
periodically via USB cable. The participant may also track data such as basal insulin delivery, 
exercise, and carbohydrate or meal intake on the RMA. 
Data from the study platform components gathered in the Glooko RMA provides the participant 
with information to: 
 assess omitted or suboptimal dose data 
 get access retrospectively to his/her own data in case he/she needs to, and 
 provide the participant with an opportunity for productive and objective discussion with 
his/her HCPs to better adjust insulin treatment and optimise the way he/she manages 
his/her diabetes. 
 
User-tracked data will be available to HCP through the Glooko HCP platform which can: 
 provide an objective history of user’s own diabetes management, and 
 generate meaningful conversations between the user and HCP to improve insulin 
treatment (e.g., reduce the number of missed boluses, discuss impact of injection timing, 
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and also help users learn how to adjust insulin doses) and ultimately improve glycaemic 
outcomes. 
2.3. Description of Devices  
The devices used in the study are described in the following sections. 
2.3.1. Commercial Devices and Products  
2.3.1.1. 
Tempo Smart Button  
The Tempo Smart Button (manufactured by Lilly, Indianapolis, IN USA) is a reusable data 
transmitter (or data transfer module) that: 
 detects and stores information from a Tempo Pen, and then 
 transfers insulin dose-related data to a compatible mobile application via Bluetooth® 
wireless technology. 
 
The dose-related data corresponds to the brand of insulin, dose amount, date, and time. Figure 
2.2 provides an illustration of the Tempo Smart Button. 
Figure 2.2. 
Tempo Smart Button.  
 
The Tempo Smart Button is designed to be attached and detached from a Tempo Pen and is only 
functional when attached to a Tempo Pen. 
When paired with an RMA, the Tempo Smart Button transmits stored data 
 
 the RMA user interface. The Tempo Smart Button is designed so that no outside information 
or data can be received by the Smart Button. The communication is only in one direction: from 
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the Tempo Smart Button to the RMA. It is not possible to use the RMA to modify the 
 
 data stored on the Tempo Smart Button. 
Once the Tempo Smart Button module is paired to the RMA on the study-provided mobile 
device, the module will automatically transfer data to the RMA after a dose is delivered, as long 
as: 
 the user has placed the Tempo Smart Button in the proximity of the paired mobile device 
 Bluetooth is enabled on the participant’s mobile device, and 
 the RMA is launched and open. 
 
If the Tempo Smart Button is not in proximity of the mobile device before Bluetooth Low 
Energy (BLE) shuts down, then the data will be transferred the next time that the Tempo Smart 
Button is activated, and the RMA is open (that is, data are not lost). The dose records, up to a 
total of 5840 (Tempo Smart Button IFU) remain in the Smart Button data storage for the life of 
the module; dose records are not deleted after transmission to the RMA. 
The Tempo Smart Button to be used in this study will be the CE-marked presentation (Class I 
EU MDR). 
2.3.1.2. 
Humalog Tempo Pen  
Humalog (Lilly) is a rapid acting human insulin analogue used in the treatment of adults and 
children with diabetes mellitus who require insulin for the maintenance of normal glucose 
homeostasis. Humalog is also indicated for the initial stabilization of diabetes mellitus. 
The Humalog Tempo Pen (manufactured by Lilly, Indianapolis, IN USA) is used for the 
subcutaneous administration of insulin. 
The Humalog Tempo Pen (Figure 2.3) is a disposable single-patient-use prefilled pen (medicinal 
product) that comprises: 
 Humalog insulin (insulin lispro);  
 a dose knob that allows for attachment of the Tempo Smart Button module; and 
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 an embedded magnet that allows the Tempo Smart Button module to detect the Tempo 
Pen. Once the Tempo Smart Button detects the Tempo Pen, the Tempo Smart Button will 
be activated. 
 
 
Figure 2.3. 
Humalog Tempo Pen.  
 
The Humalog Tempo Pen to be used in this study is the EC-approved presentation and will be 
provided as a 100-units/mL solution in a 3-mL Humalog Tempo Pen. 
2.3.1.3. 
Dexcom G6 Continuous Glucose Monitor  
The Dexcom G6 Continuous Glucose Monitor (also referred to as CGM; manufactured by 
Dexcom, Inc, San Diego, CA, USA) is a glucose monitoring system indicated for persons aged 2 
years and older, including pregnant women. The Dexcom G6 system is intended for use by 
patients at home and in healthcare facilities. 
The Dexcom G6 CGM is designed to replace fingerstick blood glucose (BG) testing for 
treatment decisions. The system also aids in the detection of episodes of hyperglycaemia and 
hypoglycaemia, facilitating both acute and long term therapy adjustments. 
The Dexcom G6 sensor inserted under the skin checks glucose levels in interstitial fluid and the 
transmitter sends readings to the receiver, where user can read the glucose values in real time. 
The CGM G6 Glucose Monitoring System to be used in this study will be the commercially 
available, CE-marked presentation (Class IIb EU MDD [Dexcom Letter of Conformity Form]). 
The Dexcom G6 CGM system (Figure 2.4) consists of 3 main components: 
 Applicator with built-in sensor - a small sensor which is worn on the back of the user’s 
upper arm or belly. The sensor applicator is used to insert the sensor under the skin. The 
sensor then gets the glucose information. The sensor can be worn for up to 10 days, after 
which it automatically stops working and must be replaced. 
 Transmitter – attaches to the sensor holder and sends glucose information from sensor to 
display device (receiver or smart device). If connection is lost between the transmitter 
and display device, up to 3 hours of data will be transmitted from the transmitter to the 
display device upon re-connection. Once snapped into place, the transmitter is water 
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resistant. The transmitter is reusable, lasts 3 months, and can be re-used with multiple 
sensors. 
 Receiver – a rechargeable, display device which is used to receive the data from the 
Dexcom G6 transmitter. The data transmitted from the transmitter is presented to the user 
as a graph and glucose level trend indications are also available. 
 Smart Device – a rechargeable, study-provided, Android smartphone which is used to 
receive the data from 
 Glooko RMA (via USB cable).  
 
 
 
Figure 2.4. 
Components of Dexcom G6 CGM System.  
 
2.3.1.4. 
Glooko Medical Device Software  
Glooko RMA and Glooko HCP platform will be used in the study to track participant’s insulin 
dosing data 
 and interstitial glucose values from the Dexcom 
G6 CGM. Data (including basal insulin delivery, carbohydrate or meal intake, exercise) will be 
shared with HCP through the Glooko HCP platform to generate meaningful conversations 
between the participant and HCP to improve insulin treatment (e.g., reduce the number of missed 
boluses, discuss impact of injection timing, and also help users learn how to adjust insulin doses) 
and ultimately improve glycaemic outcomes. 
2.3.1.4.1. 
Glooko research mobile application  
Glooko Research Mobile Application (Glooko Inc.) is a CE-marked (Class I EU MDD) software 
for PwD to aid in management of T1D (adults and children), T2D, and gestational diabetes. 
The Glooko RMA is designed to receive and display user data as part of self-management of 
diabetes. Data in Glooko RMA can be manually input by the user (e.g., meals, physical exercise, 
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basal insulin delivery) transferred from connected devices via Bluetooth 
 
, or uploaded via USB cable from non-
connected devices (e.g. CGM readings). The Glooko RMA is a modified version of the 
commercial app that includes the data masking function.  
The Glooko RMA also contains the following functionalities to support the study design: 
User Information 
 
The Glooko RMA/Glooko platform allows the assignment of participant ID numbers to identify 
study participants and study data while protecting privacy during the trial. 
 
Masking Tempo Smart Button and Pen Details 
 
During Study IORW Period 1 (6 weeks, Visits 1, 2, and 3), participants will be masked to the 
data 
. Masking during 
Study Period 1 is necessary to obtain baseline data for bolus self-administration and dosing 
adjustments performed by the participant. 
 
The Glooko RMA will be installed on the study-provided mobile phone running Android 
(Version 6.0 or higher) operating system with passcode protection. The mobile device will be 
configured to limit use to study-specific activities.  
Participants will be provided with a study-specific, password-protected user account for the 
Glooko RMA. Healthcare professionals use their own Glooko HCP secured platform/portal to 
access the users’ data and provide treatment advice and prescriptions during a remote or in-
person medical appointment. 
The data will be converted and presented in Glooko RMA in a graphical summary to the study 
participants. Additionally, participant’s diabetes management data will be made available to 
HCPs through Glooko HCP platform via cloud connection. 
2.3.1.4.2. 
Glooko HCP Platform  
The Glooko Research platform allows site administrators to view all participant data in a near 
real time basis as data is being uploaded remotely by the users from the Glooko RMA.  
2.3.1.4.3. 
Glooko cloud data storage  
Glooko Data storage is Health Insurance Portability and Accountability Act- (HIPAA-) and 
General Data Protection Regulation- (GDPR-) compliant. Data storage for the European Union 
(EU) is in Germany for French participants. Data is transferred from the Glooko RMA to the 
Glooko cloud via secure cloud transfer that is encrypted in transit and at rest. 
2.4. Benefit/Risk Assessment  
This study will be conducted with products within their respective intended use and indication 
for use in a way representative of their routine, everyday use, and routine 
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interventions/examinations for PwD. It is anticipated that the probability and severity of any 
potential harm or discomfort to the study participants will be no greater than those ordinarily 
encountered in daily life or during the performance of routine examinations and interventions for 
PwD. 
2.4.1. Clinical Benefit  
With the aid of methods and devices used in this study, some participants may improve 
glycaemic control as a result of: 
 reduction of MBDs 
 ability to reliably and objectively track and view data on insulin dosing 
 
 and CGM leading to more accurate insulin dose adjustments and 
disease understanding during unmasked Study Period 
 availability of other tracking features in Glooko RMA, and 
 more interactions with HCP via regular remote visits during the trial period engaging in 
productive conversations based on reliable, objective data to better manage the disease. 
 
The results of this study will: 
 offer valuable insights into the potential advantages of the connected devices in insulin 
treatment and diabetes management, and 
 provide further and more reliable clinical evidence to confirm what was observed in 
Adolfsson et al. (2020) study, focusing on showing a reduction of MBDs, and potential 
improvement in TIR, for patients with T1D as well as T2D on basal bolus therapy. 
In addition, the objective collection of bolus dosing data 
 will 
help to better understand actual dosing behaviour in relation to the assessment of interstitial 
glucose values measured by the commercially available CGM device used by the person. The 
completion of participant behaviour and satisfaction questionnaires will help to better understand 
user behaviour for daily diabetes management (timing of insulin injection, missing bolus, etc.) 
and its relationship with bolus dosing. 
As a result, it is anticipated that the productive conversations between the study participant and 
HCP, based on the data generated by the connected study platform, may result in a reduction of 
MBDs and improvement in participant’s own diabetes management. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of using a connected insulin management platform may be found 
in the Investigator’s Brochure. 
2.4.2. Potential Risks  
Potential Risks Associated with Diabetes Disease State and Insulin Treatment 
 Hyperglycaemia: the symptoms of hyperglycaemia include: nausea, vomiting, abdominal 
pain, difficulty breathing, a fruity smell of the breath, dry or flushed skin, and confusion, 
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difficulty paying attention, and in severe cases, diabetic ketoacidosis (DKA). Diabetic 
ketoacidosis can include: excessive thirst, frequent urination, nausea and vomiting, 
weakness or fatigue, shortness of breath, fruity-scented breath, high blood sugar level, 
high ketone levels in urine. 
 Hypoglycaemia: the symptoms of hypoglycaemia can include low energy, hunger, 
confusion, pounding heart, sweating, shakiness, headache, seizures, loss of 
consciousness, and coma. 
Potential Risks Associated with the Study Platform 
 Hyperglycaemia and/or hypoglycaemia, severe or otherwise, due to user insulin dosing 
behaviour negatively impacted by the study platform components resulting in overdose, 
underdose, or delay in therapy may be caused by: 
o incorrect or missing data stored or sent to Glooko RMA 
o repeated injection due to Tempo Smart Button or CGM malfunction 
o user misunderstanding or confusion caused by platform components, or 
o user inability to effectively use the platform or a component thereof. 
Potential Risks Associated with Tempo Smart Button 
 Incorrect insulin dose due to the: 
o user not pushing the Smart Button straight down during injection, or 
o Smart Button not flashing 3 times resulting in the user repeating the injection. 
 Personal harm or device damage by tampering with the Tempo Smart Button, device 
battery or exposing the Tempo Smart Button to: 
o strong electromagnetic field (e.g., magnetic resonance imaging [MRI]) 
o moisture, or 
o excessive light. 
 Choking can occur with Tempo Smart Button. If inhaled or ingested, the Smart Button 
may cause internal injury which could require medical assistance. 
 
For additional information please refer to the Tempo Smart Button Instructions for Use (IFU). 
Potential Risks Associated with Humalog Tempo Pen 
 Severe, life-threatening generalised allergy, including anaphylaxis, to Humalog insulin. 
 Pain, bruising, scarring, and infection resulting from insulin injections. 
 Lipodystrophy and cutaneous amyloidosis can occur due to incorrect injection technique. 
 Minor skin irritation, sensitisation, or localised inflammatory response can occur if skin 
contacts bioincompatible materials. 
 Hypokalaemia. 
 People with renal impairment may be at increased risk of hypoglycaemia and may require 
more frequent Humalog dose adjustment and more frequent glucose monitoring. 
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 People with hepatic impairment may be at increased risk of hypoglycaemia and may 
require more frequent Humalog dose adjustment and more frequent glucose monitoring. 
 The Tempo Pen contains a magnet; fitted medical devices, such as a heart pacemaker, 
may not work correctly if the Tempo Pen is held too close; the magnetic field extends to 
approximately 1.5 cm. 
 
The occurrence and severity of these events are not expected to be different from routine use of 
insulin injection systems. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs may be found in Humalog Package Insert and Humalog Summary of Product 
Characteristics. 
Potential Risks Associated with Dexcom G6 CGM Use 
 Redness, swelling, inflammation or pain at the sensor insertion site 
 Electric shock if the CGM transmitter is damaged 
 Choking can occur with transmitter 
 Inaccurate readings due to incorrect use of the system, damaged system components, 
dialysis treatment, critical illness, treatment with hydroxyurea, and 
 Personal harm or device damage exposing the sensor to strong magnetic field or heat 
(e.g., MRI, computed tomography [CT] scan, diathermy). 
 
The occurrence and severity of these events are not expected to be different from routine use of 
CGM. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs may be found in Dexcom G6 IFU. 
Possible Risks Associated with Glooko RMA Use 
 Participants must be within 6 metres of the Glooko RMA in order for the Tempo Smart 
Button data to transfer to their Glooko Research account.  
 Participants will be able to view 
 data (number of units of Humalog 
delivered and date and time stamp details) via the Glooko RMA ONLY during study 
period 2. 
The Dexcom Clarity or Dexcom G6 applications cannot be used. Participants must periodically 
upload their CGM data from the Dexcom receiver to the Glooko RMA. Data will not be visible 
in the Glooko RMA or the HCP Portal until participants have uploaded the data. Data must be 
uploaded at least every 30 days or it will no longer be available in the receiver. More detailed 
information about the known and expected benefits and risks may be found in Glooko App IFU. 
Possible Risks Associated with Participation in the Clinical Study 
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 Loss of confidentiality, or 
 Disclosure of personal health information (PHI). 
2.4.3. Methods to Minimise Risks  
The device design and controls, nonclinical testing, user instructions, training material and 
clinical study design (including selection of participants in accordance with eligibility criteria, 
safety, and study monitoring activities) are intended to minimise the risks associated with 
participation in this study. 
Specific training and mitigations related to hypoglycaemia can be found in Section 2.4.3.1. 
The Glooko MDSW complies with the GDPR 2016/679 of the European Parliament and of the 
Council of 27 April 2016 on the protection of natural persons regarding the processing of 
personal data and on the free movement of such data. 
The user is informed about how his/her personal data will be collected and is asked to agree to 
terms of use when signing up for the use of Glooko RMA. 
The risks have been minimised and are reasonable in relation to the potential users’ benefits and 
importance of the knowledge to be gained about the use of the connected study platform for 
diabetes management. The study platform risks have been reduced to a level that is considered 
acceptable to meet the trial objectives and maintains a positive risk-benefit profile for 
participants. 
2.4.3.1. 
Hypoglycaemia  
Site personnel will review hypoglycaemia management and frequency with participants at study 
entry and subsequent visits per the SoA, Table 1.1. Participants will be trained by site personnel 
on: 
 the signs and symptoms of hypoglycaemia, and 
 treatment of hypoglycaemia. 
If hypoglycaemia occurs, participants will be instructed to: 
 apply the procedures for the correction of hypoglycaemia, as advised by the study site; 
 have a plan in place to receive assistance and emergency treatment in case of severe 
hypoglycaemia; 
 for any severe hypoglycaemia or concerns regarding severe hypoglycaemia, participants 
will be instructed to contact the study site at the earliest opportunity once the severe 
hypoglycaemia has resolved and the participant is safe. 
 
The investigator or designee will review the participant data from the Glooko app and document 
his/her review, as per SoA (Table 1.1). Suspected or confirmed hypoglycaemia (Levels 1, 2 and 
3 as described by the International Hypoglycaemia Study group 2017), and frequency of 
hypoglycaemia must be evaluated. Insulin dosing, dietary changes, and physical exercise (or any 
other contributing factor) in the development of the event should be considered. The participant 
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should receive additional education to mitigate the risk of hypoglycaemia, if deemed appropriate. 
Insulin regimen may be adjusted, and it must also be documented. 
If a hypoglycaemic event meets the criteria of severe, the investigator must report it to Lilly as a 
serious adverse event (SAE). See Section 2.5.2 for further explanation. 
2.5. Adverse Events, Serious Adverse Events, and Device 
Deficiencies  
Appendix 2 describes the full definitions of the following events: 
 Adverse Events (AEs) 
 Serious Adverse Events (SAEs), and 
 Device Deficiencies (DD). 
 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorised representative) after informed consent is signed and 
through the safety follow-up. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that: 
 are serious 
 are considered related to the study intervention or study procedures, or 
 that caused the participant to discontinue from the study (see Section 7). 
 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences, 
where possible. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until: 
 resolution 
 stabilization 
 the event is otherwise explained, or 
 the participant is lost to follow-up (as defined in Section 7.2.3). 
 
For DDs, the investigator is responsible for ensuring that follow-up includes any supplemental 
investigations, as indicated to elucidate the nature and/or causality of any DDs. Further 
information on follow-up procedures is provided in Appendix 2. 
The following events are considered reportable events in accordance with MDR Art. 80(2) and 
MDCG 2020-10/1: 
a) any serious adverse event that has a causal relationship with the investigational 
device, the comparator or the investigation procedure or where such causal 
relationship is reasonably possible; 
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b) any device deficiency that might have led to a serious adverse event if appropriate 
action had not been taken, intervention had not occurred, or circumstances had been 
less fortunate;  
c) any new findings in relation to any event referred to in points a) and b). 
Table 2.1 describes the timing, deadlines, and mechanism for collecting events. 
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Table 2.1. 
Event Collection  
Event 
Collection Start 
Collection Stop 
Timing for Reporting to 
Sponsor or Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Adverse Events 
AE 
Signing of the ICF 
Participation in 
study has ended 
As soon as possible upon 
site awareness 
AE eCRF 
N/A 
Serious Adverse Events 
SAEs and SAE updates – prior to start of 
study intervention and deemed reasonably 
possibly related with study procedures 
Signing of the ICF 
Participation in 
study has ended  
Within 24 hours of 
awareness 
SAE eCRF  
SAE paper form 
SAEs* and SAE updates  
Signing of the ICF 
Participation in 
study has ended 
Within 24 hours of 
awareness 
SAE eCRF  
SAE paper form 
SAEs* – after participant’s study 
participation has ended and the investigator 
becomes aware 
After participant’s 
study participation 
has ended 
N/A 
 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in female participants and female 
partners of male participants 
Signing of CRF 
Participation in 
study has ended 
Within 24 hours 
(See Section 2.5.2.2)  
SAE eCRF  
SAE paper form 
Device Deficiency  
DD associated with an SAE or might have 
led to an SAE 
Start of study 
intervention 
End-of-study 
intervention 
Within 24 hours of 
awareness 
DD paper form 
DD paper form 
DD not associated with an SAE 
Start of study 
intervention 
End-of-study 
intervention 
Within 1 business day of 
awareness 
DD paper form  
DD paper form 
Updated DD Information 
— 
— 
As soon as possible upon 
site awareness 
DD paper form  
DD paper form 
DD (if the investigator becomes aware) 
Participation in 
study has ended 
N/A 
Promptly 
DD paper form 
DD paper form 
Abbreviations: AE = adverse event; eCRF = electronic case report form; ICF = informed consent form; N/A = not applicable; DD = device deficiency; 
SAE = serious adverse event. 
* Serious adverse events are reported regardless of investigator’s opinion of relatedness. 
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2.5.1. Adverse Events  
An AE is any untoward medical occurrence, unintended disease or injury, or untoward clinical 
signs (including abnormal laboratory finding) in study participants, users, or other persons, 
whether or not related to the insulin or study device. 
An adverse device effect (ADE) is defined as an AE related to the use of a medical device. This 
definition includes any AEs resulting from a device deficiency, such as insufficient or inadequate 
IFU, deployment, implantation, installation, or operation; any malfunction of the medical device 
as well as any event resulting from use error or from intentional misuse of the medical device. 
After the informed consent form (ICF) is signed, site personnel will record the occurrence and 
nature of each participant’s pre-existing conditions via the eCRF, including clinically significant 
signs and symptoms of the disease under treatment in the study. 
Pre-existing conditions, anticipated disease progression, planned surgeries, and planned 
interventions will only be recorded as AEs if there is a change in or worsening of medical 
conditions during the course of the study. Any new conditions will be recorded as AEs. 
All AEs shall be reported to the Sponsor as soon as possible upon site awareness via electronic 
case report form (eCRF). For additional details on AEs reporting requirements please refer to 
Appendix 2. 
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to the insulin, study device, or a study procedure, considering the disease, 
concomitant treatment, or pathologies. A “reasonable possibility” means that there is a cause-
and-effect relationship between the drug, device, or study procedure and the AE. The 
investigator answers “yes” or “no” when making this assessment. 
The following shall be recorded/documented for each AE: 
 date of the AE 
 event treatment and resolution 
 event severity (mild, moderate, severe) 
 potential relatedness to drug, device, or study procedures, and 
 determination of SAE. 
Note: Participants will be instructed to report AEs that occur by calling the designated personnel 
at the study site as soon as possible. 
The investigator is responsible for reporting applicable AEs to the ethics committee (EC), as 
required. 
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2.5.2. Serious Adverse Events  
An SAE is defined as any adverse event that led to any of the following:  
a. death,  
b. serious deterioration in the health of the subject, that resulted in any of the following:  
i. life-threatening illness or injury,  
ii. permanent impairment of a body structure or a body function,  
iii. hospitalisation or prolongation of patient hospitalisation,  
iv. medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function,  
v. chronic disease,  
c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect 
 
All SAEs shall be reported to the Sponsor within 24 hours of site awareness via eCRF. 
For additional details on SAEs reporting requirements please refer to Appendix 2. 
2.5.2.1. 
Severe Hypoglycaemia  
Severe hypoglycaemic events (Level 3) must be reported to the Sponsor as an SAE. 
Severe hypoglycaemia is an episode with severe cognitive impairment requiring external 
assistance for recovery. Severe hypoglycaemia requires another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions. During these episodes, the participant has 
an altered mental status and cannot assist in his/her care, is semiconscious or unconscious, or 
experienced coma, with or without seizures. These episodes may be associated with sufficient 
neuroglycopenia to induce seizure or coma. The determination of severe hypoglycaemia is made 
by the investigator, based upon the clinical definition, including requirement for assistance, and 
is not predicated on the report of a participant simply having received assistance. 
2.5.2.2. 
Pregnancy  
Pregnancy during the Study Period does not meet the definition of an AE. However, to fulfil 
regulatory requirements, any pregnancy should be reported following SAE reporting via eCRF 
within 24 hours of learning of the pregnancy. 
2.5.2.2.1. 
Female study participants who become pregnant  
 The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of 
learning of a participant’s pregnancy. 
 The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
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pregnancy will be reported, regardless of gestational age, foetal status (presence or 
absence of anomalies), or indication for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
 A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring 
at ≥20 weeks gestational age) is always considered to be an SAE and will be reported as 
such. 
 Any poststudy pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the Sponsor as described in protocol 
Section 2.5.2. While the investigator is not obligated to actively seek this information in 
former study participants, he/she may learn of an SAE through spontaneous reporting. 
 Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. If the participant is 
discontinued from the study, follow the standard discontinuation process and continue 
directly to the study follow-up phase. The follow-up on the pregnancy outcome should 
continue independent of intervention or study discontinuation. 
2.5.2.2.2. 
Partners of male study participants who become pregnant  
 The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention.  
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of gestational 
age, foetal status (presence or absence of anomalies) or indication for the procedure. 
2.5.3. Device Deficiency  
A device deficiency is any inadequacy in the identity, quality, durability, reliability, safety or 
performance of an investigational device, including malfunction, use errors or inadequacy in 
information supplied by the manufacturer.  
When the ability to use the study intervention safely is impacted, the following are also DDs: 
 Deficiencies in labelling information, and 
 Use errors for device due to ergonomic design elements of the product. 
 
Device deficiencies related to study interventions used in clinical trials are collected to ensure the 
safety of participants, monitor quality, and to facilitate process and product improvements. 
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Investigators will instruct participants to contact the site as soon as possible if he/she has a DD or 
problem with the study intervention, so that the situation can be assessed. 
An event may meet the definition of both a DD and an AE/SAE. In such cases, it should be 
reported as both a DD and as an AE/SAE. 
The following shall be recorded/documented for each DD: 
 date of complaint 
 description of the complaint, and 
 any associated AE(s), if applicable. 
 
A DD may occur independently from an AE or along with an AE. 
Device deficiencies shall be reported to the Sponsor or device manufacturer in accordance with 
provided site instructions. 
Device deficiencies associated with the commercially available Dexcom G6 CGM shall be 
reported to the manufacturer as per product label by the investigator. 
Troubleshooting of technology or connectivity may be performed prior to determination of a DD. 
Additional issue resolution instruction and complaint identification guidelines can be found in 
the Sponsor-provided training materials. 
Note: Participants will be instructed to report DDs that occur during the study by calling the 
designated personnel at the study site as soon as possible. The site personnel must comply with 
the reporting obligations in this section. 
For additional details on DDs please refer to Appendix 2. 
2.6. Unanticipated Adverse Device Effects  
A unanticipated adverse device effect (UADE) is a serious adverse effect on health or safety or 
any life-threatening problem or death caused by or associated with a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of the participant. 
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3. 
Objectives and Endpoints  
Table 3.1 outlines the objectives and endpoints for the study. 
Table 3.1. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary: 
To compare the number of MBDs during the Study 
Period 2 (Weeks 15 to 18), compared to the Study 
Period 1 (Weeks 5 and 6) in participants using the 
 
Tempo Pen 
 
Tempo Smart Button 
 
Glooko RMA, and 
 
Dexcom G6 CGM. 
Primary: 
Difference in the average number of MBDs per week in 
the masked versus unmasked portions of the study. 
Missed bolus dose is defined as no insulin dose from 
1 hour prior to through 1 hour after the start of a 
glucose excursion (meal), where a glucose excursion 
was defined as a >70 mg/dL (>3.9 mmol/L) rise within 
2 hours, not preceded by a value <70 mg/dL 
(<3.9 mmol/L). 
Secondary: 
1) To evaluate difference in participant CGM TIR 
(≥70 to 180 mg/dL) in the Study Period 1 versus 
Study Period 2. 
2) To evaluate difference in participant CGM TAR 
(>180 mg/dL and >250 mg/dL) in the Study 
Period 1 versus Study Period 2. 
3) To evaluate difference in participant CGM TBR 
(54 mg/dL ≤ TBR < 70 mg/dL and < 54 mg/dL) 
in the Study Period 1 versus Study Period 2. 
4) To evaluate Coefficient of Variation and mean 
sensor glucose from of CGM values 
5) To examine occurrence and change of mistimed 
boluses between Study Period 1 versus Study 
Period 2. 
6) To evaluate the change in total insulin doses 
(basal, mealtime per meal type, correction bolus) 
between Study Period 1 versus Study Period 2. 
7) To evaluate occurrence, change, and Study Period 
1 versus Study Period 2 change in correction 
boluses 
8) To examine the association between MBD and 
TIR, TAR, TBR, HbA1c 
9) To examine the association between mistimed 
bolus and TIR, TAR, TBR, HbA1c 
10) To assess device preference, satisfaction, 
convenience and ease of use. 
Secondary: 
1) CGM TIR (≥70 to 180 mg/dL) in the masked versus 
unmasked portions of the study. 
2) CGM TAR (>180 mg/dL and >250 mg/dL) in the 
masked versus unmasked portions of the study. 
3) CGM TBR (54 mg/dL ≤ TBR < 70 mg/dL and 
< 54 mg/dL) in the masked versus unmasked 
portions of the study. 
4) Coefficient of variation and mean sensor glucose 
from CGM data collected from each participant 
5) Occurrence and change of mistimed boluses 
6) Total insulin dose per day, basal dose and insulin 
dose per type of meal (B, L, snacks, D) as well as 
corrections doses. 
7) Occurrence, change, and masked versus unmasked 
change in correction boluses 
8) CGM curves integrated with data received from the 
Tempo Pen 
9) CGM curves integrated with data received from the 
Tempo Pen 
10) Participant and HCP questionnaires 
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Exploratory: 
1) To evaluate change in HbA1c from baseline to 
Visit 7 
2) To evaluate change in HCP views on a connected 
diabetes management platform 
3) To evaluate change in participant views on a 
connected diabetes management platform 
4) To carry out analysis for calculation of MBDs 
5) To determine participant interaction with the 
mobile app and its correlation with MBD change 
between Study Period 1 versus Study Period 2 
6) To determine participant CGM wear time and 
correlation with MBD change between Study 
Period 1 versus Study Period 2 
7) To evaluate participant’s fear of hypoglycaemia 
and its correlation with MBD 
8)  To evaluate day and night time CGM profiles 
during the two periods. 
Exploratory: 
1) Summary statistics of actual and change in HbA1c 
between baseline and Visit 7 
2) Outcome of IORW HCP questionnaires 
3) Outcome of IORW participant questionnaires 
4) CGM curves integrated with data received from the 
Tempo Pen/Smart Button 
5) Glooko Mobile App data (e.g., number of 
connections to the app, number of uploads from 
CGM, number of 
 data uploads, % of CGM 
data available, number of insulin data available) 
and comparison of Study Period 1 and Study 
Period 2 app use 
6) Summary of CGM wear time data and correlation 
with MBD data and differences between Study 
Period 1 versus Study Period 2 
7) HFS-SF questionnaire score between Visit 1 and 
Visit 7 and MBD data. 
8)  Summarize nighttime (00:00 AM to 06:00 AM) 
and daytime CGM profiles during the masked/ 
unmasked periods. 
Abbreviations: B = breakfast; CGM = continuous glucose monitoring; D = dinner; HbA1c = glycated 
haemoglobin; HCP = healthcare professional; IORW = Study F3Z-MC-IORW; L = lunch; MBD = missed 
bolus dose; MDSW = medical device software; TAR = time above range; TBR = time below range; 
TIR = time-in-range. 
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4. 
Study Design  
4.1. Overall Design  
Study IORW is a multicentre, open-label, controlled, single-arm, pragmatic outpatient study in 
participants with T1D or T2D that comprises 2 study periods, including: 
 a 6-week run-in period (Study Period 1) when insulin timing and dosage data 
 is masked to the participant 
using Glooko RMA and is unmasked to the HCP using Glooko HCP platform, and 
 a 12-week intervention period (Study Period 2) when insulin timing and dosage data 
 is unmasked to the participant 
using Glooko RMA and the HCP using Glooko HCP platform. 
Study IORW will be carried out in France and will include 9 clinical study sites. The study is 
expected to last approximately 16 months, with each participant duration of approximately 18 
weeks. Approximately 50 participants will be enrolled in the study. Best efforts will be made to 
enrol a participant ratio of 4:1 for participants with T1D to participants with T2D. 
4.1.1. Study Period 1 (Run-in) – Weeks 1 to 6 (Baseline)  
Following screening, the participants who meet study criteria will: 
 receive Sponsor-provided Humalog Tempo Pen and Tempo Smart Button, Dexcom G6 
CGM, study-specific Android smartphone, and 
 be instructed on how to use the study platform and will receive guidance from the study 
team on the use of the real time CGM data on the receiver to help them manage diabetes 
and insulin dosing. They will be trained on how to upload their CGM data on the Glooko 
RMA. 
During that Study Period, mealtime insulin timing and dosage data 
 
 will not be visible (masked) to the participant using Glooko RMA. 
Mealtime insulin details 
 will be visible (unmasked) to 
the HCP using HCP platform. They will also be allowed to track the basal insulin time and 
dosing and other data (e.g., meals, exercise) manually in the RMA. Baseline (Visit 1 and Visit 3) 
study questionnaires will also be completed (Table 1.1). 
Participants will be asked to follow their pre-study insulin regimen (as prescribed by the 
investigators), lifestyle and behaviour. The study participant and HCP will not communicate, 
outside of the scheduled visit and activities described in Table 1.1, except in cases of acute 
complication, AE and DD reporting, or need for technical support. 
Following Study Period 1 (during Visit 3), mealtime insulin timing and dosage data 
 will be unmasked to the study 
participant by HCP. The study participant and HCP will then review and discuss together the 
data collected during Study Period 1, including the potential reasons for suboptimal glucose 
control. The HCP will be able to propose any educational activities to be taken during Study 
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Period 2 that would result from the review of the Glooko report, including insulin dose 
adjustments and other advices deemed appropriate (e.g., missing bolus doses, late injection 
timing, carb counting). 
4.1.2. Study Period 2 (Intervention) – Weeks 7 to 18  
Following Study Period 1, the participants will enter the 12-week Study Period 2 during which 
insulin timing and dosage data 
 will be 
visible (unmasked) to the participant and the HCP in Glooko RMA and HCP platform. 
Throughout the entire Study Period 2, data from Humalog Tempo Pen/Smart Button 
 will be 
transferred to the Glooko RMA. Participants should continue to periodically upload Dexcom G6 
CGM during Study Period 2. 
Healthcare professionals can monitor participant adherence through the HCP Portal. The 
participant list displays the date of last sync for each to determine the last Tempo Pen/Tempo 
Smart Button connection. If necessary, the study site will follow-up with participants to ensure 
adequate duration of CGM wear and timely Tempo Pen/ Smart Button study data transfer to 
Glooko RMA. It is recommended that the site does not interact with the participant with respect 
to their Glooko RMA data during the masked Study Period 1 unless required for participant 
safety. 
See Figure 1.1 for an overview of the study design and Section 6 for more information about the 
study interventions. 
4.1.3. Safety Follow-up  
Following completion of Study Period 2, study participants will complete their safety follow-up 
period (Table 1.1). 
4.2. Visit Overview  
For a quick reference to activities required at each visit, please refer to the SoA (Table 1.1). 
4.2.1. Administration of HCP Questionnaires  
The IORW Initial HCP Questionnaire will be completed by the physician and study 
coordinator/ nurse prior to FPV at the site. 
The IORW End-of-study HCP Questionnaire will be completed by the physician and study 
coordinator/nurse after all participants at the site complete Visit 8 (V8). 
4.2.2. Visit 1 – Participant Screening and Enrolment  
Study participants must give written consent (signed and dated) using the ICF approved by the 
Sponsor (or its designee) and the governing EC. 
This consent is required before any screening assessments are performed and before being 
allowed to participate in the study. 
After an ICF is obtained, participants will commence to study screening. 
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4.2.2.1. 
Screening  
Study Investigator(s), or qualified designees, will review the participant’s medical records and/or 
history and perform assessments to determine if the participant meets all inclusion and no 
exclusion criteria to qualify for participation in the study (see Section 5). This includes: 
 point-of-care HbA1c measurement, and 
 point-of-care urine pregnancy test in women of childbearing age. 
 
Individuals who do not meet the criteria for participation in this study must be screen failed at 
Visit 1 and may be rescreened (see Section 5.4). 
4.2.2.2. 
Enrolment  
If the participant meets all inclusion criteria and no exclusion criteria, they will be enrolled into 
the study. Study Investigator(s), or qualified designees, will review the participant’s medical 
records and/or history and perform the required study assessments. This includes: 
 medical history (including duration of disease) 
 current medications 
 demographics (excluding ethnicity information) 
 physical examination 
 vital signs (blood pressure, heart rate, respiration rate, temperature) 
 HbA1c 
 height, and 
 weight. 
 
The nature of any conditions that are present at the time of the physical examination and any pre-
existing conditions will be documented. 
For a complete list of all required assessments, please refer to the SoA (Table 1.1). 
Participants previously on non-Humalog insulin will be transitioned to Sponsor-provided 
Humalog Tempo Pen(s) at doses similar to their current regimen and in accordance with product 
labelling. All participants including those who were not previously using the Dexcom G6 system 
will be provided with a study CGM. 
This study is not designed as a titration study, but insulin doses may be adjusted to avoid 
hypoglycaemia or unacceptable hyperglycaemia in the opinion of the HCP. 
The site will complete the following activities at Visit 1: 
 administer the IORW Participant Visit 1 Questionnaire and HFS-SF questionnaire 
before the Tempo Pen/Smart Button and Glooko RMA is demonstrated 
 dispense Humalog Tempo Pen(s) 
 dispense Tempo Smart Button(s), and 
 provide study CGM and study phone to participants. 
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The site will guide the participants and document Tempo Pen/Smart Button, Dexcom G6 CGM, 
and Glooko RMA initialisation activities, including review of the Participant Instructions handout 
with participants, RMA set-up, correct provision of all required participant information in the 
RMA. The study site will train the participant in the use of study platform components, review the 
functioning, understanding, and use of the study platform components and answer any questions 
relating to the use of the Tempo Pen/Smart Button, Dexcom G6 CGM, and Glooko RMA prior to 
concluding the visit. Participants will receive guidance from the study team on the use of the real 
time CGM data on the receiver to help them manage their diabetes and insulin dosing.  
Participants will be instructed not to use the Glooko RMA “reminder” feature during study period 
1. 
Site personnel will review hypoglycaemia management and provide appropriate training to 
participants (see Section 2.4.3.1). 
For a complete list of all required activities, please refer to the SoA (Table 1.1). 
4.2.3. Visit 2 – Remote Check-in 1  
Visit 2 will be conducted approximately 1 week after Visit 1. Site will perform a remote check-in 
in which they will review the understanding and use of the study components with participants. 
During the visit, the site staff will: 
 collect DDs 
 collect AEs 
 review concomitant medications/changes in medications 
 review the functioning, understanding, and use of the study platform components, and 
 confirm up-to-date participant CGM and Tempo Pen/Smart Button data was uploaded to 
the RMA 
 
For a complete list of all required activities, please refer to the SoA (Table 1.1). 
4.2.4. Visit 3 – In-Person Check-in 1  
Visit 3 will be conducted approximately 5 weeks after Visit 2. 
At Visit 3, the participant will be required to visit the study site with his/her: 
 mobile device with RMA 
 CGM 
 Dexcom receiver 
 Tempo Pen(s) currently in use, and 
 Tempo Smart Button. 
 
Unused Tempo Pen(s) may remain at the participant’s residence so long as he/she checks how 
much is remaining to aid in resupply calculations. 
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During the visit, the site staff will: 
 collect DDs 
 collect AEs 
 review concomitant medications/changes in medications 
 review study supplies and dispense, as needed 
 review the functioning, understanding, and use of the study platform components 
 confirm up-to-date participant CGM data was uploaded to the RMA 
 administer IORW Participant V3 Questionnaire 
 administer HFS-SF Questionnaire, and 
 weigh the participant. 
 
For a complete list of all required activities, please refer to the SoA (Table 1.1). 
In addition, following completion of the IORW Participant Visit 3 Questionnaire and HFS-
SF Questionnaire, the site staff will unmask the 
 data, review the 
participants’ dosing patterns, and discuss information from the HCP Portal with the participant 
about his/her dosing habits and glucose control collected during Study Period 1. 
To accomplish this: 
 HCPs will be able to display Study Period 1 data on the HCP Portal which will contain 
previously participant-masked information about insulin dosing and glycaemic status 
 the investigator or designee will review Study Period 1 data 
 the investigator or designee will share and discuss the data collected during Study Period 
1 with the study participant 
 dose adjustments and other advices provided by the HCP will be recorded, and 
 any educational activities that would result from the review of the report would be 
documented by the HCP. 
4.2.5. Visit 4 – Remote Check-in 2  
Visit 4 will occur approximately 1 week after Visit 3. At Visit 4, site staff will perform a remote 
check-in during which they will review the understanding and use of the study components with 
participants. 
During the visit, the site staff will: 
 collect DDs 
 collect AEs 
 confirm up-to-date participant CGM and Tempo Pen/Smart Button data was uploaded to 
the RMA 
 review concomitant medications/changes in medications, and 
 review the functioning, understanding, and use of the study platform components. 
 
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For a complete list of all required activities, please refer to the SoA (Table 1.1). 
4.2.6. Visit 5 and 6 – Remote Check-in 3 & 4  
Visit 5 will occur approximately 3 weeks after Visit 4. 
Visit 6 will occur approximately 4 weeks after Visit 5. 
Site staff will perform a remote check-in with the participant during which they will: 
 collect DDs 
 collect AEs 
 review concomitant medications/changes in medications 
 review the functioning, understanding, and use of the study platform components (if 
deemed necessary based on previous visits) 
 confirm up-to-date participant CGM and Tempo Pen/Smart Button data was uploaded to 
the RMA 
 share and discuss glucose control and insulin dosing habits (adjust the dose if 
appropriate) with the participant (from last data review, i.e., approximately 4 weeks)  
 document any educational activities that would result from the review of the report by the 
HCP, and 
 review study supplies status. 
 
For a complete list of all required activities, please refer to the SoA (Table 1.1). 
4.2.7. Visit 7 – In-Person Check-in 2  
Visit 7 will occur approximately 4 weeks after Visit 6. 
At Visit 7, the participant will be required to visit the study site and bring his/her: 
 mobile device with RMA 
 CGM 
 Dexcom receiver 
 Tempo Pen(s) currently in use 
 unused Humalog Tempo Pen(s), and 
 Tempo Smart Button. 
Participants will return all appropriate Sponsor-provided study materials as per Sponsor 
instructions. 
During the visit, the site staff will: 
 collect DDs 
 collect AEs 
 review concomitant medications/changes in medications 
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 confirm up-to-date participant CGM and Tempo Smart Button data was uploaded to the 
RMA and 
 review and discuss glucose control and insulin dosing habits (since last visit, i.e., 
approximately 4 weeks) with the participant, using the HCP Portal information.  
The site will also perform the following assessments: 
 weight, and 
 point-of-care HbA1c measurement. 
 
In addition, following review of the summary on Glooko HCP platform and discussion with the 
participant, the site staff will administer the IORW Participant Visit 7 Questionnaire and 
HFS-SF Questionnaire to the participant. 
After Visit 7 is complete, participants will transition to a non-study insulin regimen and a non-
study CGM device (if applicable). 
For a complete list of all required activities, please refer to the SoA (Table 1.1). 
4.2.8. Visit 8 – Safety Follow-up and Study Exit  
Approximately 3 days after participants have stopped the study intervention (Visit 7), the study 
site will contact the participant via a phone call to: 
 review AEs and DDs, 
 review concomitant medications/changes in medications following the transition to non-
study insulin regimen and a non-study CGM device (if applicable), and 
 note that study participation ends at completion of this phone visit. 
For a complete list of all required activities, please refer to the SoA (Table 1.1). 
4.2.9. Unscheduled Visits  
At any time, the participant may request an unscheduled site visit, either in-person or remotely. 
During an unscheduled visit, the site may triage any issues with the study platform and/or refill 
the participant’s supplies. 
During any unscheduled visit, site staff will: 
 collect DDs 
 collect AEs 
 review concomitant medications/changes in medications 
 review the functioning, understanding, and use of the study platform components (if 
deemed necessary based on previous visits), and 
 review study supplies and dispense as needed. 
For a complete list of all required activities, please refer to the SoA (Table 1.1). 
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4.3. Early Discontinuation Visits  
Participants discontinuing from the study prematurely, for any reason, should return to the study site. 
The participant will be required to bring his/her: 
 mobile device with RMA 
 CGM 
 Dexcom receiver 
 Tempo Pen(s) currently in use 
 unused Tempo Pen(s), and 
 Tempo Smart Button. 
 
Participants will return all appropriate Sponsor-provided study materials as per Sponsor 
instructions. 
During the visit, the site personnel will: 
 collect DDs 
 collect AEs 
 review concomitant medications/changes in medications 
 confirm up-to-date participant CGM and Tempo Smart Button data was uploaded to the 
RMA, and 
 review and discuss glucose control and insulin dosing habits (adjust the dose if 
appropriate) with the participant, using the Glooko HCP Portal information. 
 
The site will also perform the following assessments: 
 weight, and 
 point-of-care HbA1c measurement. 
In addition, following review of Glooko summary report and discussion with the participant , the 
site staff will administer to the participant: 
 
the IORW Participant Visit 3 Questionnaire and HFS-SF Questionnaire if the Early 
Termination visit takes place before Visit 3, 
 
the IORW participant Visit 7 Questionnaire and HFS-SF Questionnaire if if the Early 
Termination visit takes place after Visit 3. 
For a complete list of all required activities, please refer to the SoA (Table 1.1). 
Site personnel should document details regarding the reason for discontinuation, if possible (see 
Section 7). Study participants will transition back to their non-study insulin (if applicable) and 
their non-study CGM devices (if applicable). 
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4.4. Scientific Rationale for Study Design  
4.4.1. Rationale for Investigation of Missed Bolus Dose  
This study objectively estimates: 
 MBDs and their relationship to short-term glycaemic control are clinically relevant, and 
 participant behaviour and satisfaction among participants. 
 
The Tempo Pen/Smart Button allows for objective collection of data that can be assessed as 
missed, mistimed, or suboptimal 
. Prior to a downloadable 
 data, 
other HCPs have collected bolus data for multiple daily injection subjectively from participants’ 
paper or electronic diaries. 
There is no standard-of-care or comparator arm because the primary objective of this study is to 
objectively estimate MBDs from reliable automated collection, which can only happen if the 
participant uses a smart insulin pen recording the injections. Therefore, the last 2 weeks of Study 
Period 1 (Week 5 to Week 6 [Visit 3]) will be used for analyses with masked RMA as baseline 
data. 
The study duration of 18 weeks (6 weeks +12 weeks) is long enough for the assessment of 
MBDs in a study setting. Each enrolled participant must be on a mealtime bolus insulin regimen 
with at least 3 or more bolus doses daily (Section 5.1). 
4.4.2. Rationale for Single-Arm Study  
A single-arm clinical study that is statistically powered to detect a difference (see Section 9) 
would provide reliable evidence to study hypothesis where participants can be their own control. 
This would allow to see the benefit of unmasking the RMA and connected pen while adjusting 
for participants’ dosing behaviour at baseline. 
The masked period will run for a duration of 6 weeks to allow participants 4 weeks to adjust 
from another rapid acting insulin analogue to Humalog, to start using Glooko RMA and Dexcom 
G6 CGM (if not already using it) and provide sufficient and reliable data for their baseline (last 2 
weeks of Study Period 1). 
The unmasked period will run for a duration of 12 weeks to allow the participant to use the data 
 on the RMA and use this information 
during the HCP interaction. 
4.4.3. Rationale for Inclusion of Predominately Participants with Type 
1 Diabetes  
Adult populations with T1D and T2D on basal bolus were chosen to participate as both can be 
treated with prandial insulin and use a connected pen with an RMA. 
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The IORW study plans to recruit predominantly participants with T1D on basal bolus who have 
uncontrolled diabetes (defined as HbA1c ≥8%) because most of them are already on CGM and 
being a younger population, they are accustomed to the use of various medical application for the 
daily management of their diabetes. 
Furthermore, there are limited data regarding MBDs in patients with T2D on basal bolus. 
Therefore, we based our power calculation on data available for patients with T1D and plan to: 
 gather data for a limited number of participants with T2D, and 
 focus this study predominantly on those with T1D. 
4.5. End-of-Study Definition  
End-of-study is the date of the last visit (Visit 8) shown in the SoA (Table 1.1) for the last study 
participant. 
No intervention is allowed following the end of the trial. 
4.6. Travel Restriction Flexibilities  
Appendix 4 describes alternative approaches to study activities, should the site or participants 
encounter national-, local-, or business-imposed travel restrictions, where travel to sites or in-
person interactions would be ill-advised or restricted. 
It is the responsibility of the Investigator to assess this situation at the site and provide real time 
feedback to Sponsor or Sponsor representative if: 
 there is the potential to impact clinical research operations, or 
 conditions at the site have the potential to impact the ability to monitor either the safety 
of participants or the scientific integrity of study. 
 
This includes reporting any disruptions that arise: 
 directly if the site is impacted by COVID-19, or 
 indirectly as the result of disruptions in travel networks, quarantines, or other social 
distancing mandates. 
 
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5. 
Study Population  
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
5.1. Inclusion Criteria  
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
Participants are eligible to be included in the study only if they meet all of the following criteria 
at enrolment: 
[1] Have been diagnosed (clinically) with T1D for at least 1 year or are patients with 
T2D on basal bolus insulin therapy for at least 6 months 
 
[2] Capable of giving signed informed consent, including compliance with the 
requirements and restrictions listed in the ICF and in this protocol 
 
[3] Men or women of age ≥18 years 
 
[4] HbA1c ≥8% as confirmed by point-of-care test at screening 
 
[5] 
Are currently using CGM and agree to use the Dexcom G6 and Glooko RMA 
during the study. 
 
[6] 
Are currently using Humalog ® insulin or another rapid acting insulin analogue 
(e.g., Apidra®, or Novorapid®) and agree to switch to study-provided Humalog 
mealtime insulin for duration of trial 
 
[7] Have been prescribed ≥3 doses of bolus insulin per day 
 
[8] Must be taking a stable insulin dose regimen (per investigator’s judgement) for at 
least 3 months preceding study screening 
 
[9] 
Have sufficient ability, in the opinion of the investigator, to communicate in the 
French language to perform study activities and comply with study requirements 
 
[10] Have no physical or cognitive disabilities that would, in the opinion of the 
investigator, preclude participant from using Glooko RMA for study activities and 
comply with study requirements 
 
[11] Have in-home refrigeration for storage of insulin 
 
[12] Female participants of childbearing potential: 
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i. cannot be breastfeeding, pregnant or intend to become pregnant during 
the trial period 
 
  
ii. must: 
 remain abstinent, or 
 use 1 highly effective method (<1% failure rate) of contraception 
or a combination of 2 effective methods of contraception, 
consistent with local regulations, for the entirety of the study (see 
Appendix 3), and 
 
 iii. test negative for pregnancy based on a urine pregnancy test at Visit 1. 
Additional local urine pregnancy tests may be conducted for duration of 
trial at discretion of investigator. 
5.2. Exclusion Criteria  
Participants will be excluded from study enrolment if they meet any of the following criteria: 
[13]  Previously used the Glooko RMA and/or Dexcom G6 CGM and were judged by the 
investigator to be non-adherent 
 
[14] Are currently enrolled in any other clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or medically 
compatible with this study 
 
[15] Have participated, within the last 30 days, in a clinical study involving an 
investigational product. If the previous investigational product has a long half-life, 
5 half-lives or 30 days (whichever is longer) should have passed 
 
[16] Have previously used or have been using an approved or investigational connected 
pen platform within the 3 months prior to screening 
 
[17] Are currently pregnant or plan to become pregnant during the next 4-6 months 
 
[18] Are on ultra-rapid insulin (e.g., Fiasp or Lyumjev) or rapid acting human insulin 
(i.e., Humulin) for previous 3 months, at the time of screening 
 
[19] Have any hypersensitivity or allergy to any of the insulins or excipients used in this 
trial 
 
[20] Use of corticosteroid therapy for more than 10 days within the 3 past months, or 
patient who ought to be treated by corticosteroid during the Study Period 
 
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[21] Are currently undergoing dialysis treatment or have any other medical condition 
which may preclude them from participating in this trial as per the investigator’s 
judgement 
 
[22] Have vision loss or vision impairment that does not allow recognition of Glooko 
RMA screen features 
 
[23] Have impaired dexterity which limits ability to use the RMA 
 
[24] Have previously completed or withdrawn from this study 
 
[25] Are investigator site personnel directly affiliated with this study and/or their 
immediate families. Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted 
 
[26] Are Lilly employees or are employees of any third party involved in the study who 
require exclusion of their employees 
 
5.3. Lifestyle Restrictions  
Participants must have a stable lifestyle with no changes to dietary or exercise habits during the 
course of the study, with the exception of those advised by the investigator as part of the Study 
Period 2. 
5.4. Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently enrolled in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes: 
 demography (excluding ethnicity) 
 screen failure details 
 eligibility criteria, and 
 any SAEs. 
 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened no earlier than after 1 month from the initial screen if study enrolment is still ongoing. 
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6. 
Study Intervention and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol. 
6.1. Study Intervention(s) Administered  
This study involves a treatment of study participants with marketed insulin lispro (Humalog 
100 units/mL), at doses as prescribed by HCP, administered via the Humalog Tempo Pen 
(provided by the Sponsor). 
The Tempo Smart Button, (provided by the Sponsor) will be used to detect, store, and transfer 
insulin dose-related data from a Tempo Pen to Glooko RMA. 
The Tempo Smart Button is hand-held and surface-contacting with intact skin only (Table 6.1). 
No participant contact components are in contact with the drug product. The user prepares the 
Smart Button for use by attaching it to the dose knob of a Tempo Pen prefilled insulin pen. With 
the Smart Button attached, the user administers a dose from the Tempo Pen. The doses will be 
administered according to the participant’s usual practices. 
Table 6.1 shows the study platform components that will contact the participants body, either on 
the surface or subcutaneously. 
Table 6.1. 
Study Platform Components that Contact the Body  
Study Platform Component  
Contact Area of Human Body  
Tempo Smart Button 
Hand 
Dexcom G6 Sensor 
Subcutaneously at:  
 
back of upper arm, or  
 
belly 
Dexcom G6 Transmitter  
Back of upper arm or belly 
Dexcom G6 Applicator 
Back of upper arm or belly 
Dexcom Receiver  
Hand 
Tempo Pen  
Subcutaneously at:  
 
stomach area,  
 
buttocks,  
 
upper legs, or 
 
upper arms. 
 
 
HCP prescribed insulin dosage modifications should not occur during Study Period 1, apart from 
acute complication or to prevent severe hypoglycaemia or hyperglycaemia, occurring during that 
Study Period. During Study Period 2, insulin adjustments are allowed based on the investigator’s 
medical judgement using the available glucose and insulin data. 
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All study participants including those who were not previously using the Dexcom G6 system will 
be provided with a study CGM and will agree to start using the Dexcom G6 if they were on a 
different CGM pre-study. All Dexcom G6 users will need to have their receiver within a 6-metre 
range of the transmitter to collect study data. 
Data from Humalog Tempo Pen/Smart Button and Dexcom G6 will be uploaded to the Glooko 
RMA/receiver throughout the study. 
The study platform set-up and appropriate training will be provided to all study participants by 
study site personnel at Visit 1. Appropriate instructions for use will also be provided to 
participants as part of the participant’s study information package. 
Study participants will continue their pre-study concomitant anti-hyperglycaemic medication and 
basal insulin therapies (Table 6.3).  
Table 6.2 shows the treatment regimens for each Study Period. 
Table 6.2. 
Treatment Regimens for Each Study Period  
Study Period 1 
Study Period 2 
Humalog (doses as prescribed by HCP) administered 
via Tempo Pen 
Humalog (doses as prescribed by HCP) administered 
via Tempo Pen 
Tempo Smart Button 
Tempo Smart Button 
Dexcom G6 CGM 
Dexcom G6 CGM 
Glooko RMA and Glooko HCP platform (
 
 data masked on RMA and unmasked 
on HCP platform) 
Glooko RMA and Glooko HCP platform (
 
 data unmasked) 
Abbreviations: HCP = healthcare professional; CGM = continuous glucose monitor; RMA = research mobile 
application. 
 
All devices used in this study (Tempo Smart Button, Dexcom G6, Glooko MDSW) will be used 
within their intended use and indications for use. All medicinal products used in this (Humalog 
Tempo Pen) are European Medicine- (EMA-) approved and will be used within their marketed 
intended use and indications for use. 
Detailed description of technical and functional features of the study platform components are 
outlined in Section 2.3. 
6.2. Preparation, Handling, Storage, Labelling and Accountability  
 Study platform components will be labelled according to applicable regulatory 
requirements. 
 The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
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 Only participants enrolled in the study may receive study intervention and only 
authorised site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorised study personnel. 
 The insulins must be stored at the study site under refrigerated conditions (between 2°C 
and 8°C) in a locked and secure place. Insulin must not be frozen. 
Detailed information on storage requirements for the study products is provided in Tempo Smart 
Button IFU and Humalog Package Insert. 
The investigator or authorised study personnel are responsible for product accountability, 
reconciliation, and record maintenance of study products (that is, receipt, reconciliation, and final 
disposition records). Traceability for all dispensed study products will be documented throughout 
the course of the trial in the eCRF utilising lot and/or serial numbers and detailed information 
about this process will be available as part of site’s training materials. 
6.3. Measures to Minimise Bias  
This is an open-label, single-arm, pragmatic study in which all study participants will be 
receiving insulin lispro 100 units/mL (Humalog) via Tempo Pen. Study participants and study 
personnel will not be blinded to insulin treatment or study devices. Study participants who meet 
all inclusion/ exclusion criteria (Sections 5.1 and 5.2) will be enrolled into the study at Visit 1 
(Week 0). 
To minimise the bias, study participants will be used as their own control by designing the study 
to include two study periods: Study Period 1 (run-in) and Study Period 2 (intervention). During 
Study Period 1, 
 dosing and timing data in Glooko RMA will be masked to study 
participants and no dosage modifications will occur during Study Period 1, apart from acute 
complication occurring during that Study Period. Study participants will only be unmasked to the 
 dosing and timing data in Glooko RMA during Study Period 2. Study personnel will 
be unmasked during both Study Period 1 and Study Period 2. 
Study questionnaires will also be administered at multiple time points (Visit 1, Visit 3, and 
Visit 7) to provide baseline and endpoint data. 
Additionally, the study will be conducted with participants in an outpatient setting with study 
interventions representative of standard clinical practices, to minimise bias associated with 
participation in a clinical trial. 
6.4. Continued Access to Study Intervention After the End of the 
Study  
No intervention is allowed following the end of the trial. Participants will be allowed to continue 
with commercially available insulin products and devices if they wish. 
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6.5. Treatment of Overdose  
Excess insulin administration may cause hypoglycaemia and hypokalaemia. Mild episodes of 
hypoglycaemia usually can be treated with oral glucose. Adjustments in drug dosage, meal 
patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic 
impairment may be treated with intramuscular/subcutaneous or nasal glucagon or concentrated 
intravenous glucose. Sustained carbohydrate intake and observation may be necessary because 
hypoglycaemia may recur after apparent clinical recovery. Hypokalaemia must be corrected 
appropriately.  
In the event of an overdose, the investigator should: 
 Refer to Humalog Tempo Pen Package Insert 
 Contact the medical monitor immediately 
 Evaluate the participant to determine, in consultation with the medical monitor, whether 
study intervention should be interrupted or whether the dose should be reduced, and 
 Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
hypoglycaemia is corrected.  
6.6.  Concomitant Therapy  
Table 6.3 summarises the medications that would and would not exclude participants from the study. 
Table 6.3. 
Summary of Concomitant Therapies that Are Permitted and Not 
Permitted during the Study  
Medications 
T1D participants 
T2D participants 
Insulin degludec (U-100 or U-200), insulin detemir (U-100), 
insulin NPH, insulin glargine (U-100 and U-300) 
Allowed 
Allowed 
Insulin glulisine, insulin aspart, or human R insulin 
Not alloweda 
Not alloweda 
Insulin lispro in any device other than study-provided pens 
Not alloweda 
Not alloweda 
Pre-mixed insulin 
Not allowed 
Not allowed 
Sulfonylureas, meglitinides, alpha-glucosidase inhibitors 
Not allowed 
Allowed as prescribed 
by the physician 
Metformin, DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 RA 
(oral or injectable),  
Not allowed 
Allowed 
Corticosteroids 
Not allowedb 
Not allowedb 
Abbreviations: DPP = Dipeptidyl peptidase; GLP-1 RA = Glucagon-Like Peptide-1 Receptor agonist; NPH = 
Neutral Protamine Hagedorn; SGLT2 = Sodium-glucose co-transporter-2 
a Not allowed unless due to emergency circumstances or factors that requires non-study insulin use and duration 
must not exceed ≥8 days. 
b  Not allowed unless due to emergency circumstances or factors that require corticosteroids use and duration must 
not exceed ≥8 days. 
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Participants are allowed to use oral diabetes medications that are being used on-label. Any 
changes to non-insulin diabetes medication use during the study should not take place unless 
medically indicated (e.g., hypoglycaemic event); any such changes must be recorded. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 
7.1. Discontinuation of the Study Intervention  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will not remain in 
the study to be evaluated. Participants should report AEs and DDs and complete other safety 
follow-up at exit visit, in accordance with this protocol. Safety follow-up should be performed as 
outlined in Section 1.3 (SoA), and Section 2.5 (AEs and SAEs of the protocol). 
The Sponsor shall be notified of any instance of participant withdrawal or discontinuation. Any 
data collected up to the point of withdrawal or discontinuation may be used in the study. 
See the SoA (Table 1.1) for data to be collected at the time of discontinuation of study 
intervention and for any further evaluations that need to be completed. 
There will not be any research-related follow-up visit once their participation in the trial has 
ended, as the study participants will be routinely monitored as part of their diabetes management. 
In the event of discontinuation or early termination, participants will be contacted 3 days after 
they have stopped the study intervention for a remote follow-up.  
7.2. Participant Discontinuation/Withdrawal from the Study  
7.2.1. Participant Withdrawal  
A participant may withdraw from the study: 
 at any time at his/her own request 
 at the request of his/her designee (for example, parents or legal guardian) 
 at the discretion of the investigator for safety, behavioural, compliance, or administrative 
reasons 
 if enrolment in any other clinical study involving an investigational product or enrolment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study 
 if the participant needs to be stopped for medical, safety, regulatory, or other reasons 
consistent with applicable laws and regulations, or 
 if the participant, for any reason, requires treatment with another therapeutic agent that 
has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent. 
7.2.2. Participant Discontinuation  
Discontinuation is expected to be uncommon. 
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At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See the SoA (Table 1.1) for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be completed. 
The participant will be permanently discontinued from both the study intervention and the study 
at that time. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
Participants will be discontinued in the following circumstances: 
 
enrolment in any other clinical study involving an investigational product or enrolment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study 
 participation in the study needs to be stopped for identified medical, safety, regulatory, or 
other reasons consistent with applicable laws and regulations 
 a participant becomes pregnant during the course of the study 
 the investigator decides that the participant should be discontinued from the study 
 a participant did not meet the enrolment criteria and was inadvertently enrolled, and 
 the participant, the participant’s designee, for example, parents or legal guardian requests 
to be withdrawn from the study. 
 
If the Sponsor or investigator identifies a participant who did not meet enrolment criteria and 
was inadvertently enrolled, then the participant should be discontinued from study treatment, 
unless there are extenuating circumstances that make it medically necessary for the participant to 
continue on study treatment. 
If the Sponsor and the investigator agree that it is medically appropriate to continue, the 
investigator must obtain documented approval from the Sponsor to allow the inadvertently 
enrolled participant to continue in the study with or without treatment with study product. 
7.2.3. Lost to Follow-Up  
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
Site personnel are expected to make diligent attempts to contact participants who fail to return 
for a scheduled visit or were otherwise unable to be followed up by the site. 
 
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8. 
Study Assessments and Procedures  
Study procedures and their timing are summarised in the SoA (Table 1.1). 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants meet 
all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Table 1.1 lists the SoA, with the study procedures and their timing (including tolerance limits for 
timing). 
8.1. Effectiveness Assessments  
8.1.1. Primary Assessments  
The primary assessment compares the number of MBDs per week in Study Period 1 and Study 
Period 2 in participants with T1D or T2D using CGM measurements and 
 
 data. Missed bolus doses will be determined by the glucose excursion as measured by the 
CGM. 
Missed bolus dose (Figure 8.1) is defined as no insulin dose from 1 hour prior to through 1 hour 
after the start of a glucose excursion (meal), where a glucose excursion was defined as a 
>70 mg/dL (>3.9 mmol/L) rise within 2 hours, not preceded by a value <70 mg/dL 
(<3.9 mmol/L) (Edwards et al. 2021). 
 
Figure 8.1. 
Illustration of missed bolus dose and mistimed bolus.  
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Using Figure 8.1 as an example, in this study: 
 if a dose between 10 and 11 am would be classified as the correct or optimum time to 
administer the insulin dose, no insulin dose between 10 am and 12 pm would be a MBD; and 
 if a dose between 5 and 6 pm would be classified as the correct or optimum time to 
administer the insulin dose before the meal, an insulin dose between 6 and 7 pm is 
defined as a mistimed bolus dose. 
Sy et al. (2022) provides a graphical representation of several days of CGM data with various 
meal bolus situations.  
8.1.2. Secondary Assessments  
Study IORW will have secondary measures as described in Table 3.1. 
The study will evaluate the change in percentage TIR, TAR, TBR, mean sensor glucose 
coefficient of variation between Study Period 1 and Study Period 2 in participants with T1D or 
T2D using CGM and 
 data. The glucose TIR for this analysis is ≥70 and ≤180 mg/dL. 
In addition, the occurrence and change in mistimed bolus will be evaluated (Figure 8.1). 
A mistimed bolus dose is defined as a bolus dose administered from the start of a glucose excursion 
(meal) up to 1 hour after the start of glucose excursion and before the peak of glucose excursion. 
Change in correction boluses from masked to unmasked period will also be evaluated. Correction 
bolus is defined as taking a bolus dose given after the peak of a glucose excursion but within 
4 hours from the start of a glucose excursion and prior to start of next glucose excursion. 
8.1.3. Exploratory Assessments  
Study IORW will also have exploratory assessments: 
 Sensitivity analysis for calculation of MBDs, using CGM curves integrated with the data 
received from the Tempo Pen/Smart Button. 
 Participant interaction with the RMA based on app usage data (e.g., number of connections 
to the app, number of 
 data uploads, percentage of CGM data available, percentage 
of 
 data available) and comparison of usage in Study Period 1 and Study Period 2. 
 Change in HbA1c from baseline to Visit 7. 
 Understanding changes in participant views on a connected diabetes management 
platform. 
 Understanding changes in HCP views on a connected diabetes management platform. 
 Understanding the participant’s fear of hypoglycaemia and correlate it with MBD. 
 Understanding and summarizing the participant’s day and night time CGM profiles 
during the two periods. 
8.2. Safety Assessments  
Not applicable as no clinical laboratory test are planned for this study. However, if any 
laboratory tests need to be performed during routine care for participant safety evaluations, it 
will be the responsibility of the HCP. 
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9. 
Statistical Considerations  
9.1. Statistical Hypotheses  
The primary objective of this single-arm study is to compare the number of MBDs during the 
masked and unmasked app periods in participants with T1D and T2D via the Tempo Pen with 
Tempo Smart Button and on CGM. 
The primary analyses will be conducted at the end of the clinical study on data collected from all 
participants as described in the Sections 9.2 and 9.3. 
9.2. Analyses Sets  
Safety analyses will be carried out on the Safety Population, which consists of all participants 
with at least 1 measurement in the masked app period and/or unmasked app period. 
Efficacy analyses will be carried out on the main analysis set. To allow for this clinical trial to be 
generalisable to the wider population and to prevent the chance of analysing a biased set of “only 
adherent” participants, efficacy analyses will be repeated on the sensitivity analysis set. 
9.2.1. Main Analysis Set  
The initial 4 weeks will allow a wider population of participants (Humalog and non-Humalog 
users as well as those using and not using Dexcom G6 CGM prior to study entry) to reach a 
routine before baseline data assessment (such as MBD, TIR, TAR, etc.) is carried out. 
Unless stated otherwise, data collected from the last 2 weeks (Weeks 5 and 6) of the masked app 
(baseline) period and the last 4 weeks (Weeks 15 to 18) of the unmasked app period will be used 
to answer the primary and secondary objectives. In other words, 2 weeks prior to Visit 3 (face-to-
face) and 4 weeks prior to Visit 7 (face-to-face). 
Following the guidelines of the Advanced Technologies and Treatments for Diabetes (ATTD) 
consensus on CGM use, only participants with at least 10 days’ worth of CGM data out of the 
last 14 days (Weeks 5 and 6) in the masked app period will be considered as evaluable 
participants (Danne et al. 2017; Battelino et al. 2023). 
Among these participants (as described above), only the participants that satisfy the below 
criteria for the unmasked app period will be considered as evaluable participants: 
 with at least 20 of 28 days’ worth of CGM data (Weeks 15 to 18), or 
 discontinuing early that have at least 20 days’ worth of CGM data in the whole unmasked 
app period (Weeks 7 to 18). 
9.2.2. Sensitivity Analysis Set  
The sensitivity analysis set includes all participants in the main analysis set, plus participants 
with at least 10 days’ worth of CGM data in the whole masked app period (Weeks 1 to 6), and all 
participants with at least 20 days’ worth of CGM data in the whole unmasked app period (Weeks 
7 to 18). 
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9.3. Statistical Analyses  
Statistical analysis of this study will be the responsibility of Lilly or its designee. Efficacy 
analyses will be conducted on the main and sensitivity analysis sets and safety analyses on the 
safety analysis set, unless stated otherwise.  
The analyses for the primary endpoint and majority of the secondary endpoints (TIR, TAR, TBR, 
mistimed bolus, correction bolus) will be conducted using a mixed-effect models for repeated 
measures which will: 
allow the model to adjust for key baseline characteristics (baseline HbA1c and body mass index) 
if appropriate, and 
compare the masked app period against the unmasked app period. 
 
Spearman rank-order correlation will be used to test the association between MBD and: 
 TIR 
 TAR 
 TBR, and 
 HbA1c. 
 
For all statistical tests, p≤0.05 is considered statistically significant. No multiplicity adjustment 
will take place. 
For continuous variables, descriptive statistics will entail: 
 mean 
 standard deviation (SD) 
 minimum 
 median, and 
 maximum. 
 
For categorical variables, frequency, and percentage will be obtained. 
Baseline characteristics (such as type of diabetes, gender, age, duration of disease, etc.) will be 
summarised for all the participants entered in the trial, and for the analysis sets described above. 
Where appropriate, graphs to illustrate glucose levels will be also be presented. 
Amount of useable data from the CGM device and pen will be summarised for the main analysis 
set. The primary reasons for discontinuation will be summarised by Study Period and participant 
allocation will be summarised by investigative site for those who have entered the trial. 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report (CSR). Additional exploratory analyses of the data will be conducted, 
as deemed appropriate. 
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9.3.1. Primary Endpoint  
The average number of MBDs per week during the masked and unmasked app periods as well as 
the difference will be summarised and analysed with the model described in Section 9.3. 
Table 3.1 outlines the objectives and endpoints for the study and provides the definition of MBD. 
Missed bolus doses will be calculated for: 
 Weeks 5-6 for Study Period 1 (masked), and 
 Weeks 15-18 for Study Period 2 (unmasked). 
9.3.2. Secondary Endpoints  
The following endpoints will be calculated and analysed with the model described in Section 9.3 
for the masked and unmasked periods: 
 Change in participant CGM TIR (≥70 and ≤180 mg/dL). 
 Change in participant CGM TAR (>180 mg/dL and >250 mg/dL). 
 Change in participant CGM TBR (<54 mg/dL and 54 mg/dL ≤ X <70 mg/dL). 
 Change in mistimed bolus dose [0,1] – administering a bolus dose from the start of a 
glucose excursion to 1 hour after the start of glucose excursion and before the peak of the 
glucose excursion, is classified as a mistimed bolus dose. The definition of a glucose 
excursion remains the same for an MBD. 
 Change in correction boluses - taking a bolus dose after the peak of a glucose excursion 
but within 4 hours from the start of a glucose excursion and prior to start of next glucose 
excursion. 
 Change in insulin doses: basal and mealtime, ratio basal/mealtime, dose per meal as well 
and total dose in IU/kg. 
 Correlations between MBD/mistimed bolus and: 
o TIR 
o TAR 
o TBR, and 
o HbA1c. 
 Other secondary analyses: 
o evaluate coefficient of variation (from CGM data) 
o evaluate mean sensor glucose (from CGM data). 
 Exploratory analyses: 
o change in HbA1c from baseline (Visit 1) to Visit 7 (last visit), 
o healthcare professional questionnaires, and 
o participant questionnaires 
o day and night time CGM profiles during the two periods. 
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9.3.3. Safety Analyses  
 Descriptive statistics of AEs (including the number of severe hypoglycaemic events) and 
Device Deficiencies (DDs) will be included and summarised. 
 Discontinuations will also be summarised. 
9.3.4. Other Analyses  
Participant and HCP feedback on individual questions will be summarised using frequency and 
percentages. The shift of responses from masked period (Visit 1, Visit 3) to unmasked period 
(Visit 7) will also be summarised using shift tables. 
In addition, exposure to the RMA will be summarised by period and overall. 
9.3.5. Subgroup Analyses  
Subgroup analysis will be performed on all participants for primary and secondary endpoints by: 
 age group, and 
 T1D or T2D.  
Only Summary statistics will be performed for all subgroups listed above. 
9.3.6. Sensitivity Analyses  
Sensitivity analyses will be performed for the primary endpoint. Varying definitions of MBD 
will be conducted as sensitivity analyses. These include: 
 MBD interval definition: 2 hours prior and 2 hours after start of glucose excursion (-2, 2), 
and 
 MBD glucose excursion: ≥80 mg/dL (>4.4 mmol/L) rise within 2 hours. 
 
Other sensitivity analyses that will be explored include the number of: 
 weeks used in the analysis for the masked app period 
 days with CGM data in the unmasked app period, and 
 participants that have dropped out during the unmasked app period. 
 
9.4. Sample Size Determination  
This clinical study aims to enroll approximately 50 participants (i.e., with signed informed 
consent and meeting all eligibility criteria) in sites across France. This sample size  provides 
≥80% power to detect a mean difference of daily MBD of 0.323 between the unmasked and 
masked RMA periods. 
The sample size also assumes: 
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 a conservative correlation estimate of 0.2 between the unmasked and masked RMA 
periods 
 an SD of 0.419 for the mean difference, and 
 a 2-sided alpha of <0.05 (Adolfsson et al. 2020). 
 
The estimated mean difference of 0.323 daily MBD is equivalent to a clinically relevant 
improvement of approximately 2.3 fewer MBD per week in the unmasked RMA period 
compared to the masked RMA period (also approximately 11% improvement). 
As this is a relatively new field with very limited data, a range of correlations and standard 
deviations was considered in the sample size calculation as well as varying dropout rates. Table 
9.1 provides an overview of how the appropriate sample size was identified. 
Table 9.1. 
Sample Sizes of Evaluable Participants Needed to Detect at Least a 
Mean Difference of 0.323 Missed Bolus Doses Per Day (Alpha=0.05, 
Power=80%)  
Correlation 
Standard deviation (SD) 
 
0.4 
0.419 
0.5 
0.6 
0.2 
22 
  24* 
33 
46 
0.3 
19 
21 
29 
40 
0.4 
17 
18 
25 
35 
0.5 
15 
16 
21 
30 
*Note: represents appropriate sample size identified for current study. 
 
 
A sample size of approximately 50 participants will be sufficient to allow: 
 at least 24 participants will complete the study with analysable data (see Table 9.1 and 
Section 9.2.1) 
 scope for increased variability (up to SD of 0.5) 
 for non-analysable participants due to technical problems 
 35% dropout rate was assumed based on previous study results (Adolfsson et al. 2020, 
Gomez-Peralta et al. 2022,) and the impact of missing CGM data which would reduce the 
number of evaluable patients. 
Participants who are entered but who do not proceed to the unmasked stage will be discontinued 
from the final efficacy analysis and may be replaced to ensure that enough participants complete 
the study. Best effort will be made to recruit an approximate ratio of 4:1 for T1D and T2D 
(approximately 40 participants with T1D and 10 participants with T2D) in this clinical study. 
Withdrawals will be monitored to ensure there are enough participants with T2D enrolled. 
9.5. Interim Analyses  
No interim analyses will be performed. 
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10.  Appendices   
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Appendix 1. 
Regulatory, Ethical, and Study Oversight 
Considerations  
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki and Council for International Organisations of Medical Sciences International Ethical 
Guidelines. 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice Guidelines. 
Applicable laws and regulations. 
The protocol, protocol amendments, ICF, and other relevant documents (for example, 
advertisements) must be submitted to an EC by the investigator and reviewed and approved by 
the EC before the study is initiated. 
Any amendments to the protocol will require EC approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to 
study participants. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The investigator will be responsible for the following: 
Providing written summaries of the status of the study to the EC annually or more frequently in 
accordance with the requirements, policies, and procedures established by the EC. 
Notifying the EC of SAEs and/or USADEs or other significant safety findings as required by EC 
procedures. 
Providing oversight of the conduct of the study at the site and adherence to requirements of 
International Organisation for Standardisation (ISO) 14155, ICH guidelines, the EC, EU 
Regulation 2017/745 for clinical studies, and all other applicable local regulations. 
Investigator sites are compensated for participation in the study as detailed in the Clinical Trial 
Agreement. 
 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. 
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Informed Consent Process 
 The investigator or his/her representative will explain the nature of the study, including 
the risks and benefits, to the participant and answer all questions regarding the study. 
 Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of ISO 
14155, local regulations, ICH guidelines, and the EC or study site. 
 The medical record must include a statement that written informed consent was obtained 
before the participant was entered in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF. 
 Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
 Participants will be informed of the emergency contact details for the principal 
investigator at each site. 
 Participants will be informed that their personal data will be stored for up to 30 years (per 
sponsor record retention rules) for potential future research in the field of diabetes. 
 A copy of the ICF(s) must be provided to the participant and is kept on file. 
 
Data Protection 
 Participants will be assigned a unique identifier by the Sponsor. Any participant records, 
datasets, or tissue samples that are transferred to the Sponsor will contain the identifier 
only; participant names or any information which would make the participant identifiable 
will not be transferred. 
 The participant must be informed that his/her personal study-related data, including the 
RMA data, will be used by the Sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant who will be required to give 
consent for his/her data to be used as described in the informed consent. 
 The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
Sponsor, by appropriate EC members, and by inspectors from regulatory authorities. 
 The Sponsor has processes in place to ensure data protection, information security and 
data integrity. These processes include appropriate contingency plan(s) for appropriate 
and timely response in the event of a data security breach. 
 
Dissemination of Clinical Trial Data 
A CSR will be provided for this study and a summary of study information, including tabular 
study results, will be provided on publicly available websites as required by local law and 
regulation. Dissemination of study data will be performed according to all applicable Lilly and 
international policies. 
Publication Policy 
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In accordance with the Sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal. 
Data Quality Assurance 
 All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (for example, data from 
Glooko RMA). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 
 The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 The investigator must permit study-related monitoring, audits, EC review, and regulatory 
agency inspections and provide direct access to source data documents. 
 Monitoring details describing strategy (for example, risk-based initiatives in operations 
and quality such as risk management and mitigation strategies and analytical risk-based 
monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues and monitoring techniques are provided in the Monitoring Plan. 
 The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 The Sponsor assumes accountability for actions delegated to other individuals (for 
example, contract research organisations). 
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for the time period outlined in the Clinical Trial 
Agreement (CTA) unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the Sponsor. No records may be transferred to another location or 
party without written notification to the Sponsor. 
 In addition, the Sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study may be 
audited by the Sponsor or its representatives, and/or regulatory agencies at any time. 
 Investigators will be given notice before an audit occurs. 
 
Deviations 
 Deviation(s) from this protocol, signed agreement, applicable regulations, and any 
conditions of approval imposed by an EC or applicable regulators shall be documented 
(including date of and reason for deviation). Site personnel must identify and report 
deviations to the Sponsor within 5 working days. 
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 Under emergency circumstances, deviations from this protocol to protect the rights, 
safety, or well-being of participants is allowed without prior approval of Lilly and the 
EC. The site shall document and report these emergent deviations to Lilly and the EC 
within 5 working days after the emergency occurred. 
 If appropriate, actions to secure compliance may be taken by Lilly. These actions may 
include discontinuation of device shipments, removal/disposal of devices from the 
investigator, or termination of an investigator’s participation in the study. 
 
Data Capture System 
 The investigator is responsible for 
o the identification of any data to be considered source and for the confirmation that 
data reported are accurate and complete by signing the eCRF, and 
o ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported to the Sponsor. 
 An electronic data capture (EDC) system will be used in this study. The system is a 
validated and secure system, allowing only those with permission (unique to each user) to 
access data. The system creates a computer generated, time stamped audit trail in 
accordance with 21 CFR Part 11. 
 The study site maintains a separate source for the data entered by the site into the Sponsor 
data capture system. Data will be stored in accordance with retention requirements in 
applicable regulations. Assessments can be directly recorded by the investigator site 
personnel or a delegate into the EDC. The directly entered data will serve as source 
documentation. 
 The investigator will maintain an original, separate, written, or electronic record of any 
data entered to EDC system. A certified copy of the respective data entry will be 
downloaded by the investigator for retention. 
 Data from DDs submitted to the Sponsor will be encoded and stored in the global PC 
management system. 
 Data will be reviewed throughout the study to identify any missing data, errors in data 
entry, or inconsistencies in the data provided. A query process will be used to resolve any 
discrepancies identified during the data review process. 
 Data collected via the Sponsor-provided data capture systems will be stored at third 
parties. The investigator will have continuous access to the data during the study and 
until decommissioning of the data capture systems. Prior to decommissioning, the 
investigator will receive an archival copy of pertinent data for retention. 
 
Source Documents 
 Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
 Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
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explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
 
 data (from the Tempo Pen/Tempo Smart Button) and glucose 
measurement data (from the CGM) transferred into the Glooko RMA or other data 
entered directly by the participant into RMA. In these instances where there is no prior 
written or electronic source data, the RMA record will serve as the source. 
 Definition of what constitutes source data can be found in the Data Capture System in the 
previous section. 
 
Trial and Site Start and Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to: 
 for study termination: 
o discontinuation of further study intervention development. 
 for site termination: 
failure of the investigator to comply with the protocol, the requirements of the EC 
or local health authorities, the Sponsor's procedures, or GCP guidelines; 
inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator; and 
total number of participants included earlier than expected. 
 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the ECs, the regulatory authorities, and any contract research organisation(s) used 
in the study of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and assures appropriate 
participant therapy and/or follow-up. 
Investigator Information 
Physicians with a specialty in endocrinology and/or diabetology will participate as investigators 
in this clinical trial. 
A complete list of investigators, and other institutions involved in this study will be maintained 
by the Sponsor and updated as needed throughout the study. A list of all participating 
investigators in the trial will be provided to each study site and EC in a separate document. 
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Appendix 2. 
Adverse Events and Serious Adverse 
Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
The definitions and procedures detailed in this appendix are in accordance with ISO 14155. 
Both the investigator and Sponsor will comply with all local medical device reporting requirements. 
The detection and documentation procedures described in this protocol apply to all Sponsor medical 
devices provided for use in the study. See Section 6.1 for the list of Sponsor medical devices. 
Definition of Adverse Event 
An AE is any untoward medical occurrence, unintended disease or injury, or untoward clinical 
signs (including abnormal laboratory finding) in study participants, users, or other persons, 
whether or not related to the medical device. This definition includes events related to the 
medical device or comparator and events related to the procedures involved except for events in 
users or other persons, which only include events related to devices. 
An adverse device effect (ADE) is defined as an adverse event related to the use of a medical 
device. This definition includes any AEs resulting from insufficient or inadequate instructions for 
use, deployment, implantation, installation, or operation; any malfunction of the medical device as 
well as any event resulting from use error or from intentional misuse of the medical device. 
Events meeting the AE definition include: 
 any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgement of the investigator (that is, not related 
to progression of underlying disease) 
 exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
 new conditions detected or diagnosed after study intervention administration even though 
they may have been present before the start of the study 
 signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction, and 
 signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdose should be reported regardless of sequelae. 
 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of efficacy” or “failure of 
expected pharmacological action” also constitutes an AE or SAE. 
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Events not meeting the AE definition include: 
 any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition 
 the disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition 
 medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE 
 situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
All AEs shall be reported to the Sponsor as soon as possible upon site awareness via eCRF. 
Definition of Serious Adverse Event 
An SAE is defined as any adverse event that led to any of the following: 
a. death,  
b. serious deterioration in the health of the subject, that resulted in any of the following:  
vi. life-threatening illness or injury,  
vii. permanent impairment of a body structure or a body function,  
viii. hospitalisation or prolongation of patient hospitalisation,  
ix. medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function,  
x. chronic disease,  
c. foetal distress, foetal death, or a congenital physical or mental impairment or birth 
defect 
Severe hypoglycaemic events must be reported to Lilly as an SAE. 
All SAEs shall be reported to the Sponsor within 24 hours of site awareness via eCRF. 
Definition of Serious Adverse Device Event 
A Serious adverse device effect (SADE) is defined as an ADE that has resulted in any of the 
consequences characteristic of a SAE. 
Definition of Unanticipated Adverse Device Event 
A UADE is a SAE on health or safety or any life-threatening problem or death caused by or 
associated with a device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the clinical plan or application (including a supplementary 
plan or application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of the participant (see Section 2.4). 
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Definition of Device Deficiency 
A device deficiency is any inadequacy in the identity, quality, durability, reliability, safety or 
performance of an investigational device, including malfunction, use errors or inadequacy in 
information supplied by the manufacturer.  
When the ability to use the study intervention safely is impacted, the following are also DDs: 
 Deficiencies in labelling information, and 
 Use errors for device or drug-device combination products due to ergonomic design 
elements of the product. 
 
Device deficiencies related to study interventions used in clinical trials are collected to ensure the 
safety of participants, monitor quality, and to facilitate process and product improvements. 
Investigators will instruct participants to contact the site as soon as possible if he or she has a DD 
or problem with the study intervention so that the situation can be assessed. 
An event may meet the definition of both a DD and an AE/SAE. In such cases, it should be 
reported as both a DD and as an AE/SAE. 
Recording and Follow-Up of Adverse Event, Serious Adverse Events, and Device Deficiencies 
 When an AE/SAE/DD occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
 The investigator will then record all relevant AE/SAE/DD information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice. AE, SAE, and DD information is reported on the appropriate data source. 
Note: An event may meet the definition of both a DD and an AE/SAE. In such cases, it 
should be reported as both a DD and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the eCRF page for AE/SAE and 
sponsor DD form. 
 There may be instances when copies of medical records for certain cases are requested by 
Sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to Sponsor of designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
 The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories: 
o Mild: A type of adverse event that is usually transient and may require only 
minimal treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
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o Moderate: A type of adverse event that is usually alleviated with additional 
specific therapeutic intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent risk of harm to 
the research participant. 
o Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention. An AE that is assessed as severe should not be confused with a SAE. 
Severe is a category utilised for rating the intensity of an event; and both AEs and 
SAEs can be assessed as severe. An event is defined as ‘serious’ when it meets at 
least 1 of the predefined outcomes as described in the definition of an SAE, NOT 
when it is rated as severe. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgement to 
determine the relationship. 
 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
The investigator will also consult the IFU and/or product information for marketed products, in 
his/her assessment. 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to Sponsor or designee. However, it is very important 
that the investigator always assess causality for every event before the initial transmission of the 
SAE data to Sponsor or designee. 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or designee 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include: 
 additional laboratory tests or investigations 
 histopathological examinations, or 
 consultation with other HCPs. 
 
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If a participant dies during participation in the study or during a recognised follow-up period, the 
investigator will provide Sponsor or designee with a copy of any post-mortem findings including 
histopathology. 
Reporting of Serious Adverse Events 
The primary mechanism for reporting an SAE will be the electronic data collection tool (eCRF): 
 If the electronic system is unavailable, then the site will use the SAE paper form (see next 
section) to report the event within 24 hours. 
 All SAEs shall be reported to the Sponsor within 24 hours of site awareness. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information to the Sponsor by telephone. 
 Contacts for SAE reporting can be found in site training package. 
 
SAE/Device Deficiency Regulatory Reporting 
Prompt notification by the investigator to the Sponsor of a SAE/DD is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, EC, and investigators, according to Section 8 Reporting Timelines of 
MDCG 2020-10/1. The reporting form will contain the appropriate information called out in the 
Clinical Investigation Summary Safety Reporting Form per MDCG 2020-10/1 Appendix. 
An investigator who receives an investigator safety report describing a SAE/DD or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 
it along with the IFU and will notify the EC, if appropriate according to local requirements. 
 
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Appendix 3. 
Contraceptive and Barrier Guidance  
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). If fertility is unclear (for example, amenorrhea in adolescents or 
athletes) and a menstrual cycle cannot be confirmed before first dose of study intervention, 
additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
premenarchal 
premenopausal female with 1 of the following: 
o documented hysterectomy 
o documented bilateral salpingectomy, and 
o documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other than the above 
(for example, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Determination can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
Postmenopausal female, defined as, women with: 
o 12 months of amenorrhea for women >55, with no need for FSH 
o 12 months of amenorrhea for women >40 years old with FSH ≥40 mIU/mL and 
no other medical condition such as anorexia nervosa and not taking medications 
during the amenorrhea (e.g., oral contraceptives, hormones, gonadotropin 
releasing hormone, anti-oestrogens, selective estrogenic receptor modulators, or 
chemotherapy that induced amenorrhea) 
Contraception Guidance 
Women of childbearing potential must use either 1 highly effective method of contraception or a 
combination of 2 effective methods of contraception. The participant may choose to use a 
double- barrier method of contraception (see Table APP.10.1.) 
Barrier protection methods without concomitant use of a spermicide are not an effective or 
acceptable method of contraception. It should be noted, however, that the use of male and female 
condoms as a double-barrier method is not considered acceptable due to the high failure rate 
when these barrier methods are combined. 
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Table APP.10.1. 
Methods of Contraception 
Highly Effective Methods of Contraception 
Effective Methods of Contraception (Must Use 
Combination of 2 Methods) 
Combined oral contraceptive pill and mini pill 
Male condom with spermicide 
Vaginal ring (e.g., NuvaRing®) 
Female condom with spermicide 
Implantable contraceptives 
Diaphragm with spermicide 
Injectable contraceptives (e.g., Depo-Provera®) 
Cervical sponge with spermicide 
Intrauterine device (e.g., Mirena®) 
Cervical cap with spermicide 
Contraceptive patch (ONLY women <198 lb or 90 kg) 
 
Bilateral tubal occlusion 
 
Total abstinence 
 
Vasectomy 
 
 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence just for the duration of a trial, and withdrawal are not acceptable 
methods of contraception. 
Collection of Pregnancy Information 
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention or be withdrawn from the study. 
 
 
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Appendix 4. 
Provisions for Changes in Study Conduct 
During Exceptional Circumstances  
The Investigator/Site must consult the Sponsor or Sponsor representative before 
implementing any mitigation measures, such as those relating to COVID-19. 
If any mitigation measure related to COVID-19 impacts on the study participants, for example 
shipping study supplies to the participant’s home, conducting participant visits remotely, 
performing trial activities at a site/facility other than the trial site, the participants must consent 
to this change. 
Verbal consent is required and should be documented in the participants medical records. 
Participant consent must be confirmed before implementing the mitigation measure. 
Participant consent is not required to conduct remote monitoring activities. 
Prospective protocol waivers remain unacceptable, and participants should not be included in 
trials without proper eligibility assessment, including performance of planned tests, and written 
informed consent according to national laws and regulations. 
Study Consent 
In cases where an update to the ICF, which requires study participants to be reconsented, occurs 
during the trial, the sites should provide the updated ICF to study participants by email, mail, or 
courier before verbal re-consent is obtained. Verbal consent should be documented by the site 
and confirmed by way of normal consent procedure at the earliest opportunity when the study 
participants are back at the site. 
Remote consent can be leveraged in situations where verbal consent alone would not be deemed 
appropriate or sufficient to ensure that the participant was able to provide fully informed consent. 
Remote consent would be appropriate in situations where participants are required to consent to 
new enrolment (e.g., roll-over studies) or new participants are consenting to new studies. The 
Sponsor or Sponsor representative should be consulted on the specific process steps for this 
scenario. 
Participant Visits 
In case of severe external disruptions, participants may not be able to come back to the site for 
their scheduled visits due to traffic restrictions and safety concerns. In these instances, remote 
visits may be conducted to ensure participants’ safety, study quality, and integrity. The same 
principles and steps should be followed as for any routine situation when a participant cannot 
come to the site for a planned visit and the duration of the restriction is not known. 
Direct entry into eCRF is not allowed. Source records should still be created by the site or mobile 
health care provider per site-specific strategy and as indicated on the site delegation of authority. 
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The Sponsor or Sponsor representative must be consulted on the specific process steps before 
implementing the mitigation measure. 
The following types of alternative participant visits can be considered: 
1. Remote Visit is defined as a phone call or videoconference (virtual) visit used to replace 
a protocol required on-site visit where remote data can be collected. A new visit in the 
CRF is triggered to collect data. These visits should be considered when: 
a. In-person site visits are not possible because the site is not conducting research 
visits, or the participant is not able or unwilling to travel to the site. 
b. Collection of limited data over the phone or videoconference will help ensure that 
safety risks are mitigated. 
a. Per protocol physical visits are reduced or postponed, and it is important that the 
investigator continue collecting AEs from the participant through alternative 
means (e.g., by phone or videoconference). 
2.  Mobile Visit is defined as an in-home visit used to replace a protocol required on-site 
visit where necessary activities are performed by a contracted health care provide (e.g., 
nurse) or a member of the site staff (e.g., nurse study coordinator). Source data are 
collected, and those data needed within the CRF are sent/taken back to the site as source 
for data entry. These visits should be considered when: 
a. It is necessary to have participant contact for protocol required activities (e.g., 
physical examination, administration of participant reported outcome assessment). 
b. A health care provider is needed to administer medication. 
c. A health care provider is needed to collect specimens (e.g., blood specimen for 
central laboratory assessment). 
3. Alternate Site Visit is defined as a visit conducted in-person at an alternative site 
participating in the same trial. These visits should be considered when: 
a. In-person site visit is needed; however, the participant’s primary site is not 
available or is less convenient for the participant. 
Additional Considerations: 
 If videoconferencing is employed, international privacy requirements (e.g., HIPAA) must 
be considered. Consult with the Sponsor or Sponsor representative for appropriate 
technology solution enablement. 
 Consent is required for visits in a participant’s home. 
Clinical Trial Supplies 
Under certain circumstances a situation may occur where participants may not be able to return 
to site for scheduled visits due to numerous factors such as site restriction and/or safety concern 
and as such cannot receive their required study materials. 
The following potential supply options may be considered when there are no alternate measures 
to meet participant needs: 
1. Participants going to another investigator site for a visit 
2. Designee obtaining CT materials on participant’s behalf 
a. Must have participant’s consent/authorisation and site must document 
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3. Investigator site staff delivering CT material to participant outside of clinic 
a. Site must document in participant files 
4. Investigator site to participant shipment 
a. The investigator site should contact the participants prior to product shipment and 
inform them of the requirement to share his/her identity with a vendor. The site 
should document the non-opposition of the participant. 
b. The shipment of the drugs must be in accordance with the defined temperature 
and environmental conditions. 
c. The site must have a process or procedure to allow them to ship drug directly to a 
participant. The process/procedure should ensure material can be transported per 
label conditions; method of packing takes steps to ensure product protection. 
d. Shipment is made via an expedited method (i.e., overnight). 
e. There is confirmation the participant received material, and participant is 
instructed to not administer the product and contact the site for instructions if 
material is delivered damaged. 
f. The investigator site must ensure the traceability of the CT material throughout 
the process. 
Lilly will reimburse sites for the additional expense related to the cost of using couriers for CT 
delivery, in accordance with national legislation and/or guidance. 
Remote Study Monitoring 
Remote monitoring activities may be implemented as a mitigation by the Sponsor or Sponsor 
representative to maintain oversight of study activities while on-site monitoring visits, including 
Site Initiation Monitoring Visits and Close Out Visits, cannot be completed. 
Provision of copies of medical records, even pseudonymised, for the purpose of remote 
monitoring is not allowed. 
 
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Appendix 5. 
Abbreviations  
Term 
Definition 
AACE 
American Association of Clinical Endocrinology 
ADA 
American Diabetes Association 
ADE 
adverse device effect 
AE 
Adverse event 
App 
application 
ATTD 
Advanced Technologies and Treatments for Diabetes 
AWS 
Amazon Web Services 
BG 
blood glucose 
BLE 
Bluetooth® Low Energy 
CE 
Conformité Européenne 
CFR 
Code of Federal Regulations 
CGM 
continuous glucose monitor/monitoring 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
case report form 
CSR 
clinical study report 
CT 
computed tomography 
DD 
device deficiency 
DKA 
diabetic ketoacidosis 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European Medicines Agency 
EU 
European Union 
FOIA 
Freedom of Information Act 
FPV 
First participant visit  
GDPR 
General Data Protection Regulation 
HbA1c 
Glycated haemoglobin 
HCP 
healthcare professional 
HFS-SF 
Hypoglycaemia Fear Survey – Short Form 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
EC 
Ethics Committee 
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Term 
Definition 
IFU 
Instructions for Use 
ISO 
International Organisation for Standardisation 
Lilly 
Eli Lilly and Company 
LPV 
Last participant visit  
MBD 
missed bolus dose 
MDD 
Medical Device Directive 
MDR 
Medical Device Regulation 
MDSW 
medical device software 
MRI 
Magnetic Resonance Imaging 
PHI 
Protected Health Information 
PoC 
Point-of-care 
PwD 
Person/People with diabetes 
RMA 
research mobile app/application  
SADE 
Serious adverse device effect 
SAE 
serious adverse event 
SD 
Standard Deviation 
SMBG 
self-monitoring of blood glucose 
SoA 
schedule of activities 
T1D 
type 1 diabetes 
T2D 
type 2 diabetes  
TAR 
Time above range 
TBR 
Time below range 
TIR 
Time-in-range 
UADE 
unanticipated adverse device effect 
US(A) 
United States (of America) 
WOCBP 
Women of childbearing potential 
 
 
 
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Appendix 6. 
Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment Version 7: (06 September 2023) 
 
Overall Rationale for the Amendment 
This protocol has been amended to incorporate feedback from Le Comité de Protection des 
Personnes (CPP). 
DOCUMENT HISTORY 
Document 
Date 
Version 7.0 
06 September 2023 
Version 6.0 
29 June 2023 
Version 5.0 
17 May 2023 
Version 4.0 
10 May 2023 
Version 3.0 
28 April 2023 
Version 2.0 
14 April 2023 
Original Protocol 
23 January 2023 
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11. References  
11.1. Literature Cited  
Adolfsson P, Hartvig NV, Kaas A, et al. Increased time in range and fewer missed bolus 
injections after introduction of a smart connected insulin pen. Diabetes Technol Ther. 
2020;22(10):709-718. https://doi: 10.1089/dia.2019.0411 
Andrade CS, Ribeiro GS, Santos C, et al. Factors associated with high levels of glycated 
haemoglobin in patients with type 1 diabetes: a multicentre study in Brazil. BMJ Open. 
2017;7(12):e018094. doi: 10.1136/bmjopen-2017-018094. 
Battelino T, Alexander CM, Amiel SA, et al. Continuous glucose monitoring and metrics for 
clinical trials: an international consensus statement. Lancet Diabetes Endocrinol. 
2022;11(1):42-57. https://doi.org/10.1016/S2213-8587(22)00319-9 
Danne T, Nimri R, Battelino T, et al. International consensus on use of continuous glucose 
monitoring. Diabetes Care. 2017;40(12):1631-1640. https://doi.org/10.2337/dc17-1600. 
Dexcom Letter of Conformity Form. Accessed November 24, 2021. https://s3-us-west-
2.amazonaws.com/dexcompdf/OUS+Specific+PDFs/DoC+RED/LBL015291+Rev+001_LBL0
16652+Rev+001_Declaration+of+Conformity+G4_G5_G6.pdf 
Edwards S, He X, Wang W, et al. Use of connected pen as a diagnostic tool to evaluate missed 
bolus dosing behavior in people with type 1 and type 2 diabetes. Diabetes Technol Ther. 
2021;24(1):1-6. Epub ahead of print. https://doi: 10.1089/dia.2021.0239. 
Gomez-Peralta F, Abreu C, Fernández-Rubio E, et al. Efficacy of a connected insulin pen cap in 
people with noncontrolled type 1 diabetes: A multicenter randomized clinical trial. Diabetes 
Care. 2022; 46(1):206-208. doi: 10.2337/dc22-0525. 
Grunberger G, Sherr J, Allende M, et al. American Association of Clinical Endocrinology 
Clinical practice guideline: the use of advanced technology in the management of persons with 
diabetes mellitus. Endocr Pract. 2021;27(6):505-507. https://doi:10.1016/j.eprac.2021.04.008. 
Heinemann L, Schnell O, Gehr B, et al. Digital diabetes management: a literature review of 
smart insulin pens. J Diabetes Sci Technol. 2021:1–9. https://doi:10.1177/1932296820983863. 
Heller S, Buse J, Ratner R, et al. Redefining Hypoglycemia in Clinical Trials: Validation of 
Definitions Recently Adopted by the American Diabetes Association/European Association 
for the Study of Diabetes. Diabetes Care. 2020; 43(2):398-404. https://doi.org/10.2337/dc18-
2361 
Kompala T, Neinstein AB. Smart insulin pens: Advancing digital transformation and a connected 
diabetes care ecosystem. J Diabetes Sci and Technol. 2021:1–9. 
https://doi:10.1177/1932296820984490. 
Munshi MN, Segal AR, Suhl E, et al. Assessment of barriers to improve diabetes management in 
older adults: a randomized controlled study. Diabetes Care. 2013;36(3):543–549. 
doi: 10.2337/dc12-1303. 
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Munshi MN, Slyne C, Greenberg JM, et al. Nonadherence to insulin therapy detected by 
Bluetooth-enabled pen cap is associated with poor glycemic control. Diabetes Care. 
2019;42(6):1129-1131. https//:doi:10.2337/dc18-1631. 
Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular 
disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643–2653. 
doi: 10.1056/NEJMoa052187. 
Peyrot M, Barnett AH, Meneghini LF, Schumm-Draeger PM. Insulin adherence behaviours and 
barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy 
study. Diabet Med. 2012a;29(5):682-689. doi: 10.1111/j.1464-5491.2012.03605.x. 
Peyrot M, Barnett AH, Meneghini LF, Schumm-Draeger PM. Factors associated with injection 
omission/non-adherence in the Global Attitudes of Patients and Physicians in Insulin Therapy 
study. Diabetes Obes Metab. 2012b;14(12):1081-1087. doi: 10.1111/j.1463-
1326.2012.01636.x. Epub 2012 Jul 17. 
Randløv J, Poulsen JU. How much do forgotten insulin injections matter to hemoglobin A1c in 
people with diabetes? A simulation study. J Diabetes Sci Technol. 2008;2(2):229–235. doi: 
10.1177/193229680800200209. 
Spaans E, van Hateren KJ, Groenier KH, et al. Mealtime insulin bolus adherence and glycemic 
control in adolescents on insulin pump therapy. Eur J Pediatr. 2018;177(12):1831–1836. 
Sy SL, Munshi MM, Toschi E. Can Smart Pens Help Improve Diabetes Management? J 
Diabetes Sci Technol. 2022; 16(3):628–634. doi: 10.1177/1932296820965600. 
Taylor A, Thrasher J, Eby E, et al. Diabetes Society of Technology Meeting 2021.  
Available at https://lillyscience.lilly.com/congress/dts2021 
Tempo Smart Button Instructions For Use. Accessed November 24, 2021. 
https://usermanual.wiki/Eli-Lilly-and/LLY00043845100-
4435803.pdf?fbclid=IwAR0xKg8WLIYWJqQwY5Yt2O0lMrIm6YbRFKt7uNJHldzBmMN_9
SpYEOCkUDk 
 
 
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11.2. Previous Investigations of the Humalog Tempo pen and Tempo 
Smart Button  
Products used in this study are CE-marked/EMA-approved. Information on prior product testing 
and/or clinical investigations is available in the 
 Humalog Tempo Pen Package Insert, and 
 Tempo Smart Button IFU. 
 
Additionally, Study F3Z-MC-IOQY (Taylor et al. 2021) has been conducted with Humalog 
Tempo Pen and Tempo Smart Button in participants with T1D and T2D. One of the secondary 
objectives of this study was to assess the overall ease of use of the Tempo Pen/Smart Button as 
part of an integrated insulin management system. 
The Smart Button, as part of the integrated insulin management system, was reported as easy to 
use. Additionally, the majority of participants (78.1%) responded that they would be highly 
likely or somewhat likely to include the system in their diabetes management. Likewise, the 
majority of site personnel (64.3%) responded that they were highly likely or somewhat likely to 
recommend the system to their patients. 
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Signature Page for VV-CLIN-110605 v7.0
Signature Page for VV-CLIN-110605 v7.0
Approval
06-Sep-2023 12:09:20 GMT+0000
Approval
or
06-Sep-2023 13:48:36 GMT+0000
Approved on 06 Sep 2023 GMT
PPD
PPD