Safety Evaluation of an Advanced Hybrid Closed Loop System Using Lyumjev With the Tandem t:Slim X2 Insulin Pump With Control-IQ Technology in Adults, Adolescents and Children With Type 1 Diabetes
Phase: NA
Conditions: Type 1 Diabetes
Sponsor: Tandem Diabetes Care, Inc.

*****CONFIDENTIAL***** 
 
Signature Page 
Safety Evaluation of an Advanced Hybrid Closed Loop System 
Using Lyumjev with the Tandem t:slim X2 with Control-IQ in 
Adults, Adolescents and Children with Type 1 Diabetes 
Protocol Identifying Number: TP-0009650 
IDE Sponsor: Tandem Diabetes Care, Inc. 
Version Number: v. 4.0 
13 APR 2022 
 
Sponsor 
 
Name, degree 
Jordan Pinsker, MD 
Signature/Date 
 
 
Sponsor  
 
Name, degree 
John W. Lum, MS 
Signature/Date 
 
 
 
Medical Monitor 
 
Name, degree 
Roy W. Beck, MD, PhD 
Signature/Date 
 
 
SIGN
SIGN
SIGN

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 2 OF 52 
Safety Evaluation of an Advanced Hybrid Closed Loop System 
Using Lyumjev with the Tandem t:slim X2 with Control-IQ in 
Adults, Adolescents and Children with Type 1 Diabetes 
Protocol Identifying Number: TP-0009650 
IDE Sponsor: Tandem Diabetes Care, Inc. 
Version Number: v. 4.0 
13 APR 2022 
 

 
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KEY ROLES 
 
Sponsor and Clinical Director 
 
Name, degree 
Jordan Pinsker, MD 
Title 
Vice President and Medical Director  
Institution Name 
Tandem Diabetes Care, Inc. 
 
JCHR Coordinating Center Director 
 
Name, degree 
John W. Lum, MS 
Title 
Coordinating Center Director 
Institution Name 
Jaeb Center for Health Research 
 
Medical Monitor 
 
Name, degree 
Roy W. Beck, MD, PhD 
Title 
Medical Director 
Institution Name 
Jaeb Center for Health Research 
 
 

 
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TABLE OF CONTENTS 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 16 
1.1 Introduction ....................................................................................................................................... 16 
1.1.1 Tandem X2 Insulin Pump with Control-IQ Technology ............................................................. 16 
1.1.2 Lyumjev Insulin .......................................................................................................................... 16 
1.2 Rationale ............................................................................................................................................ 17 
1.3 Potential Risks and Benefits .............................................................................................................. 17 
1.3.1 Known Potential Risks ................................................................................................................ 17 
1.3.1.1 Blood Draw ......................................................................................................................... 17 
1.3.1.2 CGM and Pump Catheter Risks .......................................................................................... 17 
1.3.1.3 Hypoglycemia ..................................................................................................................... 17 
1.3.1.4 Risk of Hyperglycemia ....................................................................................................... 18 
1.3.1.5 Risk of Device Reuse .......................................................................................................... 18 
1.3.1.6 Questionnaires ..................................................................................................................... 18 
1.3.1.7 Potential Risks of the CLC System ..................................................................................... 18 
1.3.1.8 Potential Risks of Using Lyumjev ...................................................................................... 18 
1.3.1.9 Other Risks .......................................................................................................................... 19 
1.3.2 Benefits ........................................................................................................................................ 19 
1.3.3 Risk Assessment .......................................................................................................................... 19 
1.4 General Considerations...................................................................................................................... 19 
CHAPTER 2: STUDY ENROLLMENT AND LEAD-IN PERIOD ...................................................................... 20 
2.1 Participant Recruitment and Enrollment ........................................................................................... 20 
2.1.1 Informed Consent and Authorization Procedures ....................................................................... 20 
2.2 Participant Eligibility Criteria ........................................................................................................... 21 
2.2.1 Inclusion Criteria ......................................................................................................................... 21 
2.2.2 Exclusion Criteria ........................................................................................................................ 22 
2.3 Screening Procedures ........................................................................................................................ 23 
2.3.1 Data Collection and Testing ........................................................................................................ 23 
2.4 Screen Failures .................................................................................................................................. 23 
2.5 Lead-in Period ................................................................................................................................... 24 
CHAPTER 3: TREATMENT PERIOD ............................................................................................................ 25 
3.1 CIQ 1.5/ Lyumjev Training Visit ...................................................................................................... 25 
3.1.1 Training on System Use .............................................................................................................. 25 
3.1.2 Training on Management of Hypoglycemia ................................................................................ 26 
3.1.3 Training on Management of Hyperglycemia............................................................................... 26 

 
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3.1.4 Participant Reporting of Infusion Set Insertion Reactions .......................................................... 27 
3.1.5 Adjustments in Insulin Pump Settings ........................................................................................ 27 
3.2 Study Visits and Phone Contacts ....................................................................................................... 27 
3.2.1 Procedures During Phone Contacts ............................................................................................. 27 
3.2.2 Procedures at Study Visits ........................................................................................................... 28 
3.2.3 Unscheduled Visits ...................................................................................................................... 28 
3.3 Exercise and Meal Challenges ........................................................................................................... 28 
Participants will complete 3 meal and 3 exercise challenges during Lyumjev use. Procedures are 
described in section 5.1. .......................................................................................................................... 28 
3.4 Early Discontinuation of Study Device ............................................................................................. 28 
CHAPTER 4: STUDY DEVICES AND DRUGS ............................................................................................... 29 
4.1 Study Devices .................................................................................................................................... 29 
4.1.1 Insulin Pump ................................................................................................................................ 29 
4.1.2 Continuous Glucose Monitoring ................................................................................................. 29 
4.1.3 Blood Glucose Meter ................................................................................................................... 29 
4.1.4 Ketone Meter ............................................................................................................................... 29 
4.2 Study Drug ......................................................................................................................................... 29 
4.3 Study Device and Drug Accountability Procedures .......................................................................... 30 
4.4 Participant Access to Study Device at Study Closure ....................................................................... 30 
CHAPTER 5: TESTING PROCEDURES AND QUESTIONNAIRES ................................................................. 31 
5.1 Meal and Exercise Challenges ........................................................................................................... 31 
5.1.1 Meal Challenges .......................................................................................................................... 31 
5.1.2 Exercise Challenges..................................................................................................................... 32 
5.2 Laboratory Testing ............................................................................................................................ 32 
5.2.1 HbA1c ......................................................................................................................................... 32 
5.2.2 Urine Pregnancy .......................................................................................................................... 32 
5.3 Questionnaires ................................................................................................................................... 33 
CHAPTER 6: UNANTICIPATED PROBLEM, ADVERSE EVENT, AND DEVICE ISSUE REPORTING ............ 34 
6.1 Unanticipated Problems ..................................................................................................................... 34 
6.2 Adverse Events .................................................................................................................................. 34 
6.2.1 Definitions ................................................................................................................................... 34 
6.2.2 Reportable Adverse Events ......................................................................................................... 35 
6.2.3 Hypoglycemic Events .................................................................................................................. 36 
6.2.4 Hyperglycemic/Ketotic Events .................................................................................................... 36 
6.2.5 Skin Reactions Related to Infusion Set ....................................................................................... 37 
6.2.6 Relationship of Adverse Event to Study Investigational Device ................................................. 37 

 
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6.2.7 Severity (Intensity) of Adverse Events ........................................................................................ 37 
6.2.8 Expectedness ............................................................................................................................... 38 
6.2.9 Coding of Adverse Events ........................................................................................................... 38 
6.2.10 Outcome of Adverse Events ...................................................................................................... 38 
6.3 Reportable Device Issues ................................................................................................................... 39 
6.4 Timing of Event Reporting ................................................................................................................ 39 
6.5 Safety Oversight ................................................................................................................................ 40 
6.6 Stopping Criteria ............................................................................................................................... 40 
6.6.1 Participant Discontinuation of Study Device .............................................................................. 40 
6.6.2 Criteria for Suspending or Stopping Overall Study ..................................................................... 41 
CHAPTER 7: MISCELLANEOUS CONSIDERATIONS ................................................................................... 42 
7.1 Drugs Used as Part of the Protocol .................................................................................................... 42 
7.2 Collection of Medical Conditions and Medications .......................................................................... 42 
7.3 Prohibited Medications, Devices, Treatments, and Procedures ......................................................... 42 
7.4 Rescue Medications, Treatments, and Procedures ............................................................................ 42 
7.5 Pregnancy Reporting ......................................................................................................................... 42 
7.6 Participant Compensation .................................................................................................................. 42 
7.7 Participant Withdrawal ...................................................................................................................... 42 
7.8 Confidentiality ................................................................................................................................... 43 
CHAPTER 8: STATISTICAL CONSIDERATIONS .......................................................................................... 44 
8.1 Statistical and Analytical Plans ......................................................................................................... 44 
8.2 Statistical Hypotheses ........................................................................................................................ 44 
8.3 Sample Size ....................................................................................................................................... 44 
8.4 Outcome Measures ............................................................................................................................ 44 
8.5 Analysis Datasets ............................................................................................................................... 45 
8.6 Statistical Methods ............................................................................................................................ 45 
8.6.1 Analysis of the Safety Event Endpoints ...................................................................................... 45 
8.6.2 Analysis of CGM Endpoints ....................................................................................................... 45 
8.6.3 Analysis of HbA1c and PRO Measures ...................................................................................... 45 
8.7 Intervention Adherence ..................................................................................................................... 46 
8.8 Protocol Adherence and Retention .................................................................................................... 46 
8.9 Baseline Descriptive Statistics ........................................................................................................... 46 
8.10 Additional Tabulations and Analyses .............................................................................................. 46 
8.11 Device Issues ................................................................................................................................... 47 
8.12 Planned Interim Analyses ................................................................................................................ 47 
8.13 Subgroup Analyses .......................................................................................................................... 47 

 
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8.14 Multiple Comparison/Multiplicity ................................................................................................... 47 
8.15 Analysis of Meal and Exercise Challenges ..................................................................................... 47 
CHAPTER 9: DATA COLLECTION AND MONITORING .............................................................................. 48 
9.1 Case Report Forms and Other Data Collection ................................................................................. 48 
9.2 Study Records Retention ................................................................................................................... 48 
9.3 Quality Assurance and Monitoring .................................................................................................... 48 
9.4 Protocol Deviations ........................................................................................................................... 49 
CHAPTER 10: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 50 
10.1 Ethical Standard ............................................................................................................................... 50 
10.2 Institutional Review Boards ............................................................................................................ 50 
10.3 Informed Consent Process ............................................................................................................... 50 
10.3.1 Consent Procedures and Documentation ................................................................................... 50 
10.3.2 Participant and Data Confidentiality ......................................................................................... 50 
10.3.3 Future Use of Stored Specimens and Data ................................................................................ 51 
CHAPTER 11: REFERENCES ....................................................................................................................... 52 
 
 
 

 
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LIST OF ABBREVIATIONS 
 
 
ABBREVIATION 
DEFINITION 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
BGM 
Blood Glucose Meter 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CGM 
Continuous Glucose Monitoring  
DCCT 
Diabetes Control & Complications Trial 
DKA 
Diabetic Ketoacidosis 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
ICH 
International Conference of Harmonization 
IDE  
Investigational Device Exemption 
IRB 
Institutional Review Board 
RBM 
Risk-Based Monitoring 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1D 
Type 1 Diabetes 
UADE 
Unanticipated Adverse Device Effect 
 

 
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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
Protocol Title: Safety Evaluation of an Advanced Hybrid Closed Loop System Using Lyumjev 
with the Tandem t:slim X2 with Control-IQ in Adults, Adolescents and Children with Type 1 
Diabetes 
Protocol Version/Date: 4.0 13 APR 2022 
I have read the protocol specified above. In my formal capacity as a Site Principal Investigator, my duties 
include ensuring the safety of the study participants enrolled under my supervision and providing the Jaeb 
Center for Health Research, which serves as the Coordinating Center for the protocol, with complete and 
timely information, as outlined in the protocol. It is understood that all information pertaining to the study 
will be held strictly confidential and that this confidentiality requirement applies to all study staff at this 
site. 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as required 
by the following: United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
Also, the trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP), and the 
Declaration of Helsinki. 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the sponsor and documented approval from the Institutional Review 
Board (IRB), or other approved Ethics Committee, except where necessary to eliminate an immediate 
hazard(s) to the trial participants. 
All key personnel (all individuals responsible for the design and conduct of this trial) have completed 
Human Participants Protection Training and Good Clinical Practice Training. Further, I agree to ensure 
that all staff members involved in the conduct of this study are informed about their obligations in 
meeting the above commitments. 
Investigator’s Signature __________________________________ 
Date: _____ / _____ / _____ 
 
dd 
mmm 
yyyy 
Investigator’s Name: ____________________________________ 
Site Name/Number: _____________________________________ 
 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Study Sponsor 
Tandem Diabetes Care, Inc. 
Protocol Number 
TP-0009650 
Protocol Title 
Safety Evaluation of an Advanced Hybrid Closed Loop System Using Lyumjev with the 
Tandem t:slim X2 with Control-IQ  in Adults, Adolescents and Children with Type 1 
Diabetes 
Précis 
This is a prospective, multi-center (US only), single-arm study in adults and children (ages 
6 to <81 years) with type 1 diabetes (T1D) who are current users of the t:slim X2 pump 
with Control-IQ technology to evaluate the safety of Lyumjev in the Control-IQ 1.5 System 
to achieve labeling updates for Lyumjev and the t:slim X2 insulin pump with Control-IQ 1.5 
technology. Participants will be current Control-IQ users who will use Humalog with the 
study pump (Control-IQ 1.5) during a ~16 day lead-in during which pump setting 
adjustments may be made in response to observed trends. This will be followed by a 3-
month outpatient treatment period in which participants will use the study pump with 
Control-IQ 1.5 and Lyumjev insulin. 
Exercise and meal challenges will be performed during the lead-in period and the main study 
period. 
Products 
Hybrid Closed Loop System: 
 t:slim X2 pump with Control-IQ 1.5 technology 
 Dexcom G6 system 
Lyumjev (insulin lispro-aabc)  
Objectives 
To evaluate the safety of Lyumjev (insulin lispro-aabc) use in the Tandem t:slim X2 insulin 
pump with Control-IQ 1.5 technology in adult and pediatric participants with diabetes in an 
outpatient setting to support system labeling.  
Number of Sites 
~10-15 clinical sites in the US. 
Study Design 
Single-arm prospective safety trial 
Number of Participants 
Up to 200 participants commencing treatment period so that at least 160 complete study (at 
least 80 participants age 6-<14 years old, and at least 80 participants age 14+). At least 20 
participants will be age 14-<18 years of age. 
 Goal to have at least 1/3 of all completers with HbA1c ≥7.5% 
 Goal to have at least 10 completers with basal insulin rate >3 units/hour (for at least part 
of the day) 
Enrollment will be staged, starting with the 14+ cohort.  After a cumulative 10,000 hours of 
use are reached in the age 14+ cohort, a Trial Level Safety Review of all adverse events and 
device issues will be performed before opening enrollment to the 6-13 year old 
cohort.                                                                                                                                             
Participant Population: 
Eligibility to enroll in the study will be assessed based on the following inclusion 
criteria: 
1. 
Age 6 to <81 years 
2. 
Diagnosis of type 1 diabetes for at least 1 year 
3. 
Currently using Control-IQ technology for at least 3 months, with system use 
(active closed loop) for at least 85% of the possible time in 14 days prior to 
enrollment 
4. 
Total daily insulin dose (TDD) at least 2 U/day 
5. 
HbA1c < 10.5% 
6. 
Residing full-time in the United States, with no anticipated travel outside the 
United States during the period of study participation.  

 
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PARTICIPANT AREA 
DESCRIPTION 
7. 
For participants <18 years old, living with one or more parent/legal guardian 
knowledgeable about emergency procedures for severe hypoglycemia, able 
to contact the participant in case of an emergency, and willing to use the Dexcom 
Follow app (with push notifications turned on) for the duration of the study. 
8. 
If >18 years old, participant has someone who lives within 30 minutes of them 
who is willing to be contacted if the study team can’t reach the participant in case 
of a suspected medical emergency.  
9. 
Participant has agreed to participate in the study; and has read, understood and 
signed the informed consent form (ICF) and assent, if applicable; and has agreed 
to follow all study procedures, including: 
 
suspending use of any personal CGM for the duration of the clinical trial once 
the study CGM is in use 
 
switching to or continuing to use Humalog during the lead-in period 
 
switching to Lyumjev for the main study period. 
 
willing and able to perform the study exercise and meal challenges. 
10. Investigator has confidence that the participant can successfully operate all study 
devices and is capable of adhering to the protocol, including ability to respond to 
alerts and alarms, and to provide basic diabetes self-management. 
11. Participant and/or parent/legal guardian have the ability to read and understand 
English 
Eligibility to enroll in the study will be assessed based on the following exclusion 
criteria:  
1. 
More than 1 episode of diabetic ketoacidosis (DKA) in the past 6 months 
2. 
More than 1 episode of severe hypoglycemia (needing assistance) in the past 6 
months 
3. 
Inpatient psychiatric treatment in the past 6 months  
4. 
History of drug abuse (defined as any illicit drug use) or history of alcohol abuse 
prior to screening or unwillingness to agree to abstain from illicit drugs throughout 
the study.  
5. 
For Female: Currently pregnant or planning to become pregnant during the time 
period of study participation 
 
A negative pregnancy test will be required for all females of child-bearing 
potential (menarchal) 
 
Counseling on appropriate birth control options will be provided to females 
with child-bearing potential in the event the participant does not have an 
acceptable plan. 
6. 
Adults lacking the capacity to provide consent and/or follow study procedures in 
the opinion of the investigator 
7. 
Concurrent use of any non-insulin glucose-lowering agent, other than  metformin 
(for example, GLP-1 agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, 
sulfonylureas). 
8. 
Hemophilia or any other bleeding disorder 
9. 
Hemoglobinopathy 
10. History of heart, liver, lung or kidney disease determined by investigator to 
interfere with the study 
11. History of allergic reaction to Humalog or Lyumjev 
12. Use of glucocorticoids, beta blockers or other medications determined by 
investigator to interfere with study 
13. Abnormal screening electrocardiogram consistent with increased risk during 
exercise, such as arrhythmia, ischemia, or prolonged QTc interval (>450 ms) 

 
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PARTICIPANT AREA 
DESCRIPTION 
(Screening ECG only required for participants age > 50, duration of diabetes > 20 
years, or history of coronary artery disease) 
14. Significant chronic kidney disease (which could impact CGM accuracy in 
investigator’s judgment) or hemodialysis 
15. History of adrenal insufficiency 
16. History of abnormal TSH consistent with hypothyroidism or hyperthyroidism that 
is not appropriately treated 
17. History of gastroparesis 
18. A condition, which in the opinion of the investigator or designee, would put the 
participant or study at risk 
19. Participation in another pharmaceutical or device trial at the time of enrollment or 
anticipated for during the time period of study participation 
20. Employed by, or having immediate family members employed by Tandem 
Diabetes Care, Inc., Eli Lilly and Co., or TypeZero Technologies, LLC, or having 
a direct supervisor at place of employment who is also directly involved in 
conducting the clinical trial (as a study investigator, coordinator, etc.); or having a 
first-degree relative who is directly involved in conducting the clinical trial 
                                                    
Participant Duration 
Approximately 15 weeks (~16 days for run in period followed by 13 weeks of study device 
use with Lyumjev). 
Study Endpoints 
The adult and pediatric populations will be combined for primary analysis. Separate 
secondary analyses also will be performed for the adult and pediatric cohorts. CGM metric 
analyses will be analyzed separately for the challenge days and subsequent nights and not 
included in the overall analyses. 
Primary Safety Endpoints: 
 Severe hypoglycemia (with cognitive impairment such that assistance of another 
individual is needed for treatment) during study compared with data on severe 
hypoglycemic events reported by T1D Exchange clinic registry over a 3-month time 
period. 
 Diabetic ketoacidosis 
 Unanticipated adverse device effects 
 Other serious adverse events 
 Adverse drug reactions 
Secondary Safety Endpoints: 
 All adverse events (including infusion site reactions) 
 CGM hypoglycemia outcomes  (compared with baseline run-in data and separately 
when possible with 4 weeks of pre-study CGM  data collected at enrollment) 
 Overall % time <54 mg/dL 
 Postprandial % time <54 mg/dL (30 min, ≤1, ≤2, ≤4, >1 to ≤2 and >2 to ≤4hr) 
 Overall and postprandial % time <70 mg/dL 
 Rate of hypoglycemia events defined as 15 or more consecutive minutes 
<54 mg/dL 
Exploratory: 
 Postprandial incremental area under the glucose curve (4 hr) 
 Peak postprandial glucose 
 Times in ranges-overall and postprandial (70-180 mg/dL, >180 mg/dL, >250 mg/dL, 
70-140 mg/dL) 
 Mean glucose 
 Rate of hyperglycemia events, defined as 90 or more minutes >300 mg/dL within 
120 minutes 

 
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PARTICIPANT AREA 
DESCRIPTION 
 Overall variability (CV and SD) 
 HbA1c change from baseline   
 Patient-reported outcomes 
Exercise and Meal Challenges: 
 
Endpoints will be CGM metrics and safety outcomes as indicated above 
 
Separate analyses conducted for the overnight following the challenge  
Protocol Overview/Synopsis 
After consent is obtained, eligibility will be assessed. Eligible participants will enter the 
Lead-in Period. 
Lead-in Period: 
The lead-in Period will last approximately 16 days, and may begin the same day the 
screening visit is completed. Participants will switch from their current Control-IQ system 
to the study pump (Control-IQ 1.5 technology) and study sensor, and will be trained by 
qualified study staff on the new study devices including use of Humalog (insulin lispro 
injection). Study participation will require use of the Control-IQ technology with at least 
85% of active closed loop over ~16 days of the lead-in period. The lead-in period data 
collection may be repeated if this threshold is not met. 
A study meal challenge and exercise challenge will be performed with Humalog during the 
lead in period. Those day and overnight periods will be analyzed separately. 
Treatment Period: 
Participants will return to clinic to undergo device training with Lyumjev in the study pump. 
Participants will then use the study pump and the investigational insulin for ~90 days during 
the study period. Participants will have a phone follow up visit at 1 week and 3 weeks, a 
clinic follow up visit at 6 weeks, a phone follow up visit at 9 weeks, and a final clinic visit 
at ~13 weeks. 
Participants will use the t:slim X2 insulin pump with Control-IQ technology turned on with 
the investigational insulin. It is acceptable to use manual mode when there is a loss of CGM 
data. 
Weekly phone/email/text contacts will be performed as part of the comprehensive plan to 
monitor for adverse events, to include infusion site reactions. 
Each participant will perform 3 meal and 3 exercise challenges during Lyumjev use. 
An assessment of adverse events, using open ended questions to capture hyperglycemic and 
hypoglycemic events, and their underlying cause and relationship to the study device, study 
insulin or other parts of the system (such as the infusion set), will occur at all visits/contacts. 
Study Safety Plan:  
Participants will be given a blood glucose and ketone meter to use throughout the study, and 
will be trained on their use by qualified staff. BGM readings will be performed 
in accordance with the study safety plan and per CGM manufacturer instructions. 
Ketone readings will be performed per the study safety plan. 
Site investigators may adjust insulin delivery profile settings as needed throughout the study 
in accordance with their clinical practice. 
 

 
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SCHEMATIC OF STUDY DESIGN 
 
 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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SCHEDULE OF STUDY VISITS AND PROCEDURES 
1 
 
2 
 
3 
a A qualified medical professional must perform a medical assessment at each office visit. During each office visit, the skin 
4 
surrounding the infusion sites should be assessed as part of a focused physical exam. This also applies for all phone visits 
5 
converted to an office visit, as well as unscheduled visits that occur in the office. 
6 
b ECG performed at screening for participants age >50 years, duration of diabetes > 20 years, or history of coronary artery disease 
7 
c TRIM-D, Trim-DD (Diabetes Device), ITSQ (Insulin Treatment Satisfaction Questionnaire) 
8 
 
9 
 
10 
 
11 
 
Screening 
Visit 
CIQ 1.5/ 
Humalog 
Training 
Visit  
CIQ 1.5/ 
Lyumjev 
Training 
Visit 
Control-IQ Use 
 
 
Lead-In 
Start Main 
Trial 
~16 days 
after start 
of Lead-In 
3d 
1w 
2w 
3w 
6w 
9w 
13w 
UV 
Visit (V) or Contact (C) 
V 
V 
V 
C 
C 
C 
C 
V 
C 
V 
V/C 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
 
 
 
Medical history/ 
physical exama 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight, 
blood pressure and pulse 
X 
 
X 
 
 
 
 
 
 
 
 
HbAlc (POC or local lab) 
X 
 
 
 
 
 
 
 
 
 
 
ECG b 
X 
 
 
 
 
 
 
 
 
 
 
Questionnaires/Surveys 
(PRO Assessments)c 
X 
 
 
 
 
 
 
 
 
X 
 
Pregnancy test (females 
of child-bearing potential) 
X 
 
X 
 
 
 
 
 
 
 
 
Assessment of Device Use 
X 
 
X 
 
 
 
 
 
 
 
 
Study system training 
 
X 
X 
 
 
 
 
 
 
 
 
HbA1c (Central Lab) 
 
 
X 
 
 
 
 
 
 
X 
 
AE Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Upload device data 
from home 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
Download device data 
at clinic visit 
X 
X 
X 
 
 
 
 
X 
 
X 
X 

 
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12 
 
13 
Chapter 1: Background Information 
14 
1.1 Introduction 
15 
1.1.1 Tandem X2 Insulin Pump with Control-IQ Technology 
16 
The Tandem X2 insulin pump with Control-IQ technology is an FDA-approved closed-loop control 
17 
(CLC) system based on the control algorithm developed and initially tested in the University of 
18 
Virginia’s DiAs system and then implemented in the inControl system (TypeZero, Technologies, Inc.). 
19 
Use of the Control-IQ system has been extensively tested in adults and children with type 1 diabetes 
20 
(T1D), demonstrating its efficacy and safety when used with insulin lispro (Humalog) or insulin aspart 
21 
(Novolog).1,2 The system is currently approved for ages 6 years and older and it is use in younger children 
22 
is currently being studied (clinical trials.gov NCT04796779). There are over 150,000 users of the 
23 
system since it became commercially available in 2020. A recent evaluation of real-world use of the 
24 
system in 9,451 users age >6 years with at least 12 months of system use found results comparable to 
25 
those found in the randomized trials.3  
26 
Since the initial approval of the system, modifications have been made in the software, which is referred 
27 
to as version 1.5. These modifications include modest usability improvements and other enhancements 
28 
intended to further reduce risk. 
29 
1.1.2 Lyumjev Insulin 
30 
Lyumjev™ is a rapid-acting human insulin analog indicated to improve glycemic control in adults with 
31 
diabetes mellitus. It has a faster onset of action and shorter duration of action than Humalog® (insulin 
32 
lispro). Insulin lispro appears in the bloodstream approximately 1 minute after injection of Lyumjev, 5 
33 
minutes faster than Humalog. In pharmacodynamic euglycemic clamp studies comparing Lyumjev and 
34 
Humalog, onset of action was 10-min faster and duration of action was 44 minutes shorter with Luymjev 
35 
compared to Humalog across all populations and dose range.4 Lyumjev may be given as part of a multiple 
36 
daily insulin regimen or administered via continuous subcutaneous insulin infusion.  This is the first 
37 
clinical trial evaluating Lyumjev with Control-IQ technology. 
38 
   
  
39 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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The differences in insulin lispro PK profiles between LY900014 and Humalog following SC injection 
40 
were similar in children, adolescents, and adults. LY900014 demonstrated an accelerated insulin lispro 
41 
absorption with a reduction in the late exposure and an overall shorter PK duration compared to Humalog. 
42 
Following a single subcutaneous bolus infusion with CSII therapy, there was a trend towards an 
43 
accelerated absorption of insulin lispro and the duration of exposure was shorter with LY900014 whilst 
44 
maintaining a similar overall exposure and maximum concentration compared to Humalog in children and 
45 
adolescents with type 1 diabetes (Lilly Internal data).  
46 
1.2 Rationale 
47 
The rationale for the study is based on the premise that use of an insulin with a more rapid onset of action 
48 
in a CLC system may reduce hyperglycemic excursions, particularly after meals, and may also reduce the 
49 
risk of hypoglycemia due to shorter duration of action. The initial needed determination is that use of 
50 
Lyumjev in the Control-IQ system is safe. 
51 
1.3 Potential Risks and Benefits 
52 
Risks and Benefits are detailed below. Loss of confidentiality is a potential risk; however, data are handled 
53 
to minimize this risk. Hypoglycemia, hyperglycemia and ketone formation are always a risk in participants 
54 
with type 1 diabetes and participants will be monitored for these events. 
55 
1.3.1 Known Potential Risks 
56 
1.3.1.1 Blood Draw 
57 
A venipuncture and/or fingerstick will be performed to obtain blood for HbA1c measurement. 
58 
Venipuncture can cause common reactions like pain, bruising, or redness at the sampling site. 
59 
Less common reactions include bleeding from the sampling site, formation of a small blood clot or 
60 
swelling of the vein and surrounding tissues, and fainting. A fingerstick frequently causes transient pain 
61 
and there may be a small, localized bruise, which may be followed by a small scar that may persist for 
62 
several weeks. The risk of local infection is less than 1 in 1000 with either venipuncture or fingerstick. 
63 
1.3.1.2 CGM and Pump Catheter Risks 
64 
There is a small risk of bleeding where the sensor or infusion set is inserted. There is a small risk for 
65 
developing a local skin infection at the site of CGM sensor placement of pump infusion set placement. 
66 
This may be associated with swelling, redness and pain; and may require antibiotic therapy. Rarely, a 
67 
CGM sensor may break and leave a small portion of the sensor under the skin that may cause redness, 
68 
swelling or pain at the insertion site. 
69 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure the 
70 
CGM, or to secure the insulin infusion sets for the continuous subcutaneous insulin infusion. If these 
71 
reactions occur, different adhesives or “under-taping” (such as with IV 3000, Tegaderm, etc.) will be 
72 
tried, sites will be rotated frequently, and a mild topical steroid cream or other medication may be 
73 
required. Skin irritation or allergic reactions at the infusion site could also occur with infusion of 
74 
insulin. As a new insulin is being used in this study, this is a possible risk. 
75 
1.3.1.3 Hypoglycemia 
76 
As with any person having type 1 diabetes and using insulin, there is always a risk of having 
77 
hypoglycemia. The frequency of hypoglycemia should be no more and possibly less than it would be 
78 
as part of daily living. Symptoms of hypoglycemia can include sweating, jitteriness, and not feeling well. 
79 
There is the possibility of fainting or seizures (convulsions) and that for a few days the participant may 
80 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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not be as aware of symptoms of hypoglycemia. A CGM functioning poorly and significantly over-
81 
reading glucose values could lead to inappropriate insulin delivery. 
82 
1.3.1.4 Risk of Hyperglycemia 
83 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
84 
extended period or if the pump or infusion set is not working properly. A CGM functioning poorly 
85 
and significantly under-reading glucose values could lead to inappropriate suspension of insulin delivery. 
86 
1.3.1.5 Risk of Device Reuse 
87 
The study CGM system is labeled for single use only. The sensor (the component of the system that 
88 
enters the skin) will be single use only. The receiver, if used, is a hand-held device. The transmitter and 
89 
receiver may be reused during the study after cleaning the device using a hospital-approved cleaning 
90 
procedure. The transmitter is attached to the sensor but does not enter the skin. Participants will be 
91 
informed that FDA or relevant national authorities have approved these devices for single use and that 
92 
by using them among multiple patients, bloodborne pathogens (i.e. Hepatitis B) may be spread through 
93 
the use of multiple users. 
94 
The study insulin pump is labeled for single-patient use. During the study, this device may be reused 
95 
after cleaning adhering to a hospital-approved cleaning procedure. All infusion set equipment will be 
96 
single patient use only (infusion set insertion kits, tubing, cartridges etc.)  Participants will be informed 
97 
that FDA or relevant national authorities typically approve the insulin pump device for single use and 
98 
that by using them among multiple patients, bloodborne pathogens (i.e. Hepatitis B) may be spread 
99 
through the use of multiple users. 
100 
The study blood glucose meter and blood ketone meter are labeled for single-patient use. 
101 
During the study, only one person can use each device as there are rare risks that bloodborne 
102 
pathogens (i.e. Hepatitis B) may be spread through the use of multiple users. 
103 
1.3.1.6 Questionnaires 
104 
As part of the study, participants (or their parent/legal guardian) will complete questionnaires which 
105 
include questions about their private attitudes, feelings and behavior related to the investigational 
106 
equipment as well as managing diabetes. It is possible that some people may find these questionnaires to 
107 
be mildly upsetting. Similar questionnaires have been used in previous research and these types of 
108 
reactions have been uncommon. 
109 
1.3.1.7 Potential Risks of the CLC System 
110 
Even though the study system has been tested prior to this study, there is still a risk that parts of the 
111 
system may not function properly. The following are possible reasons the system may deliver too much 
112 
insulin or incorrectly stop insulin delivery: 
113 
 
CGM sensor reads higher or lower than the actual glucose level which increases risk for 
114 
hypoglycemia and hyperglycemia with automated insulin delivery system; 
115 
 
Device malfunctions that could produce a suspension of insulin delivery or over delivery of 
116 
insulin. 
117 
1.3.1.8 Potential Risks of Using Lyumjev 
118 
Potential adverse reactions with Lyumjev are similar to other insulins: hypoglycemia, hypokalemia, 
119 
allergic reactions, injection-site reactions, lipodystrophy, localized cutaneous amyloidosis, pruritus, rash, 
120 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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weight gain, and peripheral edema. Infusion site reactions and discomfort will be carefully monitored for 
121 
in the study. 
122 
1.3.1.9 Other Risks 
123 
Data downloaded from the CGM, pump, and the home glucose and ketone meter will be collected for the 
124 
study. The downloaded data from the participant’s home pump will include data from prior to the date of 
125 
the screening visit and will include data from the period beyond the last 4 weeks prior to screening. Some 
126 
people may be uncomfortable with the researchers' having such detailed information about their daily 
127 
diabetes habits. 
128 
1.3.2 Benefits 
129 
Participants may achieve better glucose control than they are currently achieving using the Control IQ 
130 
system. It is expected that this protocol will yield increased knowledge about using the Control-IQ system 
131 
with Lyumjev insulin that will lead to its becoming approved for use. 
132 
The individual participant may not benefit from study participation. 
133 
1.3.3 Risk Assessment 
134 
Based on the facts that (1) study participants are already using the Control-IQ system, (2),  mitigations 
135 
are in place, and have been tested in prior studies using the investigational device system in the home 
136 
setting, that limit the likelihood of excessive insulin dosing or prolonged withdrawal of insulin, and 
137 
(3) rapid reversal of hypoglycemia and hyperglycemia can be achieved, it is the assessment of the 
138 
investigators that this protocol falls under DHHS 46.405 which is a greater than mimimal risk, but also 
139 
presents prospect of direct benefit to the participants. 
140 
1.4 General Considerations 
141 
The study is being conducted in compliance with the policies described in the study policies document, 
142 
with the ethical principles that have their origin in the Declaration of Helsinki, with the protocol 
143 
described herein, and with the standards of Good Clinical Practice (GCP). 
144 
When feasible, data will be directly collected in electronic case report forms, which will be considered 
145 
the source data. 
146 
The protocol is considered a significant risk device study, due to the fact that the intervention is 
147 
experimental. Therefore, an investigational device exemption (IDE) from the U.S. Food and Drug 
148 
Administration (FDA) is required to conduct the study. 
149 
 
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Chapter 2: Study Enrollment and Lead-in Period 
151 
2.1 Participant Recruitment and Enrollment 
152 
Enrollment will proceed with the goal of having up to 200 participants commencing the treatment period 
153 
so that at least 160 participants complete the trial (approximately 80 participants age 6-<14 years of age, 
154 
and approximately 80 partipants age 14+). At least 20 participants will be age 14-<18 years of age. 
155 
A maximum of 200 individuals may be enrolled into screening (ie, be consented) in the study in order 
156 
to achieve this goal. 
157 
Study participants will be recruited from ~10-15 clinical centers in the United States without regard to 
158 
gender, race, or ethnicity. There is no restriction on the number of participants to be enrolled by each site 
159 
toward the overall recruitment goal. 
160 
In addition, there will be a study-wide goal to have at least 1/3 of completers with baseline HbA1c ≥7.5%; 
161 
and at least 10 completers with basal insulin rate >3 units/hour (for at least part of the day).  
162 
Enrollment will be staged, starting with the 14+ cohort.  After a cumulative 10,000 hours of use are 
163 
reached in the age 14+ cohort, a Trial Level Safety Review of all adverse events and device issues will be 
164 
performed before opening enrollment to the 6-13 year old cohort. Participants in this review will include 
165 
the Medical Monitor, Sponsor personnel, and a medical representative from Eli Lilly. The decision to 
166 
proceed with enrollment of younger participants will be driven by the totality of the safety data including 
167 
any relevant device or drug 
168 
data.                                                                                                                                                                                             
169 
2.1.1 Informed Consent and Authorization Procedures 
170 
Potential eligibility may be assessed as part of a routine-care examination. Before completing any 
171 
procedures or collecting any data that are not part of usual care, electronic informed consent will be 
172 
obtained. 
173 
For potential study participants ≥18 years old, the study protocol will be discussed with the potential 
174 
study participant by study staff. The potential study participant will be given the Informed Consent 
175 
Form to read. Potential study participants will be encouraged to discuss the study with family members 
176 
and their personal physicians(s) before deciding whether to participate in the study. If the potential study 
177 
participant agrees to participate, the Informed Consent Form will be electronically signed through the 
178 
JCHR website. 
179 
For potential participants under 18 years of age, a parent/legal guardian (referred to subsequently as 
180 
“parent”) will be provided with the Informed Consent Form to read and will be given the opportunity 
181 
to ask questions. Potential participants meeting the IRB’s minimum age of assent will be given a Child 
182 
Assent Form to read and discuss with his/her parents and study personnel. If the parent and child agree 
183 
to participate, the child will provide explicit verbal assent and the Informed Consent Form will be 
184 
electronically signed by the parent through the JCHR website. Both the parent and the Investigator must 
185 
attest that the child provided explicit assent. A failure to object or a lack of response shall not be 
186 
construed to be assent. 
187 
A copy of the consent form (and assent form as applicable) will be provided to the participant or the 
188 
participant and his/her parent and another copy will be added to the participant’s study record. 
189 
As part of the informed consent process, each participant/parent will be asked to sign an authorization for 
190 
release of personal information. The investigator, or his or her designee, will review the study-specific 
191 
information that will be collected and to whom that information will be disclosed. After speaking with 
192 
the participant, questions will be answered about the details regarding authorization. 
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LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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A participant is considered enrolled when the informed consent form and authorization have been signed 
194 
by all applicable parties. 
195 
Participants who turn 7 during the course of the study will need to read the Child Assent Form and 
196 
provide explicit verbal assent as attested by the parent and Investigator. Participants who turn 18 during 
197 
the course of the study will need to re-consent and provide re-authorization with an adult Informed 
198 
Consent Form. 
199 
2.2 Participant Eligibility Criteria 
200 
2.2.1 Inclusion Criteria 
201 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate in the 
202 
study. 
203 
1. Age 6 to <81 years 
204 
2. Diagnosis of type 1 diabetes for at least 1 year 
205 
3. Currently using Control-IQ technology for at least 3 months, with CGM data recorded indicative 
206 
of system use (active closed loop) for at least 85% of the possible time in 14 days prior to 
207 
enrollment 
208 
4. Total daily insulin dose (TDD) at least 2 U/day 
209 
5. HbA1c < 10.5% 
210 
6. Residing full-time in the United States, with no anticipated travel outside the United States during 
211 
the period of study participation. 
212 
7. For participants <18 years old, living with one or more parent/legal guardian knowledgeable 
213 
about emergency procedures for severe hypoglycemia and able to contact the participant in case 
214 
of an emergency, and willing to use the Dexcom Follow app (with push notifications turned on) 
215 
for the duration of the study. 
216 
8. If >18 years old, participant has someone who lives within 30 minutes of them who is willing to 
217 
be contacted if the study team can’t reach the participant in case of a suspected medical 
218 
emergency.  
219 
9. Participant has agreed to participate in the study; and has read, understood and signed the 
220 
informed consent form (ICF) and assent, if applicable; and has agreed to follow all study 
221 
procedures, including: 
222 
 
suspending use of any personal CGM for the duration of the clinical trial once the study 
223 
CGM is in use 
224 
 
switching to or continuing to use Humalog during the lead-in period 
225 
 
switching to Lyumjev for the main study period. 
226 
 
willing and able to perform the study exercise and meal challenges. 
227 
10. Investigator has confidence that the participant can successfully operate all study devices and is 
228 
capable of adhering to the protocol, including ability to respond to alerts and alarms, and to 
229 
provide basic diabetes self-management. 
230 
11. Participant and/or parent/legal guardian have the ability to read and understand English  
231 

 
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2.2.2 Exclusion Criteria 
232 
Individuals meeting any of the following exclusion criteria at baseline will be excluded from study 
233 
participation. 
234 
1. More than 1 episode of diabetic ketoacidosis (DKA) in the past 6 months 
235 
2. More than 1 episode of severe hypoglycemia (needing assistance) in the past 6 months 
236 
3. Inpatient psychiatric treatment in the past 6 months 
237 
4. History of drug abuse (defined as any illicit drug use) or history of alcohol abuse prior to 
238 
screening or unwillingness to agree to abstain from illicit drugs throughout the study. 
239 
5. For Female: Currently pregnant or planning to become pregnant during the time period of study 
240 
participation 
241 
 
A negative pregnancy test will be required for all females of child-bearing potential 
242 
(menarchal) 
243 
 
Counseling on appropriate birth control options will be provided to females with child-
244 
bearing potential in the event the participant does not have an acceptable plan. 
245 
6. Adults lacking the capacity to provide consent and/or follow study procedures in the opinion of 
246 
the investigator  
247 
7. Concurrent use of any non-insulin glucose-lowering agent, other than  metformin (for example, 
248 
GLP-1 agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas). 
249 
8. Hemophilia or any other bleeding disorder 
250 
9. Hemoglobinopathy 
251 
10. History of heart, liver, lung or kidney disease determined by investigator to interfere with the 
252 
study 
253 
11. History of allergic reaction to Humalog or Lyumjev 
254 
12. Use of glucocorticoids, beta blockers or other medications determined by investigator to interfere 
255 
with study 
256 
13. Abnormal screening electrocardiogram consistent with increased risk during exercise, such as 
257 
arrhythmia, ischemia, or prolonged QTc interval (>450 ms) (Screening ECG only required for 
258 
participants age > 50 years, duration of diabetes > 20 years, or history of coronary artery disease) 
259 
14. Significant chronic kidney disease (which could impact CGM accuracy in investigator’s 
260 
judgment) or hemodialysis 
261 
15. History of adrenal insufficiency 
262 
16. History of abnormal TSH consistent with hypothyroidism or hyperthyroidism that is not 
263 
appropriately treated 
264 
17. History of gastroparesis 
265 
18. A condition, which in the opinion of the investigator or designee, would put the participant or 
266 
study at risk 
267 
19. Participation in another pharmaceutical or device trial at the time of enrollment or anticipated for 
268 
during the time period of study participation 
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LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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20. Employed by, or having immediate family members employed by Tandem Diabetes Care, Inc., 
270 
Eli Lilly and Co., or TypeZero Technologies, LLC, or having a direct supervisor at place of 
271 
employment who is also directly involved in conducting the clinical trial (as a study investigator, 
272 
coordinator, etc.); or having a first-degree relative who is directly involved in conducting the 
273 
clinical trial 
274 
2.3 Screening Procedures 
275 
After informed consent has been signed, a potential participant will be evaluated for study eligibility 
276 
through the elicitation of a medical history, performance of a physical examination by study personnel 
277 
and local laboratory testing if needed to screen for exclusionary medical conditions. 
278 
2.3.1 Data Collection and Testing 
279 
A standard physical exam (including vital signs and height and weight measurements) will be performed 
280 
by the study investigator or designee (a physician, fellow, nurse practitioner or a physician assistant). 
281 
The following procedures will be performed/data collected/eligibility criteria checked and documented: 
282 
 
Inclusion and exclusion criteria assessed 
283 
 
Demographics (date of birth, sex, race and ethnicity) 
284 
 
Contact information (retained at the site and not entered into study database) 
285 
 
Medical history 
286 
 
Substance use history (drinking, smoking, and drug habits) 
287 
 
Concomitant medications 
288 
 
Physical examination to include: 
289 
 
Weight, height 
290 
 
Vital signs including measurement of blood pressure and pulse 
291 
 
Blood draw (venipuncture or fingerstick) for local HbA1c measurement 
292 
 
Urine pregnancy test (test not required for any female that has not reached menarche, is surgically 
293 
sterile, or is at least 1 year post-menopausal) 
294 
 
For those not excluded from testing, counseling on appropriate birth control options will be 
295 
provided in the event the participant does not have an acceptable plan. 
296 
 
ECG performed at screening for participants age > 50 years, duration of diabetes > 20 years, or 
297 
history of coronary artery disease 
298 
 
Completion of the following patient-reported outcomes (PRO) surveys by the participant 
299 
(age 14+) or parent: TRIM-D, Trim-DD (Diabetes Device), ITSQ (Insulin Treatment Satisfaction 
300 
Questionnaire) 
301 
Screening procedures will last approximately 1-2 hours. 
302 
2.4 Screen Failures 
303 
Individuals who do not initially meet study eligibility requirements may be rescreened one more time at a 
304 
later date per investigator discretion. 
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2.5 Lead-in Period 
306 
All participants will complete the Lead-in Period as an outpatient for approximately 16 days. The Lead-in 
307 
Period may begin the same day the screening visit is completed or within 4 weeks after informed consent 
308 
is signed. The lead-in period will last at least 16 days and no more than 21 days. 
309 
At the initiation of the Lead-in Period (CIQ 1.5/ Humalog Training Visit), participants will switch from 
310 
their current Control-IQ system to the study pump (Control-IQ 1.5 technology), study sensor, and study-
311 
provided Humalog (insulin lispro injection). Training will be provided by qualified study staff on the 
312 
study pump, the study CGM sensor, the study glucose meter, and the study ketone meter. The study 
313 
investigator may adjust insulin delivery profile settings as indicated.  
314 
During the lead-in period, each participant will perform one meal and exercise challenge to determine a 
315 
baseline using Humalog and Control-IQ 1.5. Those day and overnight periods will be analyzed separately. 
316 
Procedures are described in section 5.1. A minimum of 48 hours will occur between all challenges for 
317 
each participant. 
318 
After 16 days (and up to 21 days), the participant will have a visit. System use will be assessed and to 
319 
proceed to the Treatment Period, it is necessary that a participant used the Control-IQ system, with at 
320 
least 85% of system use (active closed loop) reported over the time of the lead-in period (ie, minimum of 
321 
85% of 14 days). 
322 
The lead-in period data collection may be repeated if this threshold is not met. 
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Chapter 3: Treatment Period 
324 
3.1 CIQ 1.5/ Lyumjev Training Visit 
325 
At the end of the Lead-in Period, participants will have a clinic visit at which their use of the CIQ 1.5 
326 
system with Humalog will be assessed. Participants who successfully used the system with at least 
327 
85% of system use (active closed loop) will undergo device training with Lyumjev in the study pump.  
328 
A blood sample (venipuncture or fingerstick) will be obtained to send to the central laboratory for 
329 
HbA1c measurement. 
330 
Participants will receive supplies for blood glucose and ketone testing. QC testing will be performed on 
331 
the meters before they are dispensed. 
332 
3.1.1 Training on System Use 
333 
All participants will receive study system training from a qualified trainer. Since all of the participants 
334 
will be experienced Control-IQ users, the amount of training will be customized for each participant. 
335 
For pediatric participants, a parent (or legal guardian) will be required to attend the training procedures. 
336 
At a minimum training will include the following: 
337 
 
Calibration of the CGM in accordance with manufacturer labeling 
338 
 
Use of Lyumjev in the study pump 
339 
 
Procedures for treating severe hypoglycemia 
340 
 
Procedures for identifying potential infusion set failure and steps to take including the checking 
341 
of the blood ketone level and changing the infusion set 
342 
The participant will be given a User Guide as a reference as well as Hypoglycemia and Hyperglycemia 
343 
Guidelines. 
344 
Participants will be instructed to download the study device prior to each phone contact or office visit. 
345 
The participant will be instructed to use the system in closed-loop mode except 1) when no calibrated 
346 
CGM sensor is available or 2) if insulin is delivered by any means other than the study pump (e.g. 
347 
injection of subcutaneous insulin via syringe in the event of infusion site failure). If insulin is delivered 
348 
by any means other than the study pump, participant will be instructed to turn off Control-IQ for four 
349 
hours. 
350 
The participant will also be instructed to contact study staff during periods of illness with an elevated 
351 
temperature >101.5 degrees Fahrenheit (38.6 degrees Celsius), periods of significant illness, or during 
352 
periods of use of medications such as epinephrine for the emergency treatment of a severe allergic 
353 
reaction or asthma attack in addition to use of oral or injectable glucocorticoids to determine if closed-
354 
loop use should be temporarily discontinued. 
355 
Participants will be provided with contact information and will be asked to call the study clinical staff 
356 
for any health-related issues and for technical issues with the system. Participants may use the study 
357 
pump without Control-IQ activated and study CGM during periods of component disconnections or 
358 
technical difficulties. 
359 
Adult participants may use available manufacturer-provided CGM software and features of the study 
360 
CGM related to mobile data access or remote monitoring, but will be instructed not to use any third-party 
361 
components for this purpose. For pediatric participants, the parent/caregiver will use the Dexcom Follow 
362 
app (with push notifications turned on) for the duration of the study. 
363 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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The t:connect mobile app from Tandem Diabetes Care will not be available for use during the trial, and 
364 
will not pair to the study pump. 
365 
Study staff will discuss with the participant that routine contact is required and will make arrangements 
366 
with the participant for the contacts. If the participant cannot be reached, the participant’s other contact 
367 
methods will be utilized, including the emergency contact. Participants who are not compliant with the 
368 
arranged contacts on two separate occasions may be discontinued at the discretion of the investigator. 
369 
Following the CIQ 1.5/Lyumjev Training Visit, participants will use the study pump and the 
370 
investigational insulin for ~90 days during the Treatment Period. 
371 
3.1.2 Training on Management of Hypoglycemia 
372 
The t:slim X2 with Control-IQ system will issue a predictive hypoglycemia alert (Control-IQ Low Alert) 
373 
when the system predicts BG <70 mg/dL within the next 15 minutes (<80 mg/dL when exercise mode is 
374 
activated). Participants will be permitted to change the CGM low glucose threshold alert setting on their 
375 
device or mobile app, but will be instructed to choose a value no less than 70 mg/dL. 
376 
If the participant receives a Control-IQ Low Alert, a message appears on the user interface (UI) that is 
377 
accompanied by vibration followed by vibrations and/or sound if not acknowledged by the user in 5 
378 
minutes. This alert remains on the screen until acknowledged by the participant. The user is prompted 
379 
to test blood glucose and treat with carbohydrate. 
380 
The participant and companion if available will be instructed that if severe hypoglycemia occurs, the 
381 
study pump’s insulin delivery should be suspended and glucagon administration if the participant is 
382 
unable to consume carbohydrate. 
383 
Participants will be required to have a home glucagon emergency kit. Participants who currently do not 
384 
have one will be given a prescription for the glucagon emergency kit. 
385 
3.1.3 Training on Management of Hyperglycemia 
386 
The t:slim X2 with Control-IQ system will issue a predictive hyperglycemia alert (Control-IQ High Alert) 
387 
when the system has increased insulin delivery, but detects a CGM value above 200 mg/dL and does not 
388 
predict the value will decrease in the next 30 minutes. During the course of the study, participants will be 
389 
permitted to change the CGM high glucose threshold alert setting on their device or mobile app, but will 
390 
be instructed to choose a value no greater than 300 mg/dL. 
391 
If the participant receives a Control-IQ High Alert, a prompt appears on the user interface to check the 
392 
site for occlusion and test blood glucose. 
393 
If a participant’s CGM reading is >300 mg/dL for more than 60 minutes or is ≥400 mg/dL at any point, 
394 
the participant will be instructed to take the following steps: 
395 
 
Perform a blood glucose meter check. 
396 
 
If the blood glucose is >300 mg/dL, check for blood ketones with the study ketone meter. 
397 
 
If the ketone level is ≥ 0.6 mmol/L (or ≥ 2.5 mmol\L at any time), take correction insulin, change 
398 
insulin (pump) infusion site and contact study staff. Continue to monitor their glucose and blood 
399 
ketone levels until they return to normoglycemia and ketones are < 0.6 mmol/l. 
400 
 
If ketones are <0.6 mmol/l, they will be advised to continue to monitor their glucose until it 
401 
returns to normoglycemia and to repeat the ketone measurement in 90 minutes if necessary 
402 
 
If correction insulin is administered via insulin syringe, turn Control-IQ off for four hours and 
403 
until glucose level has returned to <180 mg/dL. 
404 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 27 OF 52 
3.1.4 Participant Reporting of Infusion Set Insertion Reactions 
405 
Participants will receive a weekly contact (phone, email and/or text message) to assess any issues related 
406 
to their current infusion site.  
407 
Participants will be instructed to take a photo at time of removal of the first 2 infusion sets and 
408 
subsequently photo at the time of removal only if there is redness on skin when the infusion set is 
409 
removed. Additional photos may be needed if during a virtual visit, video is not available. 
410 
3.1.5 Adjustments in Insulin Pump Settings 
411 
Insulin and glucose data from the Lead-in Period will be reviewed and the site investigator may adjust 
412 
insulin delivery profile settings as needed in accordance with their clinical practice. 
413 
3.2 Study Visits and Phone Contacts 
414 
Participants will have a phone (or video-conference) follow-up visit at 3 days, 1 week, 2 weeks, and 3 
415 
weeks, a clinic follow-up visit at 6 weeks, a phone follow-up visit at 9 weeks, and a final clinic visit at 13 
416 
weeks, within the windows specified below. 
417 
TARGET 
DAY/WEEK 
VISIT OR 
PHONE 
TARGET WINDOW 
(AROUND TARGET 
DAY/WEEK) 
3 day 
P 
+1 day 
1 week 
P 
+2 days 
2 week 
P 
+2 days 
3 weeks 
P 
+7 days 
6 weeks 
V 
+7 days 
9 weeks 
P 
+7 days 
13 weeks 
V 
91-98 days 
If necessary, visits should be completed out-of-window rather than missed. A visit is not considered 
418 
missed until the next visit/phone window opens.  
419 
The goal will be for all participants to complete all scheduled visits. However, participants who 
420 
(because of unforeseen circumstances or due to changes in contact precautions that may be needed 
421 
during the evolving COVID-19 pandemic) are unable or unwilling to return for all follow-up visits 
422 
will be permitted to return for key visits only as an alternative to withdrawal from the study. When a 
423 
participant is placed into this status, missed visits will not be recorded as protocol deviations (since 
424 
they would not be recorded as protocol deviations if the participant was dropped from the study). 
425 
Additional office visits may occur as needed. 
426 
3.2.1 Procedures During Phone Contacts 
427 
Phone contacts can be with or without video. Phone contacts will include the following: 
428 
 
Assessment of device issues that have occurred 
429 
 
Assessment of adverse events (such as hyperglcyemia, hypoglcyemia, and infusion set reactions) 
430 
using open ended questions, and their underlying cause and relationship to the study device, study 
431 
insulin or other parts of the system (such as the infusion set). 
432 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 28 OF 52 
 
Completion of a detailed case report form with respect to any infusion site reactions that have 
433 
occurred. 
434 
For the first three contacts (3 day, 1 week, 2 week), if a video virtual visit can be done, visual inspection 
435 
will be performed of the current and most recent infusion set insertion site. If video is not possible, then 
436 
the participant will be requested to take a photo of the current and most recent infusion set insertion sites. 
437 
3.2.2 Procedures at Study Visits 
438 
The following procedures will be performed at each visit, unless otherwise specified: 
439 
 
Review of study device data 
440 
 
Assessment of compliance with study device use by review of any available device data 
441 
 
Assessment of device issues that have occurred 
442 
 
Assessment of adverse events, using open ended questions to capture hyperglycemic and 
443 
hypoglycemic events, and their underlying cause and relationship to the study device, study 
444 
insulin or other parts of the system (such as the infusion set). 
445 
 
A focusesd physical exam to include skin and infusion sites will be performed at each in person 
446 
visit. 
447 
 
Completion of a detailed case report form with respect to any infusion site reactions that have 
448 
occurred. 
449 
At 13 weeks, the following additional procedures will be performed: 
450 
 
Blood draw (venipuncture or fingerstick) for HbA1c measurement at central lab (13 weeks only) 
451 
 
Completion of the following PRO surveys by the participant (age 14+) or parent: TRIM-D, 
452 
Trim-DD (Diabetes Device), ITSQ (Insulin Treatment Satisfaction Questionnaire) 
453 
3.2.3 Unscheduled Visits 
454 
Participants may have unscheduled visits during the study period if required for additional device training 
455 
or other unanticipated needs per the study investigator discretion. 
456 
3.3 Exercise and Meal Challenges 
457 
Participants will complete 3 meal and 3 exercise challenges during Lyumjev use. Procedures are 
458 
described in section 5.1. 
459 
3.4 Early Discontinuation of Study Device 
460 
Participants who discontinue the study device prior to 13 weeks, either by choice or by investigator 
461 
decision, will be asked to come for an end of study visit and then will be dropped from the study. 
462 
If the visit occurs at 6 weeks or after, blood will be drawn for the central-lab HbA1c measurement and 
463 
the PROs will be completed. 
464 
 
465 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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Chapter 4: Study Devices and Drugs 
466 
4.1 Study Devices 
467 
The investigational device (CLC system) includes an insulin pump and a continuous glucose monitor. 
468 
4.1.1 Insulin Pump 
469 
The study system will include the Tandem t:slim X2 with Control-IQ technology. 
470 
4.1.2 Continuous Glucose Monitoring 
471 
The study CGM that is part of the CLC system is the Dexcom G6, which includes a transmitter and 
472 
sensors. The CGM sensor will be replaced at least once every 10 days. 
473 
4.1.3 Blood Glucose Meter 
474 
The study blood glucose meter is the Contour® NEXT (Ascencia Diabetes Care). 
475 
Blood glucose levels will be measured using the study’s blood glucose meter (glucometer) and the 
476 
CGM device will be calibrated if needed using the study glucometer and strips in accordance with the 
477 
manufacturer’s labeling. 
478 
4.1.4 Ketone Meter 
479 
The study blood ketone meter is the Precision Xtra Blood Glucose and Ketone Monitoring System 
480 
(Abbott Diabetes Care ). 
481 
Blood ketone levels will be measured when needed to evaluate prolonged hyperglycemia. The blood 
482 
glucose meter component of the Precision Xtra device will not be used. 
483 
4.2 Study Drug 
484 
The study drug is Lyumjev (insulin lispro-aabc). The drug is a formulation of insulin lispro that includes 
485 
the addition of two excipients, treprostinil and sodium citrate. Treprostinil enhances absorption by local 
486 
vasodilatation without eliciting a systemic effect while citrate further enhances the speed of absorption. 
487 
 
Acquisition 
488 
Study drug will be shipped by Eli Lilly to the study’s central pharmacy for distribution to the 
489 
clinical sites. 
490 
 
Formulation, Appearance, Packaging, and Labeling 
491 
LYUMJEV (insulin lispro-aabc) injection is a sterile, aqueous, clear, and colorless solution for 
492 
subcutaneous or intravenous administration. Each mL of LYUMJEV U-100 contains 100 units of 
493 
insulin lispro-aabc and the inactive ingredients: glycerol (12.1 mg), magnesium chloride 
494 
hexahydrate (1.02 mg), metacresol (3.15 mg), sodium citrate dihydrate (4.41 mg), treprostinil 
495 
sodium (1.06 mcg), zinc oxide (content adjusted to provide 39 mcg zinc ion), and Water for 
496 
Injection, USP. 
497 
 
Product Storage and Stability 
498 
Dispense in the original sealed carton with the enclosed Instructions for Use.  
499 
Refrigerate unopened LYUMJEV vials between 36°F to 46°F (2°C to 8°C) until time of use and 
500 
keep in the original carton to protect from light. Do not freeze or use LYUMJEV if it has been 
501 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 30 OF 52 
frozen. Do not expose to direct heat. Discard opened or unopened LYUMJEV vials stored at 
502 
room temperature below 86°F (30°C) after 28 days.  
503 
Change the LYUMJEV U-100 in the pump reservoir at least every 9 days, or according to the 
504 
pump user manual, whichever is shorter, or after exposure to temperatures that exceed 98.6°F 
505 
(37°C). 
506 
  
507 
  
Not in-use 
(Unopened) 
In-use 
(Opened) 
  
Room Temperature 
(below 86 F [30 C]) 
Refrigerated 
(36 F to 46 F [2 C to 
8 C]) 
Room 
Temperature 
(below 86 F [30 C]) 
Refrigerated 
(36 F to 46 F [2 C to 
8 C]) 
10 mL 
vial a,b 
28 days 
Until expiration 
date 
28 days 
28 days 
a In-use (opened) vials, whether or not refrigerated, must be used within 28 days.  
508 
b When stored at room temperature, LYUMJEV can only be used for a total of 28 days including 
509 
both not in-use (unopened) and in-use (opened) storage time.  
510 
  
511 
4.3 Study Device and Drug Accountability Procedures 
512 
Device and drug accountability procedures will be detailed in the clinical center procedures manual. 
513 
4.4 Participant Access to Study Device at Study Closure 
514 
Participants will return all investigational study devices and supplies (insulin pump, CGM and related 
515 
supplies, and unused insulin) at their final visit. Participant may keep the study ketone meter and study 
516 
glucometer if these devices are not marked for investigational use only. 
517 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 31 OF 52 
Chapter 5: Testing Procedures and Questionnaires 
518 
5.1 Meal and Exercise Challenges 
519 
Participants will complete 1 missed meal bolus and 1 exercise challenge during the Humalog lead-in 
520 
period, then 3 meal and 3 exercise challenges during Lyumjev use.  
521 
A minimum of 48 hours will occur between all challenges for each participant. 
522 
Participants will be instructed to communicate with study staff within one day prior to each challenge to 
523 
review procedures and to have a contact with study staff after the completion of each challenge. 
524 
5.1.1 Meal Challenges 
525 
The same meal should be used for each of the four meal challenges—either lunch or dinner (participant 
526 
choice).  
527 
For the lead-in phase meal challenge, no bolus will be given for the meal.  
528 
During Lyumjev use, the three meal challenges will consist of: 
529 
 
No bolus for the meal 
530 
 
50% bolus - calculate the bolus dose using the bolus calculator, and deliver half the 
531 
recommended dose of insulin. 
532 
 
Full bolus for the meal based on calculated bolus dose using the bolus calculator. 
533 
 For each meal challenge, participants will: 
534 
1. Be in a fasting state for two hours prior to consuming the meal and the last manual insulin bolus 
535 
more than two hours ago.   
536 
2. Only begin the meal challenge if the glucose is between 70 mg/dL and 200 mg/dL.  Subjects with 
537 
hyperglycemia > 200mg/dL will reschedule their challenge for another time. If < 70 mg/dL, 
538 
carbohydrate treatment can be given and then continue. 
539 
3. Consume at least 50 grams carbohydrate for the meal. Each participant will use the same meal 
540 
for all of their meal challenges in the study. Participants will be encouraged to use the same 
541 
frozen entrée of their choice for consistency. 
542 
4. Write down the start and end time of eating the meal, as well as the meal content (to include 
543 
amount of carbohydrate, protein and fat) on the study provided logbook. 
544 
5. Not give an additional bolus for up to 3 hours after the meal challenge, unless BG is above 300 
545 
mg/dL for more than 1 hour, or symptoms of hyperglycemia develop. 
546 
6. Not take additional carbohydrates for up to 3 hours after the meal challenge, unless BG is < 70 
547 
mg/dL, or symptoms of hypoglycemia develop. 
548 
7. Not exercise for 3 hours after the meal challenge. 
549 
For pediatric participants, caregivers/parents will be instructed to:  
550 
 
Be physically present with the participant and monitor CGM glucose during the 3 hours of 
551 
each meal bolus challenge timeline. 
552 
 
Follow the study hypoglycemia and hyperglycemia safety guidelines, as well as the above 
553 
guidelines for the challenge. 
554 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 32 OF 52 
 
Be in same residence with the participant for the overnight period after the challenges and to 
555 
continue to monitor the participant. 
556 
5.1.2 Exercise Challenges 
557 
For each exercise challenge, participants will: 
558 
1. Have extra carbohydrate containing snacks and glucagon on hand during and after exercise. 
559 
2. Per their usual routine and investigator guidance, consider activation of “exercise activity” on the 
560 
pump up to 45 minutes ahead of actual exercise, to allow for less insulin on board when starting 
561 
exercise. 
562 
3. Consider reducing the last meal bolus prior to exercise as a way to reduce insulin on board and 
563 
limit hypoglycemia. 
564 
4. Perform two hours of exercise, including at least one hour of moderate activity 
565 
5. Only begin exercise if CGM glucose is ≥ 120 mg/dL and CGM glucose is not trending 
566 
downward.  
567 
6. Write down the time of last meal and amount and time of last insulin dose, type of exercise 
568 
performed, as well as the start and stop time of each exercise session in the study logbook (as this 
569 
may not correlate exactly with exercise activity use on the pump). 
570 
7. Stop the exercise challenges at any point for injury or development of new symptoms 
571 
(development of chest pain/pressure, feeling unwell, development of hypoglycemic symptoms, 
572 
undue shortness of breath, signs of poor perfusion (leg pain/claudication), or for any other reason. 
573 
8. Notify the site within 24 hours after completion of each exercise challenge if they develop new 
574 
symptoms and review guidance on the need to stop future exercise challenges if any adverse 
575 
events or new symptoms occurred per clinician judgement based on the severity of symptoms. 
576 
For pediatric participants, caregivers/parents will be instructed to:  
577 
 
Be physically present with the participant and monitor CGM glucose during and through 2 hours 
578 
after the exercise challenge completes. 
579 
 
Follow the study hypoglycemia and hyperglycemia safety guidelines, as well as the above 
580 
guidelines for the challenge. 
581 
 
Be in same residence with the participant for the overnight period after the challenges to continue 
582 
to monitor the participant. 
583 
5.2 Laboratory Testing 
584 
5.2.1 HbA1c 
585 
HbA1c measurement will be performed locally at the Screening visit. 
586 
An additional blood sample will be obtained (venipuncture or fingerstick) and sent to central lab at the 
587 
CIQ 1.5/Lyumijev Training visit and at the 13-week visit. 
588 
5.2.2 Urine Pregnancy 
589 
Urine pregnancy testing performed locally at clinical site for females of child-bearing potential at the 
590 
Screening visit and anytime pregnancy is suspected. 
591 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 33 OF 52 
5.3 Questionnaires 
592 
Questionnaires are completed during Screening and at the time of the 13-week visit. Each questionnaire 
593 
is described briefly below. Questionnaires will be completed by participants age 14 years and older, and 
594 
by parent/guardian for younger participants. The procedures for administration are described in the study 
595 
procedures manual. 
596 
Each questionnaire is described briefly below. The procedures for administration are described in the 
597 
study procedures manual. 
598 
MEASURE 
DESCRIPTION 
Treatment Related Impact Measure of Diabetes (TRIM-D) 
28-item measure with 5 domains assessing treatment burden, 
daily life, diabetes management, compliance and 
psychological health. Higher score indicates a better health 
state 
Treatment Related Impact Measure of Diabetes Device 
(TRIM-DD) 
8-item measure with 2 domains assessing Device Bother and 
Device Function. Higher score indicates a better health state 
Insulin Treatment Satisfaction Questionnaire (ITSQ) 
22-item measure with a 5-factor structure assessing insulin 
satisfaction: satisfaction with insulin delivery device, glycemic 
control, hypoglycemic control, convenience of regimen and 
lifestyle flexibility. Scores range from 0 to 100 with higher 
score indicating a better health state 
 
599 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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Chapter 6: Unanticipated Problem, Adverse Event, and 
600 
Device Issue Reporting 
601 
6.1 Unanticipated Problems 
602 
Site investigators will promptly report to the Coordinating Center on an eCRF all unanticipated problems 
603 
meeting the criteria below. Sites overseen by the JCHR IRB must report Unanticipated Problems to the 
604 
IRB within seven calendar days of recognition. For this protocol, an unanticipated problem is an incident, 
605 
experience, or outcome that meets all of the following criteria: 
606 
 
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
607 
described in the protocol related documents, such as the IRB-approved research protocol and 
608 
informed consent document; and (b) the characteristics of the subject population being studied 
609 
 
Related or possibly related to participation in  the research (possibly related means there is a 
610 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
611 
procedures involved in the research) 
612 
 
Suggests that the research places participants or others at a greater risk of harm than was 
613 
previously known or recognized (including physical, psychological, economic, or social harm) 
614 
The Coordinating Center also will report to the IRB all unanticipated problems not directly involving a 
615 
specific site such as unanticipated problems that occur at the Coordinating Center or at another 
616 
participating entity such as a pharmacy or laboratory. These instances must be reported to the JCHR IRB 
617 
within seven calendar days of recognition. The Director of the Human Research Protection Program 
618 
(HRPP) will report to the appropriate regulatory authorities to fulfill the obligations of the HRPP if the 
619 
IRB determines that the event indeed meets the criteria of an Unanticipated Problem requiring additional 
620 
reporting. 
621 
6.2 Adverse Events 
622 
6.2.1 Definitions 
623 
Adverse Event (AE): Any untoward medical occurrence (including laboratory findings) associated with 
624 
study procedures, the use of a device, biologic in a study participant, including any comparator used, 
625 
irrespective of the relationship between the adverse event and the device(s) under investigation (referred 
626 
to as Adverse Reaction when caused by a drug). 
627 
Serious Adverse Event (SAE): Any untoward medical occurrence that meets at least one of the following: 
628 
 
Results in death. 
629 
 
Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
630 
become life-threatening, is not necessarily considered a serious adverse event). 
631 
 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
632 
 
Results in persistent or significant disability/incapacity or substantial disruption of the ability 
633 
to conduct normal life functions (sight threatening). 
634 
 
Is a congenital anomaly or birth defect. 
635 
 
Is considered a significant medical event by the investigator based on medical judgment (e.g., 
636 
may jeopardize the participant or may require medical/surgical intervention to prevent one of 
637 
the outcomes listed above). 
638 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 35 OF 52 
Suspected Adverse Reaction: any adverse event for which there is a reasonable possibility that the drug 
639 
caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means there 
640 
is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse 
641 
reaction implies a lesser degree of certainty about causality than adverse reaction, which means any 
642 
adverse event caused by a drug (21 CFR 312.32(a)). 
643 
Suspected Unexpected Serious Adverse Reaction (SUSAR): any adverse event considered to be related 
644 
to a drug that is both unexpected and meets criteria for an SAE. Unexpected means that the adverse 
645 
reaction is not listed in the investigator brochure or protocol 21 CFR 312.32(a). 
646 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or any 
647 
life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death 
648 
was not previously identified in nature, severity, or degree of incidence in the investigational plan or 
649 
application (including a supplementary plan or application), or any other unanticipated serious problem 
650 
associated with a device that relates to the rights, safety, or welfare of participants (21 CFR 812.3(s)). 
651 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which the device 
652 
may have caused or to which the device may have contributed (Note that an Adverse Event Form is to be 
653 
completed in addition to a Device Deficiency or Issue Form, unless excluded from reporting as defined in 
654 
section 6.2.2). 
655 
Comparator: Medical device, therapy (e.g. active treatment, normal clinical practice), placebo or no 
656 
treatment, used in the control group in a clinical investigation. (ISO 14155:2020) 
657 
Device Complaints and Malfunctions: A device complication or complaint is something that happens 
658 
to a device or related to device performance, whereas an adverse event happens to a participant. A device 
659 
complaint may occur independently from an AE, or along with an AE. An AE may occur without a 
660 
device complaint or there may be an AE related to a device complaint. A device malfunction is any 
661 
failure of a device to meet its performance specifications or otherwise perform as intended. 
662 
Performance specifications include all claims made in the labeling for the device. The intended 
663 
performance of a device refers to the intended use for which the device is labeled or marketed. 
664 
(21 CFR 803.3). Note: for reporting purposes, sites will not be asked to distinguish between device 
665 
complaints and malfunctions. 
666 
Use Error: User action or lack of user action while using the medical device (3.34) that leads to a 
667 
different result than that intended by the manufacturer or expected by the user. Includes the inability of 
668 
the user to complete a task. Use errors can result from a mismatch between the characteristics of the user, 
669 
user interface, task or use environment. Users might be aware or unaware that a use error has occurred. 
670 
An unexpected physiological response of the patient is not by itself considered a use error. A malfunction 
671 
of a medical device that causes an unexpected result is not considered a use error. (ISO 14155:2020) 
672 
6.2.2 Reportable Adverse Events 
673 
A reportable adverse event includes all events meeting the definition of an adverse event, except for the 
674 
following: 
675 
 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
676 
events unless associated with an Adverse Device Effect or discontinuation of the study device or 
677 
study drug.  
678 
 
Skin reactions from sensor or pump infusion set placement are only reportable as everse advents 
679 
if severe and/or required treatment (see section 6.2.5). 
680 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 36 OF 52 
All reportable AEs—whether volunteered by the participant, discovered by study personnel during 
681 
questioning, or detected through physical examination, laboratory test, or other means—will be reported 
682 
on an AE form online. Each AE form is reviewed by the Medical Monitor to assess safety and to verify 
683 
the coding and the reporting that is required. 
684 
6.2.3 Hypoglycemic Events 
685 
Hypoglycemia not associated with an Adverse Device Effect or discontinuation of the study device or 
686 
study drug is only reportable as an adverse event when one of the following criteria is met: 
687 
 
a hypoglycemic event occurred meeting the following definition of severe hypoglycemia:  the 
688 
event required assistance of another person due to altered consciousness, and required another 
689 
person to actively administer carbohydrate, glucagon, or other resuscitative actions. This means 
690 
that the participant was impaired cognitively to the point that he/she was unable to treat 
691 
himself/herself, was unable to verbalize his/ her needs, was incoherent, disoriented, and/or 
692 
combative, or experienced seizure or loss of consciousness. These episodes may be associated 
693 
with sufficient neuroglycopenia to induce seizure or loss of consciousness. If glucose 
694 
measurements are not available during such an event, neurological recovery attributable to the 
695 
restoration of glucose to normal is considered sufficient evidence that the event was induced by 
696 
a low glucose concentration. 
697 
 
evaluation or treatment was obtained at a health care provider facility for an acute event involving 
698 
hypoglycemia, or the participant contacted the site and received guidance following the 
699 
occurrence of an acute event involving hypoglycemia 
700 
When a severe hypoglycemia event occurs (as defined above), a Hypoglycemia Form should be 
701 
completed in addition to the Adverse Event Form. Severe hypoglycemia events should be considered 
702 
to be serious adverse events with respect to reporting requirements. When a severe hypoglycemia event 
703 
occurs during use of a study device, it generally will be considered to be unrelated to the device (per 
704 
section 6.2.6) if the device functioned as intended and there does not appear to be a flaw in how the 
705 
device is intended to function. 
706 
6.2.4 Hyperglycemic/Ketotic Events 
707 
Hyperglycemia not associated with an Adverse Device Effect or discontinuation of the study device or 
708 
study drug is only reportable as an adverse event when one of the following criteria is met:   
709 
 
the event involved DKA, as defined by the Diabetes Control and Complications Trial (DCCT) 
710 
and described below 
711 
 
evaluation or treatment was obtained at a health care provider facility for an acute event involving 
712 
hyperglycemia or ketosis, or the participant contacted the site and received guidance on how to 
713 
manage the hyperglycemia/ketosis 
714 
 
blood ketone level ≥1.0 mmol/L, even if there was no communication with a health care provider 
715 
at the time of the event 
716 
Hyperglycemic events are classified as DKA if the following are present: 
717 
 
Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
718 
 
Serum ketones >1.5 mmol/L or large/moderate urine ketones; 
719 
 
Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate (or CO2) <15; and 
720 
 
Treatment provided in a health care facility 
721 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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When a hyperglycemia/ketotic event qualifies as an SAE as defined in section 6.2.1, a Hyperglycemia/ 
722 
DKA Form should be completed in addition to the Adverse Event Form. Events meeting DKA criteria 
723 
should be considered to be serious adverse events with respect to reporting requirements. Hyperglycemia 
724 
events not meeting criteria  for DKA generally will not be considered as serious adverse events unless one 
725 
of the SAE criteria in section 6.2.1 is met. 
726 
When a hyperglycemia/DKA event occurs during use of a study device, it generally will be considered to 
727 
be unrelated to the device (per section 6.2.6) if the device functioned as intended and there does not 
728 
appear to be a flaw in how the device is intended to function. 
729 
6.2.5 Skin Reactions Related to Infusion Set 
730 
When a skin reaction related to the infusion set is considered to be mild or moderate in nature, an infusion 
731 
site reaction case report form will be completed at each scheduled visit and phone contact, or in response 
732 
to the weekly contact from the sites. When a skin reaction related to the infusion set is considered severe 
733 
or treatment was received, an infusion site reaction case report form and an Adverse Event Form also will 
734 
be completed. 
735 
6.2.6 Relationship of Adverse Event to Study Investigational Device 
736 
The study investigator will assess the relationship of any adverse event to the study device or study drug. 
737 
The Medical Monitor also will make this assessment, which may or may not agree with that of the study 
738 
investigator. Reporting requirements will be based on the Medical Monitor’s assessment. 
739 
To ensure consistency of adverse event causality assessments, investigators should apply the following 
740 
general guidelines when determining whether an adverse event is related to a study device or study drug: 
741 
Unrelated: The AE is clearly not related to a study drug/device and a likely alternative etiology exists 
742 
such as an underlying disease, environmental or toxic factors or other therapy. 
743 
Unlikely Related: The AE does not follow a reasonable temporal sequence during or after use of study 
744 
drug/device and a more likely alternative etiology exists such as an underlying disease, environmental or 
745 
toxic factors, or other therapy.  
746 
Possibly Related: The AE occurred in a reasonable time during or after use of study drug/device; but 
747 
could be related to another factor such as an underlying disease, environmental or toxic factors, or other 
748 
therapy; and there is a possible, though weak, scientific basis for establishing a causal association 
749 
between the AE and the study drug/device. 
750 
Probably Related: The AE occurred in a reasonable time during or after use of study drug/device; is 
751 
unlikely to be related to another factor such as an underlying disease, environmental or toxic factors, or 
752 
other therapy; and there is a plausible, though not strong, scientific basis for establishing a causal 
753 
association between the AE and the study drug/device.  
754 
Definitely Related: The AE occurred in a reasonable time during or after use of study drug/device; 
755 
cannot be explained by another factor such as an underlying disease, environmental or toxic factors, or 
756 
therapy; and there is a strong scientific basis for establishing a causal association between the AE and the 
757 
study drug/device.  
758 
Events determined to be Possibly Related, Probably Related, or Definitely Related will be considered 
759 
‘Related’ with respect to any required IRB and FDA reporting. 
760 
6.2.7 Severity (Intensity) of Adverse Events 
761 
The severity (intensity) of an adverse event will be rated on a three-point scale: (1) mild, (2) moderate, 
762 
or (3) severe. A severity assessment is a clinical determination of the intensity of an event. Thus, a severe 
763 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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adverse event is not necessarily serious. For example, itching for several days may be rated as severe, but 
764 
may not be clinically serious. 
765 
MILD: Usually transient, requires no special treatment, and does not interfere with the participant’s daily 
766 
activities. 
767 
MODERATE: Usually causes a low level of inconvenience, discomfort or concern to the participant 
768 
and may interfere with daily activities, but is usually ameliorated by simple therapeutic measures and 
769 
participant is able to continue in study. 
770 
SEVERE: Interrupts a participant’s usual daily activities, causes severe discomfort, may cause 
771 
discontinuation of study device, and generally requires systemic drug therapy or other treatment. 
772 
6.2.8 Expectedness 
773 
For a serious adverse event that is considered possibly related to study device or drug, the Medical 
774 
Monitor will classify the event as unexpected if the nature, severity, or frequency of the event is not 
775 
consistent with the risk information previously described in the protocol, labeling, or Investigator 
776 
Brochure. 
777 
6.2.9 Coding of Adverse Events 
778 
Adverse events will be coded using the MedDRA dictionary. To facilitate coding, the site will enter a 
779 
preliminary MedDRA code which the Medical Monitor may accept or change (the Medical Monitor’s 
780 
MedDRA coding will be used for all reporting). The Medical Monitor will review the investigator’s 
781 
assessment of causality and may agree or disagree. Both the investigator’s and Medical Monitor’s 
782 
assessments will be recorded. The Medical Monitor will have the final say in determining the causality 
783 
as well as whether an event is classified as a serious adverse event and/or an unanticipated adverse device 
784 
effect. 
785 
6.2.10 Outcome of Adverse Events 
786 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
787 
 
RECOVERED/RESOLVED – The participant recovered from the AE/SAE without sequelae. 
788 
Record the AE/SAE stop date. 
789 
 
RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had stabilized 
790 
without change in the event anticipated. Record the AE/SAE stop date. 
791 
 
FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the event that was 
792 
the cause of death should be reported as fatal. AEs/SAEs that were ongoing at the time of death; 
793 
however, were not the cause of death, will be recorded as “resolved” at the time of death. 
794 
 
NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is defined as the 
795 
event was ongoing with an undetermined outcome. 
796 
An ongoing outcome will require follow-up by the site in order to determine the final outcome 
797 
of the AE/SAE. The outcome of an ongoing event at the time of death that was not the cause of 
798 
death, will be updated and recorded as “resolved” with the date of death recorded as the stop 
799 
date. 
800 
 
UNKNOWN – An unknown outcome is defined as an inability to access the participant or the 
801 
participant’s records to determine the outcome (for example, a participant that was lost to follow-
802 
up). 
803 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 39 OF 52 
If any reported adverse events are ongoing when a participant completes the study (or withdraws), 
804 
adverse events classified as UADEs or related SAEs or SUSARs will be followed until they are either 
805 
resolved, or have no prospect of improvement or change, even after the participant has completed all 
806 
applicable study visits/contacts. For all other adverse events, data collection will end at the time the 
807 
participant completes the study. Note: participants should continue to receive appropriate medical care 
808 
for an adverse event after their participation in the study ends. 
809 
6.3 Reportable Device Issues 
810 
All UADEs and ADEs as defined in section 6.2.1 will be reported on both a device issue form and AE 
811 
form, except for skin reactions from CGM sensor placement or pump infusion set placement that do not 
812 
require pharmacologic treatment. 
813 
Device complaints and device malfunctions will be reported except in the following circumstances. 
814 
These occurrences are expected and will not be reported on a Device Issue Form assuming criteria for 
815 
a UADE or ADE have not been met: 
816 
 
CGM sensor lasting fewer days than expected per manufacturer 
817 
 
CGM tape adherence issues 
818 
 
Pump infusion set insertion lasting fewer days than expected per manufacturer 
819 
 
Battery lifespan deficiency due to inadequate charging or extensive wireless communication 
820 
 
Intermittent device component disconnections/communication failures not requiring system 
821 
replacement or workaround/resolution not specified in user guide/manual. 
822 
 
Device issues clearly addressed in the user guide manual that do not require additional 
823 
troubleshooting 
824 
6.4 Timing of Event Reporting 
825 
SAEs possibly related to a study device, study drug, or study participation and UADEs and SUSARs 
826 
must be reported by the investigator to the Coordinating Center within 24 hours of the site becoming 
827 
aware of the event. This can occur via phone or email, or by completion of the online serious adverse 
828 
event form and device issue form if applicable. If the form is not initially completed, it should be 
829 
competed as soon as possible after there is sufficient information to evaluate the event. All other 
830 
reportable ADEs and other reportable AEs should be submitted by completion on the on line form 
831 
within 7 days of the site becoming aware of the event.  
832 
The Coordinating Center will notify all participating investigators of any adverse event that is 
833 
serious, related, and unexpected. Notification will be made within 10 working days after the 
834 
Coordinating Center becomes aware of the event. 
835 
Each principal investigator is responsible for reporting serious study-related adverse events and abiding 
836 
by any other reporting requirements specific to his/her Institutional Review Board or Ethics Committee. 
837 
Where the JCHR IRB is the overseeing IRB, sites must report all serious, related adverse events within 
838 
seven calendar days. 
839 
Upon receipt of a qualifying event, the Sponsor will investigate the event to determine if a UADE has 
840 
occurred, and if indicated, report the results of the investigation to all overseeing IRBs, and the FDA 
841 
within 10 working days of the Sponsor becoming aware of the UADE per 21CFR 812.46(b). A SUSAR 
842 
must be reported within 7 calendar days if life threatening and 15 calendar days if not life threatening per 
843 
21 CFR 312.32(c)(2). The Sponsor in conjunction with the Medical Monitor must determine if the UADE 
844 
presents an unreasonable risk to participants. If so, the Sponsor must ensure that all investigations, or 
845 
parts of investigations presenting that risk, are terminated as soon as possible but no later than 5 working 
846 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 40 OF 52 
days after the Sponsor  makes this determination and no later than 15 working days after first receipt 
847 
notice of the UADE. 
848 
The investigators are also required to report, without unjustified delay, all device deficiencies that could 
849 
have led to a UADE, including device deficiencies, irrespective of whether an adverse event occurred. 
850 
6.5 Safety Oversight 
851 
The study Medical Monitor will review all adverse events and adverse device events that are reported 
852 
during the study and assess the relationship to the study device/drug. SAEs typically will be reviewed 
853 
within 24 hours of reporting. Other AEs typically will be reviewed on a weekly basis. Additionally, the 
854 
Medical Monitor will review compiled safety data at periodic intervals. 
855 
The Sponsor will be informed of all reported adverse evens and the Medical Monitor’s assessment of 
856 
relationship to the study device/drug; and informed of all reported device issues. 
857 
6.6 Stopping Criteria 
858 
6.6.1 Participant Discontinuation of Study Device 
859 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or DKA event 
860 
(or a malfunction that could have led to severe hypoglycemia or DKA), use of the study device will be 
861 
suspended while the problem is diagnosed. The UADE will be reported to the IRB and FDA. After 
862 
assessment of the problem and any correction, use of the study device will not be restarted until approval 
863 
is received from the IRB and FDA. 
864 
In the absence of a device malfunction, use of the study device by a participant will be discontinued if 
865 
any of the following occur:  
866 
 
The investigator believes it is unsafe for the participant to continue on the intervention. 
867 
This could be due to the development of a new medical condition or worsening of an existing 
868 
condition; or participant behavior contrary to the indications for use of the device that imposes 
869 
on the participant’s safety 
870 
 
The participant requests that the treatment be stopped 
871 
 
Participant pregnancy 
872 
 
Two distinct episodes of DKA as defined in section 6.2.3 
873 
 
Two distinct severe hypoglycemia events as defined in section 6.2.3 
874 
 
One episode of DKA as defined in section 6.2.4 and one severe hypoglycemia event as defined in 
875 
section 6.2.3 
876 
Each DKA, severe hypoglycemia event, or significant infusion site reaction will be reviewed by the 
877 
Medical Monitor and by the Sponsor with respect to determination of cause and whether the occurrence 
878 
of the event can be attributed to use of the study device or study drug.  
879 
An additional requirement for continued study device use following a single DKA or severe 
880 
hypoglycemia event will be that the site investigator believes that the event is unlikely to recur and that 
881 
it is safe for the participant to continue to use the system. Additionally, if the Medical Monitor determines 
882 
that the occurrence of the event indicates that it is not safe for the participant to continue to use the study 
883 
device, use will be discontinued. 
884 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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6.6.2 Criteria for Suspending or Stopping Overall Study 
885 
In addition to the suspension of device use due to a UADE as described in section 6.2.1, study activities 
886 
could be similarly suspended if the manufacturer of any constituent study device requires stoppage of 
887 
device use for safety reasons (e.g. product recall). The affected study activities may resume if the 
888 
underlying problem can be corrected by a protocol or system modification that will not invalidate the 
889 
results obtained prior to suspension. 
890 
In addition to the suspension of closed-loop mode use due to a UADE as described above, closed-loop 
891 
system use will be suspended for a root cause analysis if there are 5 or more cases of severe 
892 
hypoglycemia or five or more cases of hyperglycemia/ketotic events qualifying as SAEs across the entire 
893 
study in participants who have initiated Control-IQ technology use. 
894 
For pediatric participants, the study will be suspended for that cohort for a root cause analysis if there are 
895 
3 or more cases of severe hypoglycemia or 3 or more cases of hyperglycemia/ketotic events qualifying as 
896 
SAEs across the pediatric participants who have initiated Control-IQ technology use. 
897 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 42 OF 52 
Chapter 7: Miscellaneous Considerations 
898 
7.1 Drugs Used as Part of the Protocol 
899 
Humalog (insulin lispro) will be used during the Lead-in Period and Lyumjev (insulin lispro-aabc) will 
900 
be used during the Treatment Period. 
901 
7.2 Collection of Medical Conditions and Medications 
902 
Pre-Existing Conditions: Any medical condition that is either present at screening, a chronic disease, 
903 
or a prior condition that could impact the participant’s health during the course of the study (e.g., prior 
904 
myocardial infarction or stroke) will be recorded. 
905 
Medical Conditions Developing During the Study: Medical conditions that develop or worsen during the 
906 
study will be recorded as adverse events. 
907 
Medications: All medications for in use at the time of screening or added during the course of the study 
908 
will be recorded. Nutraceuticals and preventative treatment also will be recorded. Medications only taken 
909 
as needed either can be recorded when prescribed or only recorded if used during the study. Glucagon for 
910 
treatment of severe hypoglycemia will only be recorded if used during the study. 
911 
7.3 Prohibited Medications, Devices, Treatments, and Procedures 
912 
Treatment with any insulin other than study-provided insulin and treatment with a non-insulin 
913 
glucose-lowering agent, other than  metformin, is not permitted, including GLP-1 agonists, Symlin, 
914 
DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas. 
915 
The investigational study devices (t:slim X2 insulin pump, Dexcom CGM sensor) must be removed 
916 
before magnetic resonance imaging (MRI), computed tomography (CT) or diathermy treatment. 
917 
Participants may continue in the trial after temporarily discontinuing use if requiring one of the above. 
918 
7.4 Rescue Medications, Treatments, and Procedures 
919 
Each participant will be required to have a glucagon preparation for rescue therapy for severe 
920 
hypoglycemia. 
921 
7.5 Pregnancy Reporting 
922 
If pregnancy occurs, the participant will be discontinued from the study. The occurrence of pregnancy 
923 
will be reported to the Coordinating Center within seven days and to the JCHR IRB as an Unanticipated 
924 
Problem within seven calendar days. 
925 
7.6 Participant Compensation 
926 
Participant compensation will be specified in the informed consent form. 
927 
7.7 Participant Withdrawal 
928 
Participation in the study is voluntary, and a participant may withdraw at any time. For participants who 
929 
withdraw, their data will be used up until the time of withdrawal. 
930 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 43 OF 52 
7.8 Confidentiality 
931 
For security and confidentiality purposes, participants will be assigned an identifier that will be used 
932 
instead of their name. Protected health information gathered for this study will be shared with the 
933 
coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-identified participant 
934 
information may also be provided to research sites involved in the study. 
935 
 
936 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 44 OF 52 
Chapter 8: Statistical Considerations 
937 
8.1 Statistical and Analytical Plans 
938 
The approach to sample size and statistical analyses are summarized below. 
939 
8.2 Statistical Hypotheses 
940 
The primary objective of the study is assessment of safety. Therefore, there is no formal statistical 
941 
hypothesis testing for efficacy. Safety endpoints will be compared with historical published data. 
942 
8.3 Sample Size 
943 
The sample size of 160 completers of the trial was selected to have reasonable precision for assessing 
944 
safety endpoints and is not based on statistical principles. 
945 
8.4 Outcome Measures 
946 
Key Safety Endpoints 
947 
 
Severe hypoglycemia as defined in section 6.2.3 
948 
 
Diabetic ketoacidosis as defined in section 6.2.4 
949 
 
Unanticipated adverse device effects 
950 
 
Other serious adverse events 
951 
 
Adverse drug reactions 
952 
Secondary Safety Endpoints 
953 
 
All reportable adverse events 
954 
 
CGM hypoglycemia outcomes 
955 
 
Overall % time <54 mg/dL 
956 
 
Postprandial % time <54 mg/dL (30 min, ≤1, ≤2, ≤4, >1 to ≤2 and >2 to ≤4hr) 
957 
 
Overall and postprandial % time <70 mg/dL 
958 
 
Rate of hypoglycemia events defined as 15 or more consecutive minutes <54 mg/dL 
959 
Exploratory Endpoints 
960 
 
Postprandial incremental area under the glucose curve (4 hr) 
961 
 
Peak postprandial glucose 
962 
 
Times in ranges-overall and postprandial (70-180 mg/dL, >180 mg/dL, >250 mg/dL, 70-140 
963 
mg/dL) 
964 
 
Mean glucose 
965 
 
Rate of hyperglycemia events, defined as 90 or more minutes >300 mg/dL within 120 minutes 
966 
 
Overall variability (CV and SD) 
967 
 
HbA1c change from baseline 
968 
 
CGM metrics for hypoglycemia, hyperglycemia, and variability during  daytime  and nighttime 
969 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 45 OF 52 
Patient-Reported Outcomes 
970 
 
TRIM-D 
971 
 
Trim-DD 
972 
 
ITSQ 
973 
8.5 Analysis Datasets  
974 
For the main analyses, adult and pediatric participants will be pooled. Secondarily separate analyses will 
975 
be conducted for adults (>18 years) and pediatric (<18 years) participants. Further exploratory analyses 
976 
will be conducted within pediatric subgroups. 
977 
All participants who initiate the Treatment Period and use the study device with the study drug will be 
978 
included in the safety analyses. 
979 
For inclusion in the analysis of CGM metrics, participants must have at least 24 hours of CGM data 
980 
during the Treatment Period. 
981 
8.6 Statistical Methods 
982 
8.6.1 Analysis of the Safety Event Endpoints 
983 
Safety events (ie, not including CGM defined events) will be tabulated for each type of event as the 
984 
number of events per participant, the number of participants with > 1 event, and the rate of events per 
985 
100 person-years. 
986 
Since study eligibility excluded participants with 2 or more severe hypoglycemia or DKA events in the 
987 
prior 6 months, an unbiased comparison of the event rate during the Treatment Period with the pre-study 
988 
event rate is not possible. Therefore, the severe hypoglycemia and DKA event rates will be compared 
989 
with the T1D Exchange data,5 which reported the frequency of 1 or more severe hypoglycemia and DKA 
990 
events in the prior 3 months according to age group; this will allow for age-matching with this trial. The 
991 
proportion of participants with events during the Treatment Period will be compared with the T1D 
992 
Exchange frequency using Barnard’s exact test. Study endpoint will be met if severe hypoglycemia and 
993 
DKA event rates are not significantly higher during follow-up compared with T1D Exchange frequency. 
994 
8.6.2 Analysis of CGM Endpoints 
995 
CGM metrics will be computed for (1) 4 weeks pre-study (personal CGM), (2) Lead-in Period, and 
996 
(3) Treatment Period. CGM metrics will be computed over 24 hours, during daytime (6am-11:59pm), 
997 
during nighttime (12mn-5:59am), and during scheduled exercise and meal challenges. 
998 
The main statistical comparison will be made between the Treatment Period and the Lead-in Period. The 
999 
lead-in period time for analysis will exclude the day and night of the baseline exercise and meal 
1000 
challenges. Additionally the Treatment Period will be compared with the pre-study CGM data. 
1001 
Linear mixed models will be used to test the change from pre-Treatment Period to Treatment Period.  
1002 
Missing data will be handled by the method of direct likelihood, which assumes outcomes are missing at 
1003 
random and estimates follow-up values via maximimum likelihood.  Sensitivity analyses will be 
1004 
performed to assess the robustness of the results under different missing data assumptions.   
1005 
8.6.3 Analysis of HbA1c and PRO Measures 
1006 
Linear mixed models will be used to test the change in HbA1c and PRO scores from baseline to 
1007 
13 weeks.  Missing data will be handled by the method of direct likelihood, which assumes outcomes are 
1008 
missing at random and estimates follow-up values via maximimum likelihood. 
1009 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 46 OF 52 
8.7 Intervention Adherence 
1010 
The following tabulations will be performed: 
1011 
 
Sensor use–percent time of use 
1012 
 
Closed loop system use–percent time of use 
1013 
 
% time in different operational modes 
1014 
8.8 Protocol Adherence and Retention 
1015 
The following tabulations and analyses will be performed to assess protocol adherence for the study: 
1016 
 
Number of protocol deviations  
1017 
 
Flow chart accounting for all enrolled participants  
1018 
 
Number of and reasons for unscheduled visits and phone calls 
1019 
 
Number of participants who were enrolled but did not enter the Treatment Period and reasons 
1020 
 
Number of participants who stopped treatment and reasons 
1021 
8.9 Baseline Descriptive Statistics 
1022 
Baseline demographic and clinical characteristics of the cohort of participants who initiate the Treatment 
1023 
Period will be summarized in a table using summary statistics appropriate to the distribution of each 
1024 
variable. Descriptive statistics will be displayed by treatment group for the following: 
1025 
 
Age 
1026 
 
Sex 
1027 
 
Race/Ethnicity 
1028 
 
Socio-economic factors (income, education, and/or insurance status) 
1029 
 
Diabetes duration 
1030 
 
HbA1c 
1031 
 
BMI 
1032 
 
Total daily insulin 
1033 
 
Prior severe hypoglycemia and DKA events 
1034 
 
Baseline CGM metrics 
1035 
8.10 Additional Tabulations and Analyses 
1036 
The following data will be tabulated at baseline and at or over 13 weeks 
1037 
 
Insulin metrics (units/kg): total daily insulin, total daily basal insulin, total daily bolus insulin 
1038 
(plus total daily manual bolus, total daily automated bolus) 
1039 
 
Weight 
1040 
 
Number and type of infusion set reactions 
1041 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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8.11 Device Issues 
1042 
The following tabulations will be performed with respect to device issues: 
1043 
 
Reported device issues according to type of issue 
1044 
8.12 Planned Interim Analyses 
1045 
No formal interim analyses are planned. 
1046 
8.13 Subgroup Analyses 
1047 
Results will be tabulated according to age group, HbA1c, and total daily insulin. Additional subgroups 
1048 
will be defined in the Statistical Analysis Plan. 
1049 
8.14 Multiple Comparison/Multiplicity 
1050 
Safety event endpoints will not be corrected for multiple comparisons. For CGM, HbA1c, and PRO 
1051 
endpoint analyses, the false discovery rate will be controlled  using the adaptive Two Stage Group 
1052 
Benjamini-Hochberg (TST GBH) method.6,7 
1053 
8.15 Analysis of Meal and Exercise Challenges 
1054 
The meal and exercise challenges will be analyzed with the same CGM metrics and safety outcomes 
1055 
above to be tabuled during, 2 hours after and overnight for each challenge, and will be detailed in the 
1056 
statistical analysis plan. Separate analysis will be conducted for each type of challenge.
1057 

 
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Chapter 9: Data Collection and Monitoring 
1058 
9.1 Case Report Forms and Other Data Collection 
1059 
The main study data are collected on electronic case report forms (eCRFs). When data are directly 
1060 
collected in electronic case report forms, this will be considered the source data. For any data points 
1061 
for which the eCRF is not considered source (e.g. lab results that are transcribed from a printed report 
1062 
into the eCRF), the original source documentation will be maintained in the participant’s study chart 
1063 
or medical record. This source must be readily verifiable against the values entered into eCRF. 
1064 
Even where all study data are directly entered into the eCRFs at office visits, evidence of interaction 
1065 
with a live subject must be recorded (e.g., office note, visit record, etc.). 
1066 
Electronic device data files are obtained from the study software and individual hardware components. 
1067 
These electronic device files are considered the primary source documentation. 
1068 
HbA1c measurements will be made by the central laboratory and the data will be transmitted to the 
1069 
Coordinating Center. 
1070 
9.2 Study Records Retention 
1071 
Each participating site will maintain appropriate medical and research records for this trial, in 
1072 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1073 
confidentiality of participants. 
1074 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
1075 
application in an ICH region and until there are no pending or contemplated marketing applications in an 
1076 
ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical development 
1077 
of the investigational product. These documents should be retained for a longer period, however, 
1078 
if required by local regulations. No records will be destroyed without the written consent of the sponsor, 
1079 
if applicable. It is the responsibility of the sponsor to inform the investigator when these documents no 
1080 
longer need to be retained. 
1081 
9.3 Quality Assurance and Monitoring 
1082 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1083 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1084 
conducted and data are generated, documented and reported in compliance with the protocol, Good 
1085 
Clinical Practice (GCP) and the applicable regulatory requirements, as well as to ensure that the rights 
1086 
and wellbeing of trial participants are protected and that the reported trial data are accurate, complete, 
1087 
and verifiable. Adverse events will be prioritized for monitoring. 
1088 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course of 
1089 
the study, consistent with the FDA “Guidance for Industry Oversight of Clinical Investigations — 
1090 
A Risk Based Approach to Monitoring” (August 2013). Study conduct and monitoring will conform 
1091 
with 21 Code of Federal Regulations (CFR) 812. This plan describes in detail who will conduct the 
1092 
monitoring, at what frequency monitoring will be done, at what level of detil monitoring will be 
1093 
performed, and the distribution of monitoring reports. 
1094 
The data of most importance for monitoring at the site are participant eligibility and adverse events. 
1095 
Therefore, the RBM plan will focus on these areas. As much as possible, remote monitoring will be 
1096 
performed in real-time with on-site monitoring performed to evaluate the verity and completeness of 
1097 
the key site data. Elements of the RBM may include: 
1098 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
PAGE 49 OF 52 
 
Qualification assessment, training, and certification for sites and site personnel 
1099 
 
Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
1100 
 
Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol review 
1101 
of entered data and edits, statistical monitoring, study closeout 
1102 
 
On-site monitoring (site visits): source data verification, site visit report 
1103 
 
Agent/Device accountability 
1104 
 
Communications with site staff 
1105 
 
Patient retention and visit completion 
1106 
 
Quality control reports 
1107 
 
Management of noncompliance 
1108 
 
Documenting monitoring activities 
1109 
 
Adverse event reporting and monitoring 
1110 
Coordinating Center representatives or their designees may visit the study facilities at any time in order 
1111 
to maintain current and personal knowledge of the study through review of the records, comparison 
1112 
with source documents, observation and discussion of the conduct and progress of the study. 
1113 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
1114 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
1115 
authorities. 
1116 
9.4 Protocol Deviations 
1117 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1118 
requirements. The noncompliance may be either on the part of the participant, the investigator, or the 
1119 
study site staff. A significant (or major) deviation is any deviation that departs from the established 
1120 
materials in such a way that it poses an increase in the risk to subjects, adversely affects the welfare, 
1121 
rights, or safety of the research subjects, or negatively influences the scientific study integrity. As a 
1122 
result of a significant deviation, a corrective and preventive action plan shall be developed by the site 
1123 
and implemented promptly. 
1124 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements. Further details 
1125 
about the handling of protocol deviations will be included in the monitoring plan. 
1126 
 
1127 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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Chapter 10: Ethics/Protection of Human Participants 
1128 
10.1 Ethical Standard 
1129 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
1130 
Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR 
1131 
Part 56, and/or the ICH E6. 
1132 
10.2 Institutional Review Boards 
1133 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
1134 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form must 
1135 
be obtained before any participant is enrolled. Any amendment to the protocol will require review and 
1136 
approval by the IRB before the changes are implemented to the study. All changes to the consent form 
1137 
will be IRB approved; a determination will be made regarding whether previously consented participants 
1138 
need to be re-consented. 
1139 
10.3 Informed Consent Process 
1140 
10.3.1 Consent Procedures and Documentation 
1141 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
1142 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
1143 
benefits of participation will be provided to the participants and their families. Consent forms will be 
1144 
IRB-approved and the participant will be asked to read and review the document. The investigator will 
1145 
explain the research study to the participant and answer any questions that may arise. All participants 
1146 
will receive a verbal explanation in terms suited to their comprehension of the purposes, procedures, 
1147 
and potential risks of the study and of their rights as research participants. Participants will have the 
1148 
opportunity to carefully review the written consent form and ask questions prior to signing. 
1149 
The participants should have the opportunity to discuss the study with their surrogates or think about 
1150 
it prior to agreeing to participate. The participant will sign the informed consent document prior to any 
1151 
procedures being done specifically for the study. The participants may withdraw consent at any time 
1152 
throughout the course of the trial. A copy of the informed consent document will be given to the 
1153 
participants for their records. The rights and welfare of the participants will be protected by emphasizing 
1154 
to them that the quality of their medical care will not be adversely affected if they decline to participate 
1155 
in this study. 
1156 
10.3.2 Participant and Data Confidentiality 
1157 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
1158 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
1159 
genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
1160 
documentation, data, and all other information generated will be held in strict confidence. No information 
1161 
concerning the study or the data will be released to any unauthorized third party without prior written 
1162 
approval of the sponsor. 
1163 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, regulatory 
1164 
agencies or company supplying study product may inspect all documents and records required to be 
1165 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
1166 
and pharmacy records for the participants in this study. The clinical study site will permit access to such 
1167 
records. 
1168 

 
LYUMJEV CLINICAL PROTOCOL V4.0 2022-04-13 
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The study participant’s contact information will be securely stored at each clinical site for internal use 
1169 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
1170 
long a period as dictated by the reviewing IRB, institutional policies, or sponsor requirements. 
1171 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
1172 
be transmitted to and stored at the Coordinating Center. This will not include the participant’s contact or 
1173 
identifying information, unless otherwise specified in the informed consent form. Rather, individual 
1174 
participants and their research data will be identified by a unique study identification number. The study 
1175 
data entry and study management systems used by clinical sites and by the Coordinating Center research 
1176 
staff will be secured and password protected. At the end of the study, all study databases will be de-
1177 
identified and archived at the Coordinating Center. 
1178 
10.3.3 Future Use of Stored Specimens and Data 
1179 
Data collected for this study will be analyzed and stored at the Coordinating Center. After the study is 
1180 
completed, a dataset will be provided to the study Sponsor. 
1181 
No biologic specimens will be stored. 
1182 
 
1183 

 
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Chapter 11: References 
1184 
 
1185 
1. Brown SA, Kovatchev BP, Raghinaru D, Lum JW, Buckingham BA, Kudva YC, Laffel LM, 
1186 
Levy CJ, Pinsker JE, Wadwa RP, Dassau E, Doyle FJ 3rd, Anderson SM, Church MM, 
1187 
Dadlani V, Ekhlaspour L, Forlenza GP, Isganaitis E, Lam DW, Kollman C, Beck RW; iDCL 
1188 
Trial Research Group.  Six-month randomized, multicenter trial of closed-loop control in 
1189 
type 1 diabetes.  N Engl J Med.  2019; 381:1707-1717. 
1190 
2. Breton MD, Kanapka LG, Beck RW, Ekhlaspour L, Forlenza GP, Cengiz E, Schoelwer M, 
1191 
Ruedy KJ, Jost E, Carria L, Emory E, Hsu LJ, Oliveri M, Kollman CC, Dokken BB, 
1192 
Weinzimer SA, DeBoer MD, Buckingham BA, Cherñavvsky D, Wadwa RP; iDCL Trial 
1193 
Research Group. A randomized trial of closed-loop control in children with type 1 diabetes. 
1194 
N Engl J Med. 2020 Aug 27;383(9):836-845. 
1195 
3. Breton M, Kovatchev B. One year real-world use of the Control-IQ advanced hybrid closed 
1196 
loop technology. Diabetes Technol Ther 2021 Published Online:21 Apr 2021 
1197 
https://doi.org/10.1089/dia.2021.0097 
1198 
4. Leohr J, Dellva MA, Carter K, LaBell E, Linnebjerg H. Ultra Rapid Lispro (URLi) 
1199 
Accelerates Insulin Lispro Absorption and Insulin Action vs Humalog® Consistently Across 
1200 
Study Populations: A Pooled Analysis of Pharmacokinetic and Glucodynamic Data. Clin 
1201 
Pharmacokinet. 2021 May 27; doi: 10.1007/s40262-021-01030-0. Epub ahead of print.  
1202 
5. Foster et al. State of type 1 diabetes management and outcomes from the T1D Exchange in 
1203 
2016-2018. Diabetes Technol Ther 2019; 21: 66-72. 
1204 
6. Benjamini YB, Yekutieli D: The control of the false discovery rate in multiple testing under 
1205 
dependency, 2001; Ann Stat, 29(4):1165-1188. 
1206 
7. Hu JX, Zhao H, Zhou HH: False discovery rate control with groups. J Am Stat Assoc, 2010; 
1207 
105(491):1215-1227. 
1208