Conditions: Type1 Diabetes
Keywords: new onset verapamil hybrid closed loop hcl beta cell diabetes children T1D c-peptide pediatric
Allocation: RANDOMIZED | Intervention model: FACTORIAL
Enrollment: 113
Healthy volunteers: no

Brief summary:
Randomized trial of youth aged 7-\<18 years with newly diagnosed stage 3 type 1 diabetes (T1D) to assess the effect of both (1) near-normalization of glucose concentrations achieved through use of a hybrid closed loop (HCL) system and (2) verapamil on preservation of β-cell function 12 months after diagnosis. Participants with body weight ≥30 kg (Cohort A) will be randomly assigned in a factorial design to (1) HCL plus intensive diabetes management or usual care with no HCL and (2) verapamil or placebo. Participants with body weight \<30 kg (Cohort B) will be randomly assigned 2:1 in a parallel group design to HCL plus intensive diabetes management or to usual care with no HCL.

Detailed description:
After informed consent is obtained, potential participants will be assessed for eligibility, including eliciting medical history, physical examination, and laboratory testing (including HbA1c, auto-antibody measurement \[unless positive auto-antibody results already available\], and pregnancy test for females with childbearing potential).

Participants who already have positive auto-antibodies can be randomized immediately. All other participants will be scheduled for a randomization visit after the auto-antibody results are available; positive auto-antibodies are required for randomization.

Eligible participants with body weight ≥30 kg (Cohort A) will be randomly assigned to one of 4 groups: HCL and placebo, HCL and verapamil, non-HCL and placebo or non-HCL and verapamil. Eligible individuals with body weight \<30 kg (Cohort B) will be randomly assigned 2:1 to either HCL or non-HCL. Randomization schedules will be separate for Cohort A and Cohort B and will be stratified by site.

Participants assigned to HCL will receive intensive diabetes management with frequent contacts by study staff with the goal of near-normalization of glucose concentrations.

Participants assigned to non-HCL will receive a Dexcom G6 continuous glucose monitor (CGM) and diabetes management will follow usual care by their personal diabetes health care provider.

Participants will be followed for 12 months from diagnosis, completing a 6 week visit timed from randomization and 13, 26, 39, and 52 week visits timed from diagnosis. Participants will have a MMTT performed, HbA1c measured, and blood drawn for mechanistic studies at Randomization, 13, 26, 39 and 52 weeks. At all follow-up visits, a physical exam will be performed, pregnancy testing performed (if indicated), insulin dose (units/kg/day) recorded, and device data downloaded.

Safety assessments will be made throughout the study by querying about episodes of severe hypoglycemia and DKA, and overall health.

Participants already enrolled in the study and using the Medtronic 670G 4.0 AHCL may transition to the Medtronic 780G if desired. Contacts will be performed to review CareLink data and check for adverse events and device deficiencies on days 1, 3 and 5 after transition from 670G 4.0 AHCL to 780G.

Prior to the 780G system becoming commercially available, study participants using the Medtronic system at 52 weeks will have the opportunity to continue using the 780G system at home until the system is commercially available OR until the CLVer trial is complete (last participant's 52-week visit), whichever comes first.

Additional Procedures for Cohort A:

Drug will be double blinded. Drug dose will be weight-dependent and will be escalated at 2-4 week intervals, up to a weight-dependent maximum if tolerated. Cohort A will have additional safety visits 1 week after initiation of study drug and after each study drug dose increase, to test blood pressure and pulse.

Local lab measurement of aspartate aminotransferase/alanine aminotransferase (AST/ALT) and creatinine will occur, and an EKG will be performed at Screening, 6, 26, and 52 weeks. Over the course of the trial, study drug dose may be decreased or discontinued if side effects occur.

Arms:
arm 1: Participants assigned to HCL group will initially be randomly assigned 1:1 to use either the Tandem t:slim X2 with Control-IQ technology or a Medtronic HCL system (Medtronic 670G 4.0 AHCL (prior to protocol version 5.0) or Medtronic 780G (starting with protocol version 5.0)). This group will receive intensive diabetes management with frequent contacts by study staff with the goal of near-normalization of glucose concentrations.

Placebo will be taken orally once per day by participants in Cohort A. A dosing scheme will be followed, using 120mg tablets or 60mg half tablets.

Whether drug is active or placebo is blinded to both participant and site.

\[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\] arm 2: Participants assigned to HCL group will initially be randomly assigned 1:1 to use either the Tandem t:slim X2 with Control-IQ technology or a Medtronic HCL system (Medtronic 670G 4.0 AHCL (prior to protocol version 5.0) or Medtronic 780G (starting with protocol version 5.0)). This group will receive intensive diabetes management with frequent contacts by study staff with the goal of near-normalization of glucose concentrations.

Verapamil will be taken orally once per day by participants in Cohort A. A dosing scheme will be followed, using 120mg tablets or 60mg half tablets.

Whether drug is active or placebo is blinded to both participant and site.

\[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\] arm 3: Participants assigned to non-HCL will receive a Dexcom G6 CGM and diabetes management will follow usual care by their personal diabetes health care provider.

Verapamil will be taken orally once per day by participants in Cohort A. A dosing scheme will be followed, using 120mg tablets or 60mg half tablets.

Whether drug is active or placebo is blinded to both participant and site.

\[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\] arm 4: Participants assigned to non-HCL will receive a Dexcom G6 CGM and diabetes management will follow usual care by their personal diabetes health care provider.

Placebo will be taken orally once per day by participants in Cohort A. A dosing scheme will be followed, using 120mg tablets or 60mg half tablets.

Whether drug is active or placebo is blinded to both participant and site.

\[Cohort B participants will not receive study drug. Instead, they will be randomized 2:1 to HCL or non-HCL.\]

Interventions: intervention 1: HCL intervention 2: verapamil 120mg tablet intervention 3: non-HCL intervention 4: placebo
Intervention descriptions: intervention 1: Hybrid Closed Loop therapy intervention 2: verapamil tablet intervention 3: Usual diabetes care intervention 4: placebo pill manufactured to mimic verapamil 120mg tablet

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
Hybrid Closed Loop Therapy and Verapamil for Beta Cell 
Preservation in New Onset Type 1 Diabetes (CLVer) 
A Proof-of-Concept Study  
IDE Sponsor: Jaeb Center for Health Research 
Funded by: Juvenile Diabetes Research Foundation 
 
 
Version Number: v. 5.2 
01 Mar 2022 
 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 2 OF 64 
KEY ROLES 
 
Name, degree 
Gregory Forlenza, MD 
Title 
Co-Protocol Chair 
Institution Name 
Barbara Davis Center 
 
Name, degree 
Antoinette Moran, MD 
Title 
Co-Protocol Chair 
Institution Name 
University of Minnesota 
 
Name, degree 
Colleen Bauza, PhD, MPH 
Title 
Coordinator Center Director 
Institution Name 
Jaeb Center for Health Research (JCHR) 
 
Name, degree 
 Roy Beck, MD 
Title 
Medical Monitor 
Institution Name 
 Jaeb Center for Health Research (JCHR) 
 
 
 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 3 OF 64 
VERSION HISTORY 
The following table lists versions of the protocol: 
VERSION
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
1.0 
Jennifer 
McVean, 
Antoinette 
Moran, 
Stephanie 
DuBose 
Stephanie DuBose 
01Nov2019 
Original version 
1.1 
Stephanie 
DuBose 
Stephanie DuBose 
04Nov2019 
Expanded age group for quality of life questionnaire ‘Problem Areas in 
Diabetes’ in Section 7.3 
1.2 
Stephanie 
DuBose 
Stephanie DuBose 
22Nov2019 
JCHR IRB requested the following edits: 
 
Safety visits cannot be completed by local physician 
 
Clarify study drug is dispensed at Randomization–39 weeks 
 
Clarify email/texts should not include PHI 
 
Correct typos
2.0 
Stephanie 
DuBose, 
Jennifer 
McVean 
Stephanie DuBose 
25Nov2019 
FDA requested the following edits: 
 
Expand exclusion criteria for Cohort A  
 
Revise study drug titration schedule to be more gradual 
 
Modify timing of safety visits  
 
Specify that cardiologist should review abnormal EKG results 
throughout study 
Corrected typos
3.0 
Stephanie 
DuBose 
Stephanie DuBose 
04Dec2019 
o Clarified details regarding future use of stored samples 
o Updated psychosocial questionnaire details 
o Added possible allergy risk of Boost during MMTT 
o Clarified that non-HCL groups will do ketone testing per usual care 
o FDA requested the following edits: 
 Change timing of education visit to 7 days post randomization for 
HCL groups and indicate HCL will be initiated at that time 
 Modify min low glucose threshold details 
 Specify how initial insulin profiles will be customized for HCL 
groups  
 Add that parents/guardians should be present with participant at 
night as much as possible  
 Reference guidance docs that include instructing to check blood 
glucose when sensor glucose is low or high and how to treat 
 Add additional stopping criteria for HCL devices related to SH and 
DKA events 
 Add that all system requirements must be met before starting HCL
3.1  
Stephanie 
DuBose 
Stephanie DuBose 
13Dec2019 
o Corrected typos 
o FDA requested the following edits: 
 Increase frequency of HCL contacts  
 Add options for remote monitoring of HCL participants 
 Require overnight fingersticks for first two nights after HCL 
initiation 
 Add mechanism to ensure participants know how to adjust pump 
settings


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 4 OF 64 
VERSION
NUMBER 
AUTHOR 
APPROVER 
EFFECTIVE 
DATE 
REVISION DESCRIPTION 
4.0 
Jennifer 
McVean, 
Stephanie 
DuBose, 
Antoinette 
Moran 
Stephanie DuBose 
22Jan2020 
o Corrected typos and added clarifications 
o Updated details regarding blinded CGM wear 
o Updated location for storage of future samples 
o Removed participant questionnaires  
o Noted that pill splitting will be done at home 
o Updated timing of labs 
o FDA requested the following edits: 
 Clarify acetaminophen eligibility criteria to specify cannot have 
contraindication to ibuprofen  
 Add details on setpoint for 670G 4.0 
 Add details regarding bolusing prior to meal
4.1 
Diana Rojas, 
Stephanie 
DuBose,  
Stephanie DuBose 
06Mar2020 
o Corrected typos and added clarifications 
o Updated timing of labs (including MMTT) 
o Clarified timing of randomization 
o Removed requirement of blinded CGM wear for participants using 
Medtronic system 
o Revised blood ketone level cutoff for reportable hypoglycemic events  
o Changed description of Tandem pump to reflect Pro software
4.2 
Stephanie 
DuBose 
Stephanie DuBose 
12May2020 
o Corrected typos  
o Minor updates to procedures to allow flexibility due to COVID-19 
 Allow device training and dietitian consult to be completed within 3 
days of randomization rather than on day of randomization 
 Allow 7-day additional HCL training visit to be conducted 
remotely, per investigator discretion 
 Allow 6 week visit to be completed remotely for Cohort B, with 
physical exam not required 
4.3 
Stephanie 
DuBose 
Jennifer McVean, 
Antoinette Moran, 
Stephanie DuBose 
27Jul2020 
o Minor updates to procedures to allow flexibility due to COVID-19 
 Allow Safety Visits (collection of BP and pulse 1 week after study 
drug initiation and each dose increase for Cohort A) to be 
conducted remotely (using study provided BP/pulse machine) 
 Allow for expanded windows for Screening visit and between 
Screening and Randomization, as long as participant able to be 
randomized within 31 days of T1D diagnosis  
 Allow use of recent Tanner Staging results if available at Screening 
o Updated recommendations for number of grams of carbohydrates to 
take before blousing, if low 
o Updated setpoint details for 670G 4.0 by age group (per recent 
Medtronic data and approved by FDA) 
o Updated timing of 6 week visit to be timed from randomization instead 
of diagnosis 
4.4  
Stephanie 
DuBose 
Jennifer McVean, 
Antoinette Moran, 
Roy Beck 
18Nov2020 
o Allow 6 week visit to be conducted remotely for both Cohorts (for 
flexibility due to COVID-19) 
5.0 
Jennifer 
McVean 
Stephanie DuBose 
26May2021 
o Added new Medtronic 780G HCL system (with option for participants 
to switch over from 670G 4.0 to new system and option for continued 
access to system after trial completion) 
o Removed dietitian visit at 52 week visit 
o Removed need to re-consent at age from 14; only re-consent at 18 years 
old
5.1 
Diana Rojas 
Stephanie DuBose 
01Oct2021 
o Changed Protocol Co-Chair from Jennifer McVean to Gregory 
Forlenza
5.2 
Diana Rojas 
Colleen Bauza 
01Mar2022 
o Changed Coordinating Center Director from Stephanie Dubose to 
Colleen Bauza
 
 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 5 OF 64 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................... 9 
PROTOCOL SUMMARY ...................................................................................................................... 10 
SCHEMATIC OF STUDY DESIGN* .................................................................................................... 14 
SCHEDULE OF STUDY VISITS AND PROCEDURES ...................................................................... 15 
CHAPTER 1: INTRODUCTION ....................................................................... 17 
1.1 Background ........................................................................................................................................ 17 
1.2 Potential Risks and Benefits of the Study.......................................................................................... 21 
1.2.1 Known Potential Risks ................................................................................................................ 22 
1.2.2 Known Potential Benefits ............................................................................................................ 23 
1.2.3 Risk Assessment .......................................................................................................................... 23 
1.3 General Considerations...................................................................................................................... 23 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING ................................. 24 
2.1 Participant Recruitment and Enrollment ........................................................................................... 24 
2.1.1 Informed Consent and Authorization Procedures ....................................................................... 24 
2.2 Participant Eligibility Criteria ........................................................................................................... 24 
2.2.1 Participant Inclusion Criteria ....................................................................................................... 24 
2.2.2 Participant Exclusion Criteria ...................................................................................................... 25 
2.3 Screening Procedures ........................................................................................................................ 26 
2.3.1 Data Collection and Testing ........................................................................................................ 26 
2.4 Randomization ................................................................................................................................... 27 
2.4.1 Randomization Visit Procedures ................................................................................................. 27 
CHAPTER 3: STUDY DEVICES ...................................................................... 29 
3.1 Description of the Study Devices ...................................................................................................... 29 
3.1.1 Hybrid Closed Loop Systems ...................................................................................................... 29 
3.1.1.1 Tandem t:slim X2 with Control-IQ Technology ................................................................. 29 
3.1.1.2 Medtronic 670G 4.0 AHCL and Medtronic 780G .............................................................. 29 
3.1.2 Dexcom G6 Continuous Glucose Monitoring System ................................................................ 30 
3.1.3 Blood Glucose Meter and Strips .................................................................................................. 31 
3.1.4 Ketone Meter and Strips .............................................................................................................. 31 
3.2 Study Device Accountability Procedures .......................................................................................... 31 
3.3 Safety Measures ................................................................................................................................. 31 
3.3.1 Hypoglycemia Threshold Alert and Safety Protocol ................................................................... 31 
3.3.2 Hyperglycemia Threshold Alert and Safety Protocol .................................................................. 32 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 6 OF 64 
CHAPTER 4: STUDY DRUG ........................................................................... 33 
4.1 Study Agent(s) and Control Description ........................................................................................... 33 
4.1.1 Acquisition .................................................................................................................................. 33 
4.1.2 Dosing and Administration .......................................................................................................... 33 
4.1.3 Dose Adjustments/Modifications/Delays .................................................................................... 33 
4.1.1 Dispensing Study Drug................................................................................................................ 34 
4.1.2 Assessing Participant Adherence ................................................................................................ 34 
4.2 Study Agent Accountability Procedures ............................................................................................ 34 
CHAPTER 5: DIABETES MANAGEMENT ...................................................... 35 
5.1 Participants Using Hybrid Closed Loop ............................................................................................ 35 
5.1.1 Home Use of HCL ....................................................................................................................... 35 
5.1.2 Discontinuation of HCL .............................................................................................................. 36 
5.1.3 Transition to Usual Care at End of Study .................................................................................... 36 
5.2 Participants Assigned to Groups Not Using Hybrid Closed Loop .................................................... 37 
CHAPTER 6: FOLLOW-UP VISIT SCHEDULE ............................................... 38 
6.1 Study Visits and Phone Contacts ....................................................................................................... 38 
6.1.1 Study Visits and Windows .......................................................................................................... 38 
6.1.2 Procedures at Study Follow-up Visits ......................................................................................... 38 
6.1.3 Participant Contact outside of Study Visits ................................................................................. 40 
6.1.4 Unscheduled Visits ...................................................................................................................... 40 
CHAPTER 7: TESTING PROCEDURES ........................................................... 41 
7.1 Physical Examination ........................................................................................................................ 41 
7.2 Laboratory Testing ............................................................................................................................ 41 
CHAPTER 8: UNANTICIPATED PROBLEMS, ADVERSE EVENTS, DEVICE 
ISSUES, AND STOPPING RULES .................................................................... 43 
8.1 Unanticipated Problems ..................................................................................................................... 43 
8.2 Adverse Events .................................................................................................................................. 43 
8.2.1 Definitions ................................................................................................................................... 43 
8.2.2 Reportable Adverse Events ......................................................................................................... 44 
8.2.3 Hypoglycemic Events .................................................................................................................. 44 
8.2.4 Hyperglycemic/Ketotic Events .................................................................................................... 45 
8.2.5 Relationship of Adverse Event to Study Device, Drug, or Procedure ......................................... 45 
8.2.6 Severity (Intensity) of Adverse Events ........................................................................................ 46 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 7 OF 64 
8.2.7 Expectedness ............................................................................................................................... 46 
8.2.8 Coding of Adverse Events ........................................................................................................... 46 
8.2.9 Outcome of Adverse Events ........................................................................................................ 47 
8.3 Reportable Device Issues ................................................................................................................... 47 
8.4 Timing of Event Reporting ................................................................................................................ 48 
8.5 Independent Safety Oversight ........................................................................................................... 49 
8.6 Stopping Criteria Related to Study Devices or Drug ......................................................................... 49 
8.6.1 Participant Discontinuation of Study Device .............................................................................. 49 
8.6.2 Participant Discontinuation of Study Drug ................................................................................. 50 
8.6.3 Criteria for Suspending or Stopping Overall Study ..................................................................... 50 
8.7 Unmasking of Study Drug Due to Adverse Event ............................................................................. 51 
CHAPTER 9: MISCELLANEOUS CONSIDERATIONS ..................................... 52 
9.1 Drugs Used as Part of the Protocol .................................................................................................... 52 
9.2 Collection of Medical Conditions and Medications .......................................................................... 52 
9.3 Prohibited Medications, Devices, Treatments, and Procedures ......................................................... 52 
9.4 Rescue Medications, Treatments, and Procedures ............................................................................ 53 
9.5 Pregnancy Reporting ......................................................................................................................... 53 
9.6 Participant Compensation .................................................................................................................. 53 
9.7 Participant Withdrawal ...................................................................................................................... 53 
9.8 Confidentiality ................................................................................................................................... 53 
CHAPTER 10: STATISTICAL CONSIDERATIONS .......................................... 54 
10.1 Statistical and Analytical Plans ....................................................................................................... 54 
10.2 Statistical Hypotheses ...................................................................................................................... 54 
10.3 Sample Size ..................................................................................................................................... 54 
10.4 Outcome Measures .......................................................................................................................... 55 
10.5 Analysis Datasets ............................................................................................................................. 56 
10.6 Analysis of the Primary Efficacy Endpoint ..................................................................................... 56 
10.6.1 HCL vs. non-HCL Analysis ...................................................................................................... 56 
10.6.2 Verapamil vs. Placebo Analysis ................................................................................................ 56 
10.7 Analysis of the Secondary Endpoint................................................................................................ 56 
10.8 Safety Analyses ............................................................................................................................... 57 
10.9 Intervention Adherence ................................................................................................................... 57 
10.10 Protocol Adherence and Retention ................................................................................................ 57 
10.11 Baseline Descriptive Statistics ....................................................................................................... 57 
10.12 Device Issues ................................................................................................................................. 57 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 8 OF 64 
10.13 Planned Interim Analyses .............................................................................................................. 57 
10.14 Interaction Analyses ...................................................................................................................... 58 
10.15 Subgroup Analyses ........................................................................................................................ 58 
10.16 Multiple Comparisons ................................................................................................................... 58 
10.17 Additional Analyses ...................................................................................................................... 58 
CHAPTER 11: DATA COLLECTION AND MONITORING .............................. 59 
11.1 Case Report Forms and Device Data ............................................................................................... 59 
11.2 Study Records Retention ................................................................................................................. 59 
11.3 Quality Assurance and Monitoring .................................................................................................. 59 
11.4 Protocol Deviations ......................................................................................................................... 60 
CHAPTER 12: ETHICS/PROTECTION OF HUMAN PARTICIPANTS .............. 61 
12.1 Ethical Standard ............................................................................................................................... 61 
12.2 Institutional Review Boards ............................................................................................................ 61 
12.3 Informed Consent Process ............................................................................................................... 61 
12.3.1 Consent Procedures and Documentation ................................................................................... 61 
12.3.2 Participant and Data Confidentiality ......................................................................................... 61 
12.3.3 Future Use of Stored Specimens ............................................................................................... 62 
CHAPTER 13: REFERENCES ......................................................................... 63 
 
 
 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 9 OF 64 
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AUC 
Area Under the Curve 
BG 
Blood Glucose 
CRF 
Case Report Form 
CGM 
Continuous Glucose Monitoring 
CI 
Confidence Interval 
CSII 
Continuous Subcutaneous Insulin Infusion 
DKA 
Diabetic Ketoacidosis 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HCL 
Hybrid Closed Loop 
ID 
Identification 
IDE 
Investigational Device Exemption 
IQR 
Interquartile Range 
MDI 
Multiple daily injections 
MMTT 
Mixed Meal Tolerance Test 
POC 
Point-of-Care 
PRO 
Patient-Reported Outcome 
QA 
Quality Assurance 
QC 
Quality Control 
RCT 
Randomized Controlled/Clinical Trial 
RMB 
Risk-Based Monitoring 
SADE 
Serious Adverse Device Event 
SAE 
Serious Adverse Event 
SAP 
Sensor-Augmented Pump 
SD 
Standard Deviation 
SH 
Severe Hypoglycemia 
SMBG 
Self-Monitoring of Blood Glucose 
UADE 
Unanticipated Adverse Device Effect 
 
 
 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 10 OF 64 
PROTOCOL SUMMARY 
PARTICIPANT AREA 
DESCRIPTION 
Title 
Hybrid Closed Loop Therapy and Verapamil for Beta Cell Preservation in New 
Onset Type 1 Diabetes: A Proof-of-Concept Study 
Précis 
Randomized trial of youth aged 7-<18 years with newly diagnosed stage 3 type 1 
diabetes to assess the effect of both (1) near-normalization of glucose concentrations 
achieved through use of a hybrid closed loop (HCL) system and (2) verapamil on 
preservation of β-cell function 12 months after diagnosis. Participants with body 
weight ≥30 kg (Cohort A) will be randomly assigned in a factorial design to (1) 
HCL plus intensive diabetes management or usual care with no HCL and (2) 
verapamil or placebo. Participants with body weight <30 kg (Cohort B) will be 
randomly assigned 2:1 in a parallel group design to HCL plus intensive diabetes 
management or to usual care with no HCL.  
Objectives 
Primary Objectives 
1) To determine if initiation of HCL therapy plus intensive diabetes 
management soon after diagnosis of stage 3 T1D can achieve near-
normalization of glucose concentrations that preserves beta cell function 
(Cohort A and Cohort B will be combined for the analysis) 
2) To determine if oral verapamil started soon after diagnosis of stage 3 T1D 
preserves beta cell function (Cohort A) 
Secondary Objectives (comparing HCL vs non-HCL and verapamil vs placebo) 
1) To compare CGM parameters of blood glucose control including mean 
glucose; coefficient of variation; and time in-, above- and below- range (70-
180, >180, >250, <70, <54 mg/dL between treatment groups.  
2) To compare HbA1c between treatment groups. 
3) To compare frequency of episodes of severe hypoglycemia between 
treatment groups. 
4) To compare frequency of episodes of DKA between treatment groups. 
5) To conduct mechanistic studies, the exact nature of which will be determined 
at study end depending on study outcomes. 
Study Design 
Multi-center randomized 2x2 factorial design controlled trial for participants with 
body weight ≥30 kg (Cohort A) and 2-group parallel design RCT for participants 
with body weight <30 kg (Cohort B). 
Number of Sites 
Six 
Sample Size 
Cohort A: 98 participants with body weight ≥30 kg (for factorial design)  
Cohort B: 33 participants with body weight <30 kg (for 2-group RCT) 
Endpoint 
Primary Efficacy Outcome: C-peptide area under curve (AUC) in response to a 2-
hour MMTT at 52 weeks 
Key Secondary Efficacy Outcomes: CGM parameters (mean glucose and 
coefficient of variation, time in-, above, and below-range); HbA1c mechanistic 
studies (measures of β-cell and immune system function) 
Key Safety Outcomes: Episodes of severe hypoglycemia and DKA  
Population 
Key Inclusion Criteria: 
 
New-onset stage 3 T1D,with ability to be randomized within 31 days of 
diagnosis  
 
At least one positive type 1 diabetes auto-antibody 
 
Age 7 - <18 years at the time of enrollment 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 11 OF 64 
PARTICIPANT AREA 
DESCRIPTION 
 
Willing to have a parent or legal guardian provide informed consent and 
child assent 
 
In a female participant with childbearing potential, not currently pregnant 
and willing to avoid pregnancy and breastfeeding and undergo pregnancy 
testing throughout the study  
 
English speaking/reading  
 
Able to swallow pills (tested with an inert imitation tablet in clinic prior to 
randomization) —Cohort A only 
 
Willing to not use any non-insulin glucose-lowering agents (such as GLP-1 
agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, biguanides, 
sulfonylureas)  
 
Willing to use an insulin approved for the pump (if assigned to HCL) 
 
Willing to avoid medications containing acetaminophen, and no 
contraindications for ibuprofen use (in case assigned to Medtronic HCL 
system) 
Key Exclusion Criteria: 
 
Ongoing use of medications known to influence glucose tolerance such as 
systemic steroids 
 
Other systemic disease which in the opinion of the investigator precludes 
participation (including psychiatric illness)  
 
Unwilling to abstain from use of HCL therapy for 12 months  
o 
Personal pump and CGM use, including systems with a “suspend-
before-low” function, will be allowed for participants randomized to 
non-HCL groups 
 
“Silent” diabetes—i.e., Stage 3 diabetes that is identified by routine OGTT 
or in the course of surveillance studies but is not accompanied by fasting 
hyperglycemia or classic symptoms of diabetes 
 
Participation in another research study that involves diabetes care or 
immune modulation 
Additional exclusion criteria for Cohort A 
 
Blood pressure (either systolic or diastolic) <5th percentile for age, gender, 
and height on two out of three measurements  
 
Pulse <2nd percentile for age and gender on two out of three measurements 
 
History of vasovagal syncopal episodes related to hypotension 
 
Abnormal EKG rhythm unless cleared for study participation by a 
cardiologist 
 
Underlying cardiac disease (ex. left ventricular dysfunction, hypertrophic 
cardiomyopathy), certain arrhythmias (ex. AV block, accessory pathway 
such as Wolff-Parkinson-White or Lown-Ganong-Levine syndromes), 
known liver dysfunction, known renal impairment, Duchenne’s muscular 
dystrophy, active Graves disease or hyperthyroidism, and untreated 
hypothyroidism  
 
eGFR < 90 
 
AST and/or ALT greater than 1.5 times the upper limit of normal  
 
Need to use of any of the following medications during the study: beta 
blocker, seizure medication (carbamazepine, phenobarbital, phenytoin), 
other antihypertensive medications, HMG-CoA reductase inhibitors, 
lithium, theophylline, clonidine, or aspirin 
 
Any known hypersensitivity reaction to Verapamil 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 12 OF 64 
PARTICIPANT AREA 
DESCRIPTION 
Study Devices 
Random assignment 1:1 of HCL system to participants in HCL groups:  
 
Tandem t:slim X2 with Control-IQ and Dexcom G6 system 
 
Medtronic 670G 4.0 AHCL (prior to protocol version 5.0) or 780G (starting 
with protocol version 5.0) 
Dexcom G6 CGM (used by the non-HCL groups in both cohorts) 
Investigational Drug 
Oral verapamil (extended release)/placebo in dosage of 60-360 mg/day based on 
weight and tolerance 
Treatment Groups 
Cohort A: random assignment (1:1:1:1) to HCL and placebo, HCL and verapamil, 
non-HCL and placebo, or non-HCL and verapamil 
Cohort B: random assignment (2:1) to HCL or non-HCL 
(All groups will include use of CGM) 
Participant Duration 
12 months from time of diagnosis 
Protocol 
Overview/Synopsis 
After informed consent is obtained, potential participants will be assessed for 
eligibility, including eliciting medical history, physical examination, auto-antibody 
measurement [unless positive auto-antibody results already available], pregnancy 
test for females with childbearing potential, and if ≥30 kg (Cohort A): EKG, 
creatinine, AST, and ALT tests.  
Participants who already have positive auto-antibodies can be randomized 
immediately once other eligibility criteria are assessed. All other participants will be 
scheduled for a randomization visit after the auto-antibody results are available. 
Eligible participants with body weight ≥30 kg at Screening (Cohort A) will be 
randomly assigned to one of 4 groups: HCL and placebo, HCL and verapamil, non-
HCL and placebo or non-HCL and verapamil. Eligible individuals with body weight 
<30 kg (Cohort B) will be randomly assigned 2:1 to either HCL or non-HCL. 
Randomization schedules will be separate for Cohort A and Cohort B and will be 
stratified by site.  
Participants assigned to HCL will receive intensive diabetes management with 
frequent contacts by study staff with the goal of near-normalization of glucose 
concentrations. Participants assigned to non-HCL will receive a Dexcom G6 CGM 
and diabetes management will follow usual care by their personal diabetes health 
care provider.  
Participants will be followed for 12 months from diagnosis, completing a 6 week 
visit timed from randomization and 13, 26, 39, and 52 week visits timed from 
diagnosis. Participants will have a MMTT performed, HbA1c measured, and blood 
drawn for mechanistic studies at Randomization, 13, 26, 39 and 52 weeks. At all 
follow-up visits, a physical exam will be performed, pregnancy testing performed (if 
indicated), insulin dose (units/kg/day) recorded, and device data downloaded.  
Safety assessments will be made throughout the study by querying about episodes of 
severe hypoglycemia and DKA, and overall health.  
Participants already enrolled in the study and using the Medtronic 670G 4.0 AHCL 
may transition to the Medtronic 780G if desired.  Contacts will be performed to 
review CareLink data and check for adverse events and device deficiencies on days 
1, 3 and 5 after transition from 670G 4.0 AHCL to 780G.   
Prior to the 780G system becoming commercially available, study participants using 
the Medtronic system at 52 weeks will have the opportunity to continue using the 
780G system at home until the system is commercially available OR until the 
CLVer trial is complete (last participant’s 52-week visit), whichever comes first.   
 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
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PARTICIPANT AREA 
DESCRIPTION 
Additional Procedures for Cohort A 
Drug will be double blinded. Drug dose will be weight-dependent and will be 
escalated at 2-4week intervals, up to a weight-dependent maximum if tolerated. 
Cohort A will have additional safety visits 1 week after initiation of study drug and 
after each study drug dose increase, to test blood pressure and pulse.  
Local lab measurement of AST/ALT will occur, and an EKG will be performed at 
Screening, 6, 26, and 52 weeks. Creatinine will be assessed at Screening as part of 
eligibility. Over the course of the trial, study drug dose may be decreased or 
discontinued if side effects occur. 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
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SCHEMATIC OF STUDY DESIGN* 
1 
 
2 
*Ns are approximate; follow up timed from randomization (6-weeks) and T1D diagnosis (13, 26, 39, 52 weeks)
3 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
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SCHEDULE OF STUDY VISITS AND PROCEDURES 
4 
The table below shows the visits for all study participants. Participants assigned to HCL in both 
5 
Cohort A and Cohort B will have an additional visit after 7±2 days for HCL system training and 
6 
Cohort A will have a safety visit 7±5 days after drug initiation and after each dose increase for 
7 
drug safety assessments. HCL group will have additional contacts every 1-3 days for the first 2 
8 
weeks, at least twice a week for second 2 weeks, and then every 1-2 weeks through end of study. 
9 
Participants who transition from the Medtronic 670G 4.0 AHCL to the Medtronic 780G will 
10 
have additional contacts on days 1, 3 and 5 after the transition. 
11 
 
12 
Participants who stop using a CGM or have insufficient CGM data will wear a blinded Dexcom 
13 
G6 sensor for approximately 10 days at 6, 13, 26, 39 and 52 weeks. 
14 
 
 
 
Follow-up Visits Both Cohorts/All Groups^ 
Overview of Study Procedures 
Screening Visit 
Randomization 
Visit  
(within 31d of 
diagnosis) 
6 wks*
±3 days 
13 wks 
±3 days 
26 wks 
±7 days 
39 wks 
±7 days 
52 wks 
±7 days 
Informed Consent/Assent 
X 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical Exama 
X 
 
X 
X 
X 
X 
X 
Pregnancy test (as appropriate, done 
locally) 
X 
X  
X 
X 
X 
X 
X 
Islet Auto-antibodies (central lab) 
X 
 
 
 
 
 
 
Prior/Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessments 
 
X 
X 
X 
X 
X 
X 
Daily insulin U/kgb 
 
X 
X 
X 
X 
X 
X 
MMTT (glu and cpep, central lab) 
 
X 
 
X 
X 
X 
X 
HbA1c (central lab) 
 
X 
 
X 
X 
X 
X 
Pro-insulin, Pro-IAPP, unmethylated INS 
DNAc (central lab) 
 
X 
 
X 
X 
X 
X 
Micro RNA sequencingc  (central lab) 
 
X 
 
X 
X 
X 
X 
PBMC, serum cytokinesc  (central lab)  
 
X 
 
 
X 
 
X 
Extra plasma samples for future research 
(central lab)  
 
X 
 
 
X 
 
X 
Device download-as applicable 
 
 
X 
X 
X 
X 
X 
Dietitian consult (HCL only) 
 
X 
X 
X 
X 
X 
 
Compliance Assessment  
 
 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
Additional Testing for Cohort Ad 
EKG  
X 
 
X 
 
X 
 
X 
AST, ALT (local lab) 
X 
 
X 
 
X 
 
X 
Creatinine, to calculate eGFR (local lab) 
X 
 
 
 
 
 
 
^The 6 week visit is timed from Randomization and the 13, 26, 39, and 52 week visits are timed from date of T1D diagnosis.  
15 
*The 6 week visit may be conducted remotely if an in-clinic visit is not feasible, with physical exam not required. Safety 
16 
testing will still be completed for Cohort A but may be done off-site.  
17 
aPhysical exam includes Tanner staging at Screening and 52 weeks (for participants <Tanner 5 at Screening). Limited, 
18 
directed physical exam at other visits (pulse, BP, height, weight, examination of injection/insertion sites) 
19 
bUnits/kg/day, by pump download or by patient 3-day records for those on MDI 
20 
cSamples for some of the time points may or may not be run, depending on final study results.   
21 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 16 OF 64 
dCohort A participants also will have a safety visit 7±5 days after drug initiation and after each dose increase to evaluate    
22 
 BP/pulse. (These visits may be conducted remotely, as needed.)
23 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 17 OF 64 
Chapter 1: Introduction 
24 
1.1 Background 
25 
T1D is a substantial burden for those living with the disease and their families, and is 
26 
associated with increased morbidity and mortality. 
27 
Type 1 diabetes (T1D) affects about 1.25 million people in the United States, with an incidence 
28 
of approximately 40,000 new cases per year in the US (110 people per day) (JDRF fact sheet: 
29 
https://www.jdrf.org/about/what-is-t1d/facts/). The worldwide incidence of T1D is increasing, 
30 
particularly in children; the SEARCH for Diabetes in Youth study found a 21% rise in the 
31 
prevalence of T1D from 2001-2009 in youth aged 0-19 1.  
32 
 
33 
Current standard-of-care consists of basal-bolus insulin therapy with either multiple daily 
34 
injections (MDI) of insulin, or continuous subcutaneous insulin infusion (CSII) by pump 2. 
35 
Patients and care-providers make decisions about insulin dosage based on blood glucose 
36 
measurements obtained from either self-monitoring of blood glucose by multiple daily 
37 
fingerpricks (self-monitored blood glucose, SMBG), or increasingly, by continuous glucose 
38 
monitoring (CGM) of interstitial fluid glucose levels. Despite the technologic advances in the 
39 
management of diabetes, many persons living with the condition struggle to achieve targeted 
40 
glycemic control. Indeed, data from the T1D Exchange (T1DX) highlight this as <30% of 
41 
registry participants achieve targets for glycemic control 3. While sub-optimal control increases 
42 
the risk of long-term micro- and macrovascular complications, patients may also experience 
43 
acute life-threatening episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). Such 
44 
events are not uncommon, with 7% of T1DX registry participants self-reporting an episode of 
45 
severe hypoglycemia (resulting in seizure or coma) in the past 3 months and 8% experiencing an 
46 
episode of DKA in the preceding 12 months 4. Moreover, the poor glycemic control which 
47 
increased the risk of DKA did not protect against severe hypoglycemia 5.  
48 
 
49 
T1D is caused by autoimmune β-cell destruction; this process is particularly aggressive in 
50 
the young.  
51 
Several factors predict the rate of autoimmune β-cell destruction in patients with T1D, the most 
52 
important being age 6. While incident T1D can occur at any age, the natural history and burden 
53 
of disease is different in those diagnosed as children compared to those diagnosed as adults. T1D 
54 
diagnosed in adulthood is characterized by a longer asymptomatic period before diagnosis and 
55 
increased likelihood of preservation of residual β-cell function as compared to the natural course 
56 
of youth diagnosed with this chronic condition 7. In a TrialNet consortium’s review of 191 T1D 
57 
patients followed in clinical trials, age was found to be the strongest predictor of the rate of 
58 
decline in C-peptide secretion with participants less than 21 years of age having a greater rate of 
59 
decline compared to those older than 21 years of age 6. The greatest rate of C-peptide decline 
60 
occurred in children under the age of 12, with progressively less decline in C-peptide over time 
61 
with older age of onset 8. This observation has been confirmed by others 9. Because children and 
62 
adolescents have the greatest risk for rapid disease progression as measured by loss of residual 
63 
C-peptide secretion, it is critical that intervention studies target the pediatric population.  
64 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 18 OF 64 
 
65 
Development of safe therapies that preserve residual C-peptide secretion is important to 
66 
maximally reduce the life-long risk of complications and early death for pediatric T1D 
67 
patients. 
68 
Residual C-peptide secretion has been shown to lower the risk diabetes-related complications. 
69 
The DCCT showed that rates of both retinopathy and early diabetic nephropathy increased with 
70 
greater longitudinal loss of β-cell function, regardless of treatment arm (intensive vs. 
71 
conventional treatment) 9. Therefore, retention of β-cell function is felt to confer clinical benefit 
72 
to patients and this may be particularly important for children who will live with diabetes 
73 
substantially longer than patients diagnosed in adulthood. An additional concern in the pediatric 
74 
population is evidence that both hyperglycemia and glycemic variation have a negative impact 
75 
on the developing brain, as they have been shown to be related to neuroanatomical alterations 
76 
and diminished cognitive ability in children 10. Thus, there is a clear, unmet need to improve both 
77 
the natural history of disease progression and glucose variation for everyone with T1D, but 
78 
especially for youth. It is essential that intervention efficacy is balanced with safety, especially in 
79 
the children, as the risk associated with the treatment cannot outweigh the potential benefit.  
80 
 
81 
Studies evaluating the impact of near-normalization of blood glucose levels on preservation 
82 
of residual C-peptide secretion have produced conflicting results. 
83 
Promising pre-clinical animal studies led to several small human studies that evaluated the 
84 
impact of a short-duration of very intensive insulin therapy right after T1D diagnosis, followed 
85 
by standard intensive therapy for the remainder of the first year, with the aim of preserving β-cell 
86 
function. These yielded conflicting results. Two weeks of inpatient closed-loop therapy shortly 
87 
after T1D diagnosis was reported to preserve stimulated C-peptide levels at one year in 12 
88 
adolescents compared to 14 controls 11; however, no difference was observed in a similar study 
89 
of 9 participants 12. One to two months of outpatient insulin infusion through a central venous 
90 
line using a portable infusion pump led to improved short-term C-peptide parameters in 7 
91 
adolescents compared to 7 matched controls, but the differences did not persist at 12 months 12. 
92 
In contrast to studies evaluating short-term but unsustained intensive insulin therapy very early 
93 
in the course of T1D, the DCCT compared chronic administration of what was then considered 
94 
intensive versus conventional insulin therapy. The DCCT provided the strongest evidence to date 
95 
that lowering blood glucose levels over time may help preserve β-cell function. Compared with 
96 
conventional therapy, intensive therapy with a resulting reduction in HbA1c reduced the risk of 
97 
C-peptide loss in participants who had measurable C-peptide at baseline 13. 
98 
 
99 
The landscape of diabetes management has drastically changed following completion of these 
100 
studies, including pharmacologic improvements (insulin analogs) as well as technologic 
101 
advancements, including the development and wider availability of user-friendly insulin infusion 
102 
pumps and increased accuracy, affordability and acceptance of CGM. The STAR 3 study in 485 
103 
participants, of whom 156 were children, demonstrated that sensor-augmented pump therapy was 
104 
superior to MDI with regards to HbA1c levels 14. In the ONSET study 15, all participants 
105 
received insulin pump therapy and were then randomized to treatment with either CGM or 
106 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 19 OF 64 
SMBG. While there was no change in HbA1c, the sensor-treated group had decreased glycemic 
107 
variability and preserved C-peptide secretion at 12 months. 
108 
 
109 
Most recently, Buckingham and colleagues in the DirectNet consortium conducted a RCT to 
110 
assess the benefits of intensive treatment following diagnosis as compared to usual therapy, with 
111 
stimulated C-peptide level one year after diagnosis as the primary outcome measure. The 
112 
intensively treated group underwent a 3-4 day period of inpatient hybrid closed loop therapy 
113 
within the first week of diagnosis followed by use of sensor augmented pump therapy 16. Pump 
114 
and sensor data were reviewed by clinical staff every 1-2 weeks in the first two months and then 
115 
monthly with additional data reviews if clinically indicated. Usual-therapy patients were treated 
116 
by endocrinologists who were not part of the study team. Forty-eight participants were 
117 
randomized to intensive treatment and compared to 20 participants in the control group who 
118 
received usual therapy 16. At the one-year assessment, there was no difference in stimulated C-
119 
peptide levels between the groups. Importantly, the level of metabolic control did not greatly 
120 
differ between groups, with the majority of patients in both groups being treated by insulin pump 
121 
therapy and a negligible difference in glycemic control achieved one year after diagnosis 
122 
(intensive treatment group: HbA1c 7.4% vs. usual therapy: 7.3%). Furthermore, after 12 months 
123 
only 33% of subjects in the intensive group were still using CGM. This study demonstrates it is 
124 
feasible to recruit participants shortly after diagnosis for a RCT to investigate the impact of 
125 
technology to achieve targeted control and ameliorate disease course. Yet, it does not prove or 
126 
disprove the hypothesis that near-normalization of glucose levels preserves β-cell function, as 
127 
beyond the first few days of inpatient diabetes management and with the tools available at the 
128 
time, no difference in glycemic control was demonstrated between the groups.  
129 
 
130 
Near-normalization of blood glucose levels has been an elusive goal for most patients with 
131 
T1D, and especially for children and adolescents. 
132 
Although intensive insulin therapy has been the standard-of-care for those with T1D for several 
133 
decades, most patients have remained sub-optimally controlled despite more advanced treatment 
134 
modalities. This is particularly true in the pediatric population in whom elevated HbA1c levels 
135 
continue to be observed in children and adolescents across the world as compared to adults living 
136 
with this chronic medical condition 17,18. In the T1DX registry an average HbA1c of 8.2%, which 
137 
is well above the recommended target of <7.5% for children, has been noted 17. Indeed, only 
138 
21% of T1D adolescents (ages 13-20) had HbA1c levels <7.5%; and less than half of those 6-12 
139 
years of age achieved an HbA1c <8% 19. This increased HbA1c reflects chronic abnormal 
140 
glucose metabolism, and is associated with diabetes complications and reduced lifespan 20.  
141 
 
142 
Newly available hybrid closed loop (HCL) therapy offers the potential for true chronic 
143 
near-normalization of metabolic control. 
144 
A major problem for previous studies trying to assess the impact of interventions in the first year 
145 
of T1D diagnosis has been that the vast majority of the new-onset population is in a honeymoon 
146 
phase, and this combined with improvements in diabetes care have made it difficult to observe 
147 
differences in metabolic control between the intervention and usual care cohorts 16. However, our 
148 
tools have recently been refined with the approval of the first HCL system, the MiniMed 670G, 
149 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 20 OF 64 
garnering FDA approval in September 2016. Recently, the labeling has been expanded to include 
150 
children down to age 7 years. A study including fifty 2-6 year old patients was completed and 
151 
submitted to the FDA in 2019. HCL insulin delivery is a major leap forward, as it provides more 
152 
physiologic insulin delivery since basal insulin delivery is based on sensor glucose values. 
153 
Highlighting the safety of HCL, in the pivotal trial in 124 participants (including 30 adolescents) 
154 
that allowed for regulatory approval of the system, there were no episodes of either severe 
155 
hypoglycemia or DKA 14. Importantly, over a 3-month period, HbA1c levels and the proportion 
156 
of time in-target range based on sensor glucose values improved. In addition to improving 
157 
glucose time-in-range, decreased glycemic variability was seen in participants when using HCL 
158 
therapy compared to a 2-week baseline data collection phase where they were using sensor-
159 
augmented pump therapy without automation of insulin delivery 21. Decreased glycemic 
160 
variability is associated with C-peptide preservation at 1 and 2 years post diagnosis 15,22, 
161 
suggesting that technologies that can further normalize glycemic variability may have an even 
162 
greater impact. Early real-world findings evaluating MiniMed 670G data obtained in the 6-
163 
month period following the commercial launch demonstrated that results were similar to those 
164 
reported in the pivotal trial, and sustained over the time of the observation 23. Thus, HCL therapy 
165 
allows a degree of blood glucose normalization and reduction of glucose variability to levels 
166 
previously unattainable.  
167 
 
168 
Verapamil 
169 
Loss of pancreatic beta-cell mass has long been identified as a key factor in the pathogenesis of 
170 
type 1 diabetes however decades of research in this area have failed to identify viable therapies 
171 
for human beta-cell preservation.24 Recent laboratory and animal research has identified 
172 
thioredoxin-interacting protein (TXNIP), a ubiquitously expressed cellular redox regulator, as an 
173 
attractive target for beta-cell preservation therapy.25 TXNIP overexpression has been shown to 
174 
induce beta-cell apoptosis and its role has been shown to be essential for glucotoxicity-induced 
175 
beta-cell death.26 Furthermore, lack of TXNIP has been shown to promote endogenous beta-cell 
176 
survival and to prevent type 1 diabetes in animal models.27 Calcium channel blockers, such as 
177 
verapamil, have been demonstrated to reduce TXNIP expression as well as apoptosis25,28 through 
178 
blockade of L-type calcium channels, which results in a decrease in intracellular free calcium 
179 
leading to inhibition of TXNIP transcription.25 
180 
 
181 
Based on promising pre-clinical work, Ovalle conducted a randomized double-blind placebo-
182 
controlled phase 2 clinical trial to assess the efficacy and safety of oral verapamil for 12 months 
183 
in adults with recent-onset T1D.29 A total of 26 adults 18-44 years old with T1D diagnosed in the 
184 
previous 3 months were randomized 1:1 to either once daily oral verapamil or placebo. Those 
185 
treated with verapamil had significantly higher stimulated C-peptide area under the curve in 
186 
response to a standardized mixed meal tolerance test compared with the placebo group at both 3 
187 
and 12 months following initiation of therapy (Figure).29 Given the preservation of residual beta 
188 
cell function demonstrated in this cohort of adults with recent onset type 1 diabetes, the oral 
189 
route of this agent, and its safety profile, we propose to assess this therapy in a pediatric 
190 
population who are newly diagnosed with type 1 diabetes.  
191 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
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192 
 
193 
The purpose of this study is to demonstrate proof-of-principle. 
194 
As the tools to achieve near-normalization of blood glucose levels have been primitive to-date, 
195 
the ability to assess whether this approach will preserve β-cell function has been compromised. 
196 
The current study will be proof-of-principle, as conditions will be optimized beyond those 
197 
generally achievable in “real life”. To ensure success with early generations of HCL systems and 
198 
to encourage adherence, there will be intensive engagement with the study team, to a level which 
199 
may or may not be sustainable in clinical practice. The goal for sensor wear and time in HCL 
200 
therapy is at least 85%. If this proof-of-principle study demonstrates C-peptide preservation, the 
201 
next step might be a multicenter, intent-to-treat study to determine whether this approach can 
202 
practically be implemented in routine clinical practice. However, we recognize that the ability to 
203 
perform this larger study with a control group not on HCL may not be feasible in the future if 
204 
HCL therapy becomes standard-of-care in the coming years. We anticipate that improved 
205 
features with future generations of HCL technology will make it more feasible to maintain near-
206 
universal automated insulin delivery functionality. Thus, in the future it may no longer be 
207 
possible to test our hypothesis. 
208 
1.2 Potential Risks and Benefits of the Study  
209 
The risks of this study are presented in this protocol and in the informed consent form. This study 
210 
will examine whether near normalization of blood glucose levels beginning early after diagnosis 
211 
of T1D or Verapamil will preserve beta cell function, but there is no guarantee that this will occur. 
212 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
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1.2.1 Known Potential Risks 
213 
Hybrid Closed Loop System  
214 
Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device. 
215 
 Diabetic ketoacidosis (DKA) resulting from high blood glucose due to suspension of insulin 
216 
delivery or inadequate insulin delivery (which may result from catheter occlusion, hardware 
217 
or software malfunction, erroneous CGM readings in closed loop or suspend mode, or 
218 
inadequate insulin dosing). 
219 
 Severe hypoglycemia resulting from over-delivery of insulin (which can result from 
220 
hardware or software malfunction, erroneous CGM readings in closed loop mode, or 
221 
erroneous insulin dosing), which may lead to seizure, unconsciousness, and rarely death. 
222 
 
223 
There is a risk of DKA and severe hypoglycemia in anyone with T1D and use of a HCL system 
224 
is not expected to increase this risk. 
225 
 
226 
Device-related 
227 
Potential device related non-serious events at the site of insertion include: skin irritation or 
228 
redness, infection, pain or discomfort, bruising, edema, rash, bleeding, induration of skin, 
229 
allergic reaction to adhesives. The risk of skin problems could be greater if a sensor or pump 
230 
infusion set is used for longer than it is supposed to be used. Therefore, participants (and parents) 
231 
will be carefully instructed about proper use of the sensor and pump.  
232 
 
233 
On rare occasions, the CGM sensor may break and leave a small portion of the sensor under the 
234 
skin that may cause redness, swelling or pain at the insertion site. The participant will be 
235 
instructed to notify the study coordinator immediately if this occurs. 
236 
 
237 
Verapamil 
238 
Verapamil is a calcium channel blocker. The most common side effect of verapamil is 
239 
constipation. Patients taking verapamil should also be monitored for severe hypoglycemic 
240 
episodes, hypotension, decreased heart rate, changes in electrocardiogram (EKG) including 
241 
abnormalities in QTc and PR intervals, changes in liver function (AST and ALT), and reports of 
242 
dizziness, nausea or headaches. Use of verapamil during pregnancy may cause adverse effects 
243 
towards the fetus (e.g., bradycardia, heart block, hypotension). 
244 
 
245 
Venipuncture and MMTT Risks 
246 
Blood draws can cause some common reactions like pain, bruising, or redness at the sampling 
247 
site. Less common reactions include bleeding from the sampling site, formation of a small blood 
248 
clot or swelling of the vein and surrounding tissues, and fainting. 
249 
 
250 
The Boost drink required for the MMTT contains milk and soy ingredients. People with severe 
251 
allergies to these could have a reaction. 
252 
 
253 
Fingerstick Risks 
254 
About 1 drop of blood will be removed by fingerstick for measuring blood glucose, as needed, 
255 
and sometimes other tests. Pain is common at the time of lancing. In about 1 in 10 cases, a small 
256 
amount of bleeding under the skin will produce a bruise. A small scar may persist for several 
257 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
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weeks. The risk of local infection is less than 1 in 1000. This should not be a significant 
258 
contributor to risks in this study as fingersticks are part of the usual care for people with diabetes. 
259 
 
260 
Other Risks 
261 
Data downloaded from diabetes devices will be collected for the study. Some people may be 
262 
uncomfortable with the researchers' having such detailed information about their daily diabetes 
263 
habits. 
264 
1.2.2 Known Potential Benefits 
265 
There are recognized benefits to simply being in a clinical study, including close clinical 
266 
monitoring. 
267 
 
268 
The use of HCL therapy offers the prospect of direct benefit. As described above in this protocol, 
269 
HCL therapy is a Food and Drug Administration (FDA)-approved therapy for T1D in people 7-75 
270 
years of age. It is now being used in pediatric clinical practice and has been shown to be safe and 
271 
effective in children30. However, its efficacy in treating newly diagnosed cases of T1D is not 
272 
established, and although HCL may be prescribed at the time of T1D diagnosis, at this time it is 
273 
not the standard approach of many endocrinologists. Therefore, there is strong equipoise among 
274 
the investigators with respect to the trial’s randomization. 
275 
1.2.3 Risk Assessment 
276 
The risks for events such as DKA and severe hypoglycemia are no greater and possibly less 
277 
likely with use of HCL therapy compared with usual care not using a HCL system.  
278 
 
279 
For patients in the HCL arm, the study offers the prospect of direct benefit, including closer 
280 
monitoring than is generally clinically available, as well as the potential, if the study hypothesis 
281 
is correct, for preservation of C-peptide. Likewise, the verapamil arm offers the prospect of 
282 
direct benefit if it is demonstrated to preserve C-peptide. Participants not receiving HCL therapy 
283 
will be provided with CGM, which offers the prospect of direct benefit. 
284 
 
285 
Therefore, this protocol is consistent with the United States Department of Health and Human 
286 
Services, Protection of Human Subjects, Subpart D, section 46.405 (research involving greater 
287 
than minimal risk but presenting the prospect of direct benefit to the individual child subjects 
288 
involved in the research). 
289 
1.3 General Considerations 
290 
The study is being conducted in compliance with the policies described in the study policies 
291 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
292 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
293 
 
294 
The study will involve the use of an investigational device and an investigational drug 
295 
(verapamil will be used off-label). The U.S. Food and Drug Administration (FDA) has 
296 
determined that an investigational device exemption (IDE) will be required to conduct the study, 
297 
but not a separate investigational new drug (IND) application.  
298 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
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Chapter 2: Study Enrollment and Screening 
299 
2.1 Participant Recruitment and Enrollment 
300 
The study will recruit two cohorts—Cohort A will include participants who weigh ≥30 kg at 
301 
Screening and Cohort B will include participants who weigh <30 kg at Screening.  
302 
 
303 
Enrollment will proceed with the goal of at least 98 participants in Cohort A and 33 in Cohort B 
304 
being randomized and at least 88 in Cohort A and 30 in Cohort B completing the trial. 
305 
Participants who have signed consent and started the screening process may be permitted to 
306 
continue into the trial, if eligible, even if the randomization goal has been reached. 
307 
 
308 
Potential study participants will be identified clinically from the general pediatric diabetes new-
309 
onset population and recruited from ~6 clinical centers in the United States. All eligible 
310 
participants will be included without regard to gender, race, or ethnicity. There is no restriction 
311 
on the number of participants to be enrolled by each site toward the overall recruitment goal. The 
312 
maximum number to be enrolled for screening for the study (meaning that informed consent is 
313 
signed) is 200. 
314 
2.1.1 Informed Consent and Authorization Procedures 
315 
Potential eligibility initially may be assessed as part of a routine-care examination. Before 
316 
completing any procedures or collecting any data that are not part of usual care, written informed 
317 
consent will be obtained. 
318 
 
319 
Since all potential participants will be under 18 years of age at Screening, a parent/legal guardian 
320 
(referred to subsequently as “parent”) will be provided with the Informed Consent Form to read 
321 
and will be given the opportunity to ask questions. Potential participants will be given a Child 
322 
Assent Form (for children ages 7 to 17 years old) to read and discuss with his/her parents and 
323 
study personnel. If the parent and child agree to participate, the Informed Consent Form (and 
324 
Child Assent Form) will be signed. A copy of the consent form will be provided to the 
325 
participant and his/her parent and another copy will be added to the participant’s study record. 
326 
 
327 
As part of the informed consent process, each participant will be asked to sign an authorization 
328 
for release of personal information. The investigator will review the study-specific information 
329 
that will be collected and to whom that information will be disclosed. After speaking with the 
330 
participant, questions will be answered about the details regarding authorization. 
331 
 
332 
A participant is considered enrolled when the informed consent form has been signed. 
333 
 
334 
Participants who turn 18 during the course of the study will need to re-consent with the Informed 
335 
Consent Form. 
336 
2.2 Participant Eligibility Criteria 
337 
2.2.1 Participant Inclusion Criteria 
338 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate 
339 
in the study. 
340 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
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1. New-onset stage 3 T1D, with a history of unequivocal symptoms of T1D (e.g., 
341 
persistent/severe polyuria/polydipsia and/or weight loss) and HbA1c ≥6.5%, within 21 
342 
days of diagnosis and with ability to be randomized within 31 days of diagnosis (time 
343 
from diagnosis to screening can be longer provided that investigator is confident that all 
344 
screening testing can be completed in order to randomize the participant within 31 days 
345 
of diagnosis) 
346 
 Date of diagnosis is defined as the date that insulin therapy was started. 
347 
 If informed consent is to be signed >21 days from diagnosis, the Coordinating 
348 
Center must be contacted for confirmation of timelines prior to enrollment  
349 
2. At least one positive T1D auto-antibody  
350 
 If clearly positive result (≥20% above lab’s upper limit of normal) available at 
351 
Screening, repeat antibody testing for central lab not required 
352 
 Insulin auto-antibodies only considered if insulin use <10 days when blood drawn 
353 
3. Age 7-<18 years at the time of signing informed consent 
354 
4. Willing to provide informed consent and child assent 
355 
5. In a female participant with childbearing potential, not currently pregnant and willing to 
356 
avoid pregnancy and breastfeeding and undergo pregnancy testing prior to MMTTs for 
357 
the duration of the study.  
358 
Women of childbearing potential must use an acceptable form of birth control. 
359 
Acceptable forms include oral/injection contraceptives, transdermal contraceptives, 
360 
diaphragm, intrauterine devices, condoms with spermicide, documented surgical 
361 
sterilization of either the participant or their partner, or abstinence. 
362 
6. English speaking/reading (because of the intense interaction required with the study 
363 
team) 
364 
7. Able to swallow pills (tested with an inert imitation tablet in clinic prior to 
365 
randomization)—Cohort A only 
366 
8. Willing to not use any non-insulin glucose-lowering agents (such as GLP-1 agonists, 
367 
Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, biguanides, sulfonylureas)  
368 
9. Willing to use an insulin approved for the pump (if assigned to HCL) 
369 
10. Willing to avoid medications containing acetaminophen, and no contraindications for 
370 
ibuprofen use (in case assigned to Medtronic HCL system) 
371 
2.2.2 Participant Exclusion Criteria 
372 
Individuals meeting any of the following exclusion criteria at Screening will be excluded from 
373 
study participation. 
374 
1. Ongoing use of medications known to influence glucose tolerance such as systemic 
375 
steroids.  
376 
2. Other systemic disease, which in the opinion of the investigator precludes participation 
377 
(including psychiatric illness).  
378 
3. Unwilling to abstain from use of HCL therapy for 12 months.  
379 
 Personal pump and CGM use, including systems with a “suspend-before-low” 
380 
function, will be allowed for participants randomized to a non-HCL group. 
381 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 26 OF 64 
4.  “Silent” diabetes—i.e., Stage 3 diabetes that is identified by routine OGTT in the course 
382 
of a surveillance study but is not accompanied by fasting hyperglycemia or classic 
383 
symptoms of diabetes.  
384 
5. Participation in another research study that involves diabetes care or immune modulation 
385 
Additional Exclusion Criteria for Cohort A 
386 
6. Blood pressure (either systolic or diastolic) <5th percentile for age, gender, and height on two 
387 
out of three measurements  
388 
7. Pulse <2nd percentile for age and gender on two out of three measurements 
389 
8. History of vasovagal syncopal episodes related to hypotension  
390 
9. Abnormal EKG rhythm, unless cleared for study participation by a cardiologist 
391 
10. Underlying cardiac disease (ex. left ventricular dysfunction, hypertrophic cardiomyopathy), 
392 
certain arrhythmias (ex. AV block, accessory pathway such as Wolff-Parkinson-White or 
393 
Lown-Ganong-Levine syndromes), known liver dysfunction, known renal impairment, 
394 
Duchenne’s muscular dystrophy, active Graves disease or hyperthyroidism, and untreated 
395 
hypothyroidism 
396 
11. eGFR < 90 
397 
12. AST and/or ALT greater than 1.5 times the upper limit of normal (if results available from 
398 
usual care within 4 weeks of Screening, testing does not have to be repeated at Screening)  
399 
13. Need to use of any of the following medications during the study: beta blocker, seizure 
400 
medication (carbamazepine, phenobarbital, phenytoin), other antihypertensive medications, 
401 
HMG-CoA reductase inhibitors, lithium, theophylline, clonidine, or aspirin 
402 
14. Any known hypersensitivity reaction to Verapamil 
403 
2.3 Screening Procedures 
404 
After written informed consent and assent have been obtained, a potential participant will be 
405 
evaluated for study eligibility through the elicitation of a medical history, performance of a 
406 
physical examination by study personnel, and laboratory testing. The visit and procedures may 
407 
be performed on one or over multiple days. 
408 
 
409 
Screen Failures 
410 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
411 
date per investigator discretion, provided that they still fall in the eligibility time window from 
412 
time of diagnosis. 
413 
2.3.1 Data Collection and Testing 
414 
The following procedures will be performed/data collected/eligibility criteria checked and 
415 
documented: 
416 
 Inclusion and exclusion criteria assessed 
417 
 Demographics (date of birth, sex, race and ethnicity) 
418 
 Contact information (retained at the site and not entered into study database) 
419 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
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 Medical history 
420 
 Concomitant medications 
421 
 Physical examination, including Tanner Staging (Tanner Staging does not have to be 
422 
repeated if results available from the previous 4 weeks) 
423 
 Blood draw for Islet autoantibodies (not needed if positive autoantibodies already 
424 
available and ≥20% above lab’s upper limit of normal) 
425 
 Local urine or serum pregnancy test for all females who have reached menarche  
426 
Additional procedures for Cohort A: 
427 
 EKG (The screening EKG must be read by a pediatric cardiologist to ensure there is no 
428 
underlying abnormality that precludes study participation.) 
429 
 Blood draw for AST, ALT, creatinine (local lab; does not have to be repeated if results 
430 
available from the previous 4 weeks) 
431 
2.4 Randomization 
432 
After participants and parents/legal guardians sign the assent/consent forms and eligibility is 
433 
determined, the randomization process will occur on the study website. Randomization should 
434 
occur as soon as possible but ≤31 days from diagnosis.  
435 
 Cohort A will be randomly assigned 1:1:1:1 to receive (a) HCL and placebo, (b) HCL 
436 
and verapamil, (c) non-HCL and placebo, or (d) non-HCL and verapamil.  
437 
 Cohort B will be randomly assigned 2:1 to HCL or non-HCL. 
438 
Both randomization schedules will be stratified by clinical site using a permuted block design. 
439 
(Due to small sample size in each cohort at each site, no other factors are being used for 
440 
stratification—instead, imbalances in key variables such as age and time since diagnosis will be 
441 
adjusted for in analysis.)  
442 
 
443 
Participants assigned to a HCL group will have the HCL system assignment made through 1:1 
444 
randomization, stratified by site. 
445 
 
446 
Once a study participant is randomized, that participant will be included in the data analysis 
447 
regardless of whether the assigned treatment is received. Thus, the investigator must not proceed 
448 
to randomize an individual until he/she is convinced that the individual is eligible and will accept 
449 
whichever treatment group is assigned through randomization. 
450 
2.4.1 Randomization Visit Procedures  
451 
The following procedures should be completed at the Randomization visit: 
452 
 
453 
 Concomitant medications 
454 
 Adverse event assessment  
455 
 Recording of daily insulin dose 
456 
 Urine or serum pregnancy test for all females who have reached menarche—must be 
457 
negative before the MMTT can be started 
458 
 MMTT  
459 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 28 OF 64 
 Blood draw for the following central labs: 
460 
o HbA1c 
461 
o Proinsulin – collected during MMTT at 0 and 90 minutes time points 
462 
o Pro-IAPP – collected during MMTT at 0 and 90 minutes time points 
463 
o Unmethylated INS DNA 
464 
o PBMCs 
465 
o Cytokines 
466 
o mRNAseq 
467 
o Extra plasma for storage 
468 
 Receipt of study devices/drug and training, as applicable (see Chapters 3 and 4) 
469 
 HCL groups will receive a dietitian consult (may be remote) 
470 
 
471 
*The pregnancy test, MMTT, and labs should be completed at randomization ±3 days. Device 
472 
training and dietitian consult (as applicable) should be completed within 3 days of 
473 
randomization. 
474 
 
475 
 
 
476 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 29 OF 64 
Chapter 3: Study Devices  
477 
3.1 Description of the Study Devices 
478 
3.1.1 Hybrid Closed Loop Systems 
479 
Participants assigned to a HCL group will initially be randomly assigned 1:1 to use either the 
480 
Tandem t:slim X2 with Control-IQ technology or a Medtronic HCL system (Medtronic 670G 4.0 
481 
AHCL (prior to protocol version 5.0) or Medtronic 780G (starting with protocol version 5.0)).  
482 
Randomization is being used for the assignment solely for feasibility reasons, in order 
483 
to have an approximate equal balance between the two companies’ systems and 
484 
because there are no criteria for the investigator to determine that one company’s 
485 
system or the other would be better for a given participant. There is no intent to 
486 
compare the systems. 
487 
If the participant has significant issues with the system (such as an allergy to the adhesive or 
488 
need for waterproof feature), the participant could be switched to a different HCL system, after 
489 
consultation with one of the Protocol Chairs. 
490 
3.1.1.1 Tandem t:slim X2 with Control-IQ Technology 
491 
The system will include the Tandem t:slim X2 pump with the Control-IQ Pro software 
492 
imbedded, communicating with the Dexcom G6 CGM. The system is investigational in children 
493 
aged <6 years and the Pro software is currently only available for research. 
494 
 
495 
If the CGM signal becomes unavailable for more than 20 minutes consecutively, Control-IQ or 
496 
closed loop will not operate to automatically adjust insulin. If the CGM is not connected, the 
497 
system will revert to usual function of the pump and deliver insulin with the insulin dosing 
498 
parameters programmed in the system for that individual. Resumption of closed loop will occur 
499 
automatically once CGM signal is available again. 
500 
 
501 
If the study system is unable to activate Control-IQ for any reason, the pump will automatically 
502 
revert to preprogrammed basal insulin delivery without any need for instruction from the user. The 
503 
user should assess the pump for error messages and take the necessary steps to restart closed loop.  
504 
 
505 
If the t:slim X2 detects a system error that does not allow the pump to operate, a Malfunction 
506 
Alarm will display. Participants will follow guidance documents to resolve the issue.  
507 
3.1.1.2 Medtronic 670G 4.0 AHCL and Medtronic 780G 
508 
The  Medtronic system will be either the Medtronic 670G 4.0 AHCL insulin pump 
509 
communicating with the Medtronic Guardian 3 CGM (for participants that enrolled prior to 
510 
protocol version 5.0) or, for participants that enrolled after the implementation of protocol 
511 
version 5.0, the Medtronic 780G insulin pump communicating with the Medtronic Guardian 4 
512 
CGM. Both systems are investigational.   
513 
 
514 
Participants already enrolled in the study and using the Medtronic 670G 4.0 AHCL may 
515 
transition to the Medtronic 780G if desired.  Contacts will be performed to review CareLink data 
516 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 30 OF 64 
and check for adverse events and device deficiencies on days 1, 3 and 5 after transition from 
517 
670G 4.0 AHCL to 780G.   
518 
 
519 
New study participants aged 7-13 years using the Medtronic 670G 4.0 AHCL system or 
520 
Medtronic 780G system will start at the 120 mg/dL setpoint for 2 weeks. The setpoint will then 
521 
be adjusted to 100 mg/dL. New study participants aged 14 years and older will use a setpoint of 
522 
100 mg/dL from the beginning.  
523 
 
524 
If the study system exits from HCL mode for any reason, the pump will automatically revert to 
525 
preprogrammed basal insulin delivery. The suspend before low feature will be automatically 
526 
enabled for participants using the Medtronic 780G system. The user should assess the pump for 
527 
error messages and take the necessary steps to restart Auto Mode/SmartGuard.  
528 
 
529 
If the Medtronic 670G 4.0 AHCL or Medtronic 780G detect a system error that does not allow the 
530 
pump to operate, the Malfunction Alarm will display. Participants will follow guidance documents 
531 
to resolve the issue.  
532 
 
533 
Participants will be instructed to calibrate the Medtronic 670G 4.0 AHCL system CGM in 
534 
accordance with manufacturer labelling.  With the Medtronic 780G system and the Guardian 4 
535 
Transmitter, calibration is not required.  However, a calibration is optional and will occur if a BG 
536 
is entered.  Occasionally, participants may receive a notification if the pump needs a BG to enter 
537 
or stay in Auto Mode/SmartGuard.   
538 
 
539 
Medtronic 780G Continued Access Period: 
540 
Prior to the 780G system becoming commercially available, study participants using the 
541 
Medtronic system at 52 weeks will have the opportunity to continue using the 780G system at 
542 
home until the system is commercially available OR until the CLVer trial is complete (last 
543 
participant’s 52-week visit), whichever comes first.  During the continued access period, 
544 
participants will be asked to use the system as intended. At usual care visits (post-RCT, 
545 
approximately every 3 months), adverse events and device issues will be captured. 
546 
 
547 
3.1.2 Dexcom G6 Continuous Glucose Monitoring System 
548 
Participants assigned to a non-HCL group will be provided a commercially available Dexcom 
549 
G6 CGM and will be instructed to use it according to the user manual. 
550 
 
551 
Any participants who stop using a CGM or have insufficient CGM data will wear a blinded 
552 
Dexcom sensor for approximately 10 days at 6, 13, 26, 39 and 52 weeks. The blinded sensor will 
553 
be placed at or before the clinic visit and then the participant will mail the receiver back to the 
554 
clinic or Coordinating Center (or could return it to the clinic in person) for download after 
555 
blinded wear unless there is a mechanism for data transfer to occur from home. Participants with 
556 
insufficient data may be asked to wear a blinded sensor for another 10 days at certain time 
557 
points. 
558 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 31 OF 64 
3.1.3 Blood Glucose Meter and Strips 
559 
Participants using the Medtronic HCL system will be provided with a meter and test strips for 
560 
sensor calibration for the duration of the study.  
561 
 
562 
All other participants will use a blood glucose meter and test strips that they obtain through their 
563 
insurance. 
564 
 
565 
Participants without insurance may be provided with a meter and test strips. 
566 
3.1.4 Ketone Meter and Strips 
567 
For participants using a study HCL system, blood ketone levels will be measured using the Abbott 
568 
Precision Xtra meter and blood ketone strips in accordance with the manufacturer’s labeling, 
569 
which will be provided to participants in HCL groups. The blood glucose meter component of the 
570 
Precision Xtra device will not be used. 
571 
 Participants will be instructed on how to perform blood ketone testing per manufacturer 
572 
guidelines. 
573 
 Participants will be given guidelines for treatment of elevated blood ketones. 
574 
Participants in the non-HCL group will perform ketone monitoring per usual care.  
575 
3.2 Study Device Accountability Procedures 
576 
Device accountability procedures will be detailed in the site procedures manual. 
577 
 
578 
Participant may keep the study ketone meter, blood glucose meter, and CGM if these devices are 
579 
not marked for investigational use only and there is not a requirement from the company 
580 
providing the devices to return them. Participants will need to return all investigational study-
581 
provided devices at study end. 
582 
3.3 Safety Measures 
583 
Any time glucose alerts and CGM readings do not match symptoms or expectations or CGM is 
584 
failing, a blood glucose meter should be used to make diabetes treatment decisions. 
585 
3.3.1 Hypoglycemia Threshold Alert and Safety Protocol 
586 
During the course of the study, participants will be permitted to change the CGM low glucose 
587 
threshold alert setting on their device or mobile app. If the participant’s total daily insulin dose is 
588 
< 0.5 units/kg and he/she is having <3% of sensor glucose readings <70 mg/dL, then the threshold 
589 
alarm can be lowered to 65 mg/dL. Otherwise, study participants will be advised to choose a value 
590 
no less than 70 mg/dL. 
591 
 
592 
If a participant receives a CGM hypoglycemia threshold or predictive alarm or notes that the 
593 
CGM glucose is below the hypoglycemia threshold alarm value, confirmatory fingerstick testing 
594 
will be performed if required by CGM labeling and the participant will be instructed to use the 
595 
appropriate treatment of hypoglycemia. 
596 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 32 OF 64 
3.3.2 Hyperglycemia Threshold Alert and Safety Protocol 
597 
During the course of the study, participants will be permitted to change the CGM high glucose 
598 
threshold alert setting on their device or mobile app, but will be instructed to choose a value no 
599 
greater than 300 mg/dL. If a participant receives a CGM hyperglycemia threshold alarm or notes 
600 
that the CGM glucose is above the hyperglycemia threshold alarm value, confirmatory fingerstick 
601 
testing will be performed if required by CGM labeling. If a participant’s CGM reading is >300 
602 
mg/dL for over 1 hour or ≥400 mg/dL at any point, the participant will be instructed to take the 
603 
following steps: 
604 
 Perform a blood glucose meter check. 
605 
 If the blood glucose is >300 mg/dL, check for blood ketones with the study ketone meter. 
606 
 If the ketone level is ≥1.0 mmol/L, take correction insulin via syringe/pen, change insulin 
607 
(pump) infusion site and contact study staff. 
608 
 If a participant administers correction insulin via insulin syringe/pen, participants will be 
609 
instructed to turn hybrid closed loop mode off for approximately four hours. 
610 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 33 OF 64 
Chapter 4: Study Drug 
611 
4.1 Study Agent(s) and Control Description 
612 
4.1.1 Acquisition 
613 
The Central Pharmacy will obtain commercially available verapamil extended release 120 mg 
614 
tablets and will make a placebo to match the drug (referred to collectively as Study Drug). The 
615 
placebo will be comprised of GRAS excipients and where possible, excipients included in the 
616 
commercial verapamil 120 mg XR tablet. 
617 
 
618 
The Study Drug will be bottled and labeled by the pharmacy as 100 tablets per bottle. Each bottle 
619 
label will contain a drug number provided by the Coordinating Center and both study 
620 
participants and investigators will be blinded to the drug assignment. 
621 
4.1.2 Dosing and Administration 
622 
Study Drug will be taken orally once per day. The following dosing scheme, using 120 mg 
623 
tablets or 60 mg half tablets as guided by the dosing scheme below, will be used by Cohort A:  
624 
 
625 
<30 kg: none 
626 
 
627 
30-34 kg: 
628 
60 mg/day x 4 weeks, then 120 mg/day x 48 weeks 
629 
Max Dose 3.5-4 mg/kg/day 
630 
 
631 
35-49 kg: 
632 
60 mg/day x 2 weeks, then 120 mg/day x 2 weeks, then 180 mg/day x 2 weeks, then 240 mg/day 
633 
x 46 weeks 
634 
Max dose 4.9-6.9 mg/kg/day 
635 
 
636 
50+kg: 
637 
120 mg/day 2 weeks, then 180 mg/day x 2 weeks, then 240 mg/day x 2 weeks, then 300 mg/day 
638 
x 2 weeks, then 360 mg/day x 44 weeks 
639 
Max dose 7.2 mg/kg/day 
640 
 
641 
Participants will be provided with a pill splitter and will cut the tablets at home, while half tablets 
642 
are needed during the titration.  
643 
 
644 
If a participant in Cohort B reaches body weight of ≥30 kg, he/she will not receive study drug. 
645 
4.1.3  Dose Adjustments/Modifications/Delays 
646 
The dose of Study Drug can be reduced/discontinued at investigator discretion if side effects 
647 
develop or abnormality is found on clinical exam, EKG, or blood testing. 
648 
 
649 
The dose also may be adjusted if the participant’s weight changes during the study, per above 
650 
dosing scheme. The participant’s weight will be assessed for possible dose changes at scheduled 
651 
study visits. 
652 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 34 OF 64 
4.1.1 Dispensing Study Drug 
653 
At each visit (Randomization –39 week), participants in Cohort A will be provided a sufficient 
654 
number of bottles of drug to last until the next visit (beyond the end of the window of the next 
655 
visit). 
656 
4.1.2 Assessing Participant Adherence 
657 
Participants will be asked to bring all bottles of Study Drug dispensed to them to each visit 
658 
where any remaining pills will be counted. Sites are to keep all used and unused inventory for 
659 
monitoring. 
660 
4.2 Study Agent Accountability Procedures 
661 
Drug accountability procedures will be detailed in the site procedures manual. 
662 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 35 OF 64 
Chapter 5: Diabetes Management 
663 
5.1 Participants Using Hybrid Closed Loop  
664 
Participants will be trained and will start the pump and CGM in open-loop mode with the 
665 
suspend-before-low feature activated (on Medtronic systems) within 3 days of randomization. 
666 
HCL therapy will be started at the day 7 training visit. Participants/parents will be instructed to 
667 
perform overnight fingersticks for two nights after initiation of HCL, as well as for two nights 
668 
after a decrease in setpoint. 
669 
 
670 
Participants will meet with a dietitian for education regarding carbohydrate counting. They will 
671 
be given age appropriate carb targets for meals and snacks. They will be encouraged to eat at 
672 
least 3 meals per day and add protein and fat to breakfast every day. They will also be instructed 
673 
to give insulin 15 minutes before eating, unless glucose <70 mg/dL. If glucose is <70 mg/dL 
674 
before a meal, patient will be instructed to consume 8-15 grams of carbohydrate, depending on 
675 
glucose concentration, prior to giving insulin for the meal. 
676 
 
677 
The participant’s parent/legal guardian will be required to attend the training procedures and will 
678 
be trained in all aspects aforementioned. All training will be conducted considering age of 
679 
participant and parent involvement in his/her diabetes treatment.  
680 
 
681 
Upon completion of HCL training, study staff will document using a checklist that the participant 
682 
is familiar with the function/feature and/or capable of performing each of the tasks specified. 
683 
 
684 
Participants will be provided hypoglycemia, hyperglycemia, and ketone guidelines (see Section 3.3) 
685 
for when their glucose levels are >300 mg/dL for more than 1 hour or >400 mg/dL at any time or 
686 
<70 mg/dL or ketones ≥1.0 mmol/L.  
687 
5.1.1 Home Use of HCL 
688 
The specific approach to HCL therapy will be outlined in the site procedures manual and will be 
689 
individualized to the participant’s needs. General principles include: 
690 
 
Participants will be instructed to bolus 15 minutes before meals or snacks, unless 
691 
glucose is <70 mg/dL.  
692 
o 
If glucose is 54-<70 mg/dL, participants will be instructed to consume 8-10 grams 
693 
of carbohydrate before delivering the meal or snack bolus. 
694 
o 
If glucose is <54 mg/dL, participants will be instructed to consume 15 grams of 
695 
carbohydrate before delivering the meal or snack bolus. 
696 
 
Participants will be instructed to calibrate the sensor as recommended by the 
697 
manufacturer (if needed). 
698 
 
Participants will be asked to upload their pump/CGM data prior to each contact (unless 
699 
this occurs automatically). Participants may be provided with a laptop to use during the 
700 
study if necessary. The study team will be in contact with the participants to make 
701 
adjustments to settings and recommendations to change behaviors will be made as 
702 
needed.  
703 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 36 OF 64 
 
Guidelines for time in HCL, insulin delivery, target range, and sensor wear as well as 
704 
management of diet, exercise and hypoglycemia can be found in the site procedures 
705 
manual and/or participant guidance documents. 
706 
The participant will be instructed to use the system in closed-loop mode except 1) when no 
707 
calibrated CGM sensor is available, 2) if insulin is delivered by any means other than the study 
708 
pump (e.g., injection of subcutaneous insulin via syringe/pen in the event of infusion site failure), 
709 
or 3) if participant is hospitalized. If insulin is delivered by any means other than the study 
710 
pump, participant will be instructed to turn off HCL for approximately four hours. If participant 
711 
is hospitalized, participant must be in open loop (but can use suspend before low feature). 
712 
 
713 
The participant will also be instructed to contact study staff during periods of illness with an 
714 
elevated temperature >101.5 degrees Fahrenheit (38.6 degrees Celsius), periods of significant 
715 
illness, or during periods of use of medications such as epinephrine for the emergency treatment 
716 
of a severe allergic reaction or asthma attack in addition to use of oral or injectable 
717 
glucocorticoids to determine if closed-loop use should be temporarily discontinued. 
718 
 
719 
Parents/guardians who have been trained on the study devices will be instructed to be present at 
720 
night with the participants, as much as possible. If remote monitoring is not available, baby 
721 
monitors will be provided so the parent can hear alarms. 
722 
 
723 
Participants will be provided with guidance documents with instructions for how to handle any 
724 
health-related issues and technical issues with the HCL system. The guidance will also include 
725 
instructions on checking blood glucose when sensor glucose is high or low and how to treat 
726 
based on the fingerstick blood glucose value. Participants may use the study pump without the 
727 
AID algorithm activated and study CGM during periods of component disconnections or 
728 
technical difficulties. Participants can contact study staff to ask any questions they may have 
729 
during the study. 
730 
 
731 
Study staff will discuss with the participant that routine contact is required and will make 
732 
arrangements with the participant for the contacts. If the participant cannot be reached, the 
733 
participant’s other contact methods will be utilized, including the emergency contact. 
734 
Participants who are not compliant with the arranged contacts on two separate occasions may 
735 
be discontinued at the discretion of the investigator.  
736 
5.1.2 Discontinuation of HCL 
737 
Participants in an HCL group who discontinue HCL will continue to receive diabetes 
738 
management from the study team. They will be encouraged to continue to use the study pump 
739 
and CGM in open-loop mode. Efforts will be made to help them return to HCL, including a 
740 
possible switch to another HCL system. Participants discontinuing pump use will be asked to 
741 
keep a log of insulin dose for 3 days prior to each study visit.  
742 
5.1.3 Transition to Usual Care at End of Study 
743 
At the end of the study, the participants will be required to return the study Tandem HCL system 
744 
to the site. The investigator will determine with the participant whether the participant will 
745 
switch to a personal HCL system, use multiple daily injections or an insulin pump. As noted in 
746 
section 3.1.1.2, participants initially assigned to and using the Medtronic 780G HCL system will 
747 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 37 OF 64 
be able to continue use until the HCL system is commercially available OR until the CLVer trial 
748 
is complete (last participant’s 52 week visit). 
749 
 Participants that initially started the study using the 670G, and who have opted to switch 
750 
to the 780G, will also have the option to continue using the HCL system.  
751 
5.2 Participants Assigned to Groups Not Using Hybrid Closed Loop 
752 
Participants will receive standard diabetes care and be managed by their primary diabetes team or 
753 
a designated control-arm management team. Study investigators assigned to the intensive 
754 
management group will not provide routine diabetes care for these participants. 
755 
 
756 
Since the CGM is being prescribed from the time of diagnosis of T1D with high frequency and 
757 
rapidly becoming standard care, the study will provide a commercially available Dexcom G6 
758 
CGM device and sensors for all participants. CGM initiation will be performed by the study team 
759 
but further training and management of the CGM will be provided by the participant’s primary 
760 
diabetes care team or a designated control-arm management team, not study staff assigned to the 
761 
intensive management group. 
762 
 
763 
Insulin therapy will include either MDI or insulin pump therapy per patient and provider 
764 
preference. Participants may use sensor augmented pump therapy with a suspend-before-low 
765 
feature; however, use of automated HCL insulin delivery will be prohibited. Insulin dosing 
766 
decisions and instructions will be handled by the participant’s primary diabetes team. 
767 
 
768 
Participants using MDI will be asked to keep a log of insulin dose for 3 days prior to each study 
769 
visit. 
770 
 
771 
For Cohort A, verapamil/placebo use will be managed by the study team. 
772 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 38 OF 64 
Chapter 6: Follow-up Visit Schedule 
773 
6.1 Study Visits and Phone Contacts 
774 
Follow-up visits for all groups in both cohorts will occur 6 weeks from randomization and 13, 
775 
26, 39, and 52 weeks from the date of T1D diagnosis.  
776 
 
777 
The HCL groups also will have an education visit about 7 days after randomization (i.e., ‘day 7 
778 
visit’), to cover additional training and initiate HCL. This education visit may be conducted 
779 
remotely, per investigator discretion. All system requirements for initiating HCL will be met 
780 
prior to starting HCL.  
781 
 
782 
Phone or email/text contacts will be completed by certified study staff every 1-3 days for the first 
783 
two weeks, at least twice a week for the second two weeks and then every 1-2 weeks for the 
784 
duration of the 12 months. The email/text contacts must not include any unnecessary identifying 
785 
information (e.g., cannot include protected health information (PHI) other than first names in the 
786 
greeting). Participants in the HCL groups can have unlimited contact with the study team 
787 
throughout the study. Participants enrolled in the study who desire to transition from the 
788 
Medtronic 670G 4.0 AHCL to the Medtronic 780G will have additional contacts to review 
789 
CareLink data and check for adverse events and device deficiencies on days 1, 3 and 5 after the 
790 
transition. 
791 
 
792 
Additionally, Cohort A participants will have a safety visit 7 ±5 days after drug initiation and 
793 
after each dose increase to assess blood pressure and pulse. This visit may occur in clinic with 
794 
certified study staff or remotely, via a telehealth visit, using a study-provided blood pressure and 
795 
pulse machine at home.  
796 
 
797 
Participants will remain in the study and continue use of study interventions until the final study 
798 
visit is completed, even if the final visit is delayed. 
799 
6.1.1 Study Visits and Windows 
800 
Target dates and windows for each study follow-up visit (6 week timed from randomization and 
801 
all others timed from date of diagnosis) for all treatment groups in both cohorts are shown below: 
802 
Target Day/Week 
Target Window 
(around Target 
Day/Week)
Allowable Window 
(around Target 
Day/Week)
Week 6*
+/- 3 days
+/- 7 days
Week 13 (3 mo)
+/- 3 days
+/- 7 days
Week 26 (6 mo)
+/- 7 days
+/- 14 days
Week 39 (9 mo)
+/- 7 days
+/- 14 days
Week 52 (12 mo)
+/- 7 days
+/- 14 days
*The 6 week visit may be conducted remotely  
803 
6.1.2 Procedures at Study Follow-up Visits 
804 
The following procedures will be performed at each visit listed in the table above, unless 
805 
otherwise specified: 
806 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 39 OF 64 
 Adverse event assessment  
807 
 Concomitant medications review 
808 
 Recording of total daily insulin dose 
809 
 Compliance assessment (pill count and self-report) 
810 
 Device downloads (pump, CGM, and ketone meter) 
811 
 Physical examination: Limited, targeted physical exam at visits prior to 52 week visit with 
812 
complete physical exam, including Tanner staging, performed at the 52 week visit.  
813 
o The 52 week Tanner staging is not necessary for those who were Tanner 
814 
Stage 5 at Screening 
815 
o The limited physical exam may be skipped at 6 week visit, when visit is 
816 
conducted remotely 
817 
 Urine or serum pregnancy test for all females who have reached menarche—must be 
818 
negative before the MMTT can be started (13, 26, 39, and 52 week visits) 
819 
 MMTT (13, 26, 39, and 52 week visits) 
820 
 Blood draw for central labs: 
821 
o HbA1c (13, 26, 39, and 52 week visits) 
822 
o Proinsulin – collected during MMTT at 0 and 90 minutes time points (13, 26, 39, and 
823 
52 week visits)  
824 
o Pro-IAPP – collected during MMTT at 0 and 90 minutes time points (13, 26, 39, and 
825 
52 week visits)  
826 
o Unmethylated INS DNA (13, 26, 39, and 52 week visits)  
827 
o mRNAseq (13, 26, 39, and 52 week visits)  
828 
o PBMC (26, and 52 week visits only)  
829 
o Serum cytokines (26, and 52 week visits only)  
830 
o Extra plasma for storage (26 and 52 week visits only) 
831 
 Blinded CGM placement for participants not using CGM* (except at 52 week visit, see note 
832 
below) 
833 
 Additional testing for the Cohort A participants will include: 
834 
o EKG (6, 26, and 52 week visits)  
835 
 Any automated EKG readings suggesting abnormalities in QTc and/or PR 
836 
intervals will be referred to a pediatric cardiologist for interpretation 
837 
o Blood draw for AST/ALT (6, 26, and 52 week visits) 
838 
 HCL groups will receive a dietitian consult (may be remote and is not required at 52 
839 
week visit) 
840 
 
841 
*A blinded CGM for participants not using CGM will be placed prior to, rather than at, the 52 
842 
week visit. The participant will either return to the clinic prior to the 52 week visit to have the 
843 
sensor placed or the participant will be provided with a sensor inserter kit at the 39 week visit 
844 
for the participant to place at home, wear, and return prior to the 52 week visit. Details are 
845 
described in the site procedures manual. 
846 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 40 OF 64 
6.1.3 Participant Contact outside of Study Visits  
847 
During the study, participants in the HCL therapy groups will have HCL downloads regularly 
848 
reviewed and adjustments made as indicated by the investigators. The study team will contact the 
849 
participant every 1-3 days for the first two weeks, at least twice a week for the second two 
850 
weeks, and every 1-2 weeks for the remainder of the study. The first two times pump settings are 
851 
changed by the participant, the device will be reuploaded so the site can confirm it was done 
852 
correctly.  
853 
 
854 
Participants in the non-HCL standard therapy group will have their diabetes managed by their 
855 
primary diabetes team (which will not include members of the study team assigned to the 
856 
intensive management group) according to standard clinical practice. These clinical contacts will 
857 
be standard care and not considered study contacts. 
858 
6.1.4 Unscheduled Visits 
859 
An unscheduled visit may be performed at investigator discretion.
860 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 41 OF 64 
Chapter 7: Testing Procedures 
861 
7.1 Physical Examination 
862 
A standard physical exam will be performed by the study investigator or designee (a physician, 
863 
fellow, nurse practitioner or a physician assistant) at Screening and each visit except the day 7 
864 
visit (no exam) and study drug safety visits (collection of blood pressure and pulse only). The 
865 
standard physical exam will include vital signs (including measurement of blood pressure, pulse, 
866 
height and weight) and examination of injection/insertion sites. A complete physical exam, 
867 
including Tanner staging, will be obtained at Screening and at the 52 week visit (no repeat 
868 
Tanner staging for those who are Tanner 5 at Screening).  
869 
 
870 
The physical exam is not required at the 6 week visit when visit is conducted remotely.  
871 
 
872 
For Cohort A, at Screening, blood pressure and pulse will be tested three times to assess 
873 
eligibility. At follow up visits, blood pressure and pulse are only tested one time, unless any 
874 
result has been abnormal. If abnormal, 3 readings will be obtained each time and the blood 
875 
pressure should be tested manually. 
876 
7.2 Laboratory Testing 
877 
1. Diabetes auto-antibody panel: 
878 
Blood for IAA, IA-2, GAD65, and ZnT8 measurement will be obtained at Screening visit 
879 
and sent to a central laboratory (unless auto-antibody results are already available and 
880 
≥20% above lab’s upper limit of normal).  
881 
2. EKG 
882 
For Cohort A, an EKG will be performed at Screening and at the 6, 26, and 52 week 
883 
visits. The screening EKG must be read by a pediatric cardiologist to ensure there is no 
884 
underlying abnormality that precludes study participation. The automated reading will be 
885 
acceptable if normal for subsequent EKGs. Any automated EKG readings suggesting 
886 
abnormalities in QTc and/or PR intervals will be referred to a pediatric cardiologist for 
887 
interpretation. 
888 
3. Liver function tests 
889 
For Cohort A, AST/ALT will be measured locally at Screening and at the 6, 26, and 52 
890 
week visits 
891 
4. Kidney tests 
892 
For Cohort A, creatinine will be measured locally at Screening and used to calculate 
893 
eGFR 
894 
5. Urine or serum pregnancy: 
895 
Performed locally for females with childbearing potential at Screening and each follow 
896 
up visit, and also anytime pregnancy is suspected. Must be negative to perform the 
897 
MMTT. 
898 
6. MMTT: 
899 
2-hour MMTT for stimulated glucose and C-peptide will be done at Randomization, 13, 
900 
26, 39, and 52 week visits, with samples collected at 0, 15, 30, 60, 90 and 120 minutes. 
901 
Criteria will be detailed in the site procedures manual.  
902 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 42 OF 64 
7. HbA1c: 
903 
Collected for central lab analysis at Randomization, 13, 26, 39, and 52 week visits  
904 
8. Measures of beta cell health and immune function: 
905 
Blood/serum/plasma will be drawn and sent to the appropriate lab, to assess several 
906 
measures detailed below. Samples at some of the time points may or may not be run 
907 
depending on final study results. 
908 
i. Pro-insulin and Pro-IAPP and their ratios to C-peptide during the MMTT at 0 and 
909 
90 minutes, collected at Randomization, 13, 26, 39, and 52 week visits 
910 
ii. Circulating unmethylated INS DNA, collected at Randomization, 13, 26, 39, and 
911 
52 week visits 
912 
iii. Circulating plasma miRNA sequencing, collected at Randomization, 13, 26, 39, 
913 
and 52 week visits 
914 
iv. T-cell characteristics by PBMC and peripheral cytokine levels, collected at 
915 
Randomization, 26 and 52 week visits only. 
916 
v. Collection and storage of extra samples of plasma as blood volume limitations for 
917 
size allow and/or storage of any remaining samples for future research, collected at 
918 
Randomization, 26, and 52 week visits only, as approved by the participants. 
919 
 
920 
Local laboratory testing will be performed if needed to screen for exclusionary medical 
921 
conditions. 
922 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 43 OF 64 
Chapter 8: Unanticipated Problems, Adverse Events, 
923 
Device Issues, and Stopping Rules 
924 
8.1 Unanticipated Problems 
925 
Site investigators will promptly report to the Coordinating Center on a CRF all unanticipated 
926 
problems meeting the criteria below. Sites overseen by the JCHR IRB must report Unanticipated 
927 
Problems to the IRB within seven calendar days of recognition. For this protocol, an 
928 
unanticipated problem is an incident, experience, or outcome that meets all of the following 
929 
criteria: 
930 
 Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
931 
that are described in the protocol related documents, such as the IRB-approved research 
932 
protocol and informed consent document; and (b) the characteristics of the subject 
933 
population being studied 
934 
 Related or possibly related to participation in the research (possibly related means there is 
935 
a reasonable possibility that the incident, experience, or outcome may have been caused 
936 
by the procedures involved in the research) 
937 
 Suggests that the research places participants or others at a greater risk of harm than was 
938 
previously known or recognized (including physical, psychological, economic, or social 
939 
harm) 
940 
The Coordinating Center also will report to the IRB all unanticipated problems not directly 
941 
involving a specific site such as unanticipated problems that occur at the Coordinating Center or 
942 
at another participating entity such as the central laboratory. These instances must be reported to 
943 
the JCHR IRB within seven calendar days of recognition. The Director of the Human Research 
944 
Protection Program will report to the appropriate regulatory authorities if the IRB determines 
945 
that the event indeed meets the criteria of an Unanticipated Problem requiring additional 
946 
reporting. 
947 
8.2 Adverse Events 
948 
8.2.1 Definitions 
949 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
950 
relationship between the adverse event and the drug/device(s) under investigation (see Section 
951 
8.2.2 for reportable adverse events for this protocol). 
952 
 
953 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
954 
 Results in death. 
955 
 Is life-threatening; (a non-life-threatening event which, had it been more severe, might 
956 
have become life-threatening, is not necessarily considered a serious adverse event). 
957 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
958 
 Results in persistent or significant disability/incapacity or substantial disruption of the 
959 
ability to conduct normal life functions (sight threatening). 
960 
 Is a congenital anomaly or birth defect. 
961 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 44 OF 64 
 Is considered a significant medical event by the investigator based on medical judgment 
962 
(e.g., may jeopardize the participant or may require medical/surgical intervention to 
963 
prevent one of the outcomes listed above). 
964 
 
965 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
966 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
967 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
968 
package insert, this protocol, or the informed consent document, or any other unanticipated 
969 
serious problem associated with a device that relates to the rights, safety, or welfare of 
970 
participants (21 CFR 812.3(s)). 
971 
 
972 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which 
973 
the device may have caused or to which the device may have contributed (Note that an Adverse 
974 
Event Form is to be completed in addition to a Device Deficiency or Issue Form, unless excluded 
975 
from reporting as defined in Sections 8.2.2-8.2.4). An event that occurs solely due to participant 
976 
(i.e., user) error in which the device functions properly generally will not be considered an ADE 
977 
unless it is determined that the instructions on the screen of the device or user manual (or 
978 
similar training materials) may have contributed to the event (note: the event may still meet 
979 
criteria for reporting as an adverse event). 
980 
 
981 
Device Complaints and Malfunctions: A device complication or complaint is something that 
982 
happens to a device or related to device performance, whereas an adverse event happens to a 
983 
participant. A device complaint may occur independently from an AE, or along with an AE. An 
984 
AE may occur without a device complaint or there may be an AE related to a device complaint. 
985 
A device malfunction is any failure of a device to meet its performance specifications or 
986 
otherwise perform as intended. Performance specifications include all claims made in the 
987 
labeling for the device. The intended performance of a device refers to the intended use for 
988 
which the device is labeled or marketed. (21 CFR 803.3). Note: for reporting purposes, sites will 
989 
not be asked to distinguish between device complaints and malfunctions. 
990 
8.2.2 Reportable Adverse Events 
991 
A reportable adverse event includes all events meeting the definition of an adverse event, except 
992 
as noted below. 
993 
 
994 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
995 
events unless associated with an Adverse Device Effect. Skin reactions from sensor placement 
996 
are only reportable if severe and/or required treatment. 
997 
 
998 
All reportable AEs—whether volunteered by the participant, discovered by study personnel 
999 
during questioning, or detected through physical examination, laboratory test, or other means—
1000 
will be reported on an AE form online. Each AE form is reviewed by the Medical Monitor to 
1001 
assess safety and to verify the coding and the reporting that is required. 
1002 
8.2.3 Hypoglycemic Events 
1003 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
1004 
event when the following definition for severe hypoglycemia is met: the event required 
1005 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 45 OF 64 
assistance of another person due to altered consciousness, and required another person to actively 
1006 
administer carbohydrate, glucagon, or other resuscitative actions. This means that the participant 
1007 
was impaired cognitively to the point that he/she was unable to treat himself/herself, was unable 
1008 
to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or experienced seizure 
1009 
or loss of consciousness. These episodes may be associated with sufficient neuroglycopenia to 
1010 
induce seizure or loss of consciousness. If plasma glucose measurements are not available during 
1011 
such an event, neurological recovery attributable to the restoration of plasma glucose to normal 
1012 
is considered sufficient evidence that the event was induced by a low plasma glucose 
1013 
concentration. 
1014 
 
1015 
When a hypoglycemic event meets the above reporting requirements, a Hypoglycemia Form 
1016 
should be completed in addition to the Adverse Event Form. Severe hypoglycemia events should 
1017 
be considered to be serious adverse events with respect to reporting requirements. 
1018 
8.2.4 Hyperglycemic/Ketotic Events 
1019 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
1020 
event when one of the following 3 criteria is met:  
1021 
 the event involved DKA, as defined by the Diabetes Control and Complications Trial 
1022 
(DCCT) and described below 
1023 
 evaluation or treatment was obtained at a health care provider facility for an acute event 
1024 
involving hyperglycemia or ketosis, or the participant contacted the site and received 
1025 
guidance on how to manage the hyperglycemia/ketosis 
1026 
 blood ketone level >1.5 mmol/L, even if there was no communication with a health care 
1027 
provider at the time of the event 
1028 
 
1029 
Hyperglycemic events are classified as DKA if the following are present: 
1030 
 Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
1031 
 Serum ketones >1.5 mmol/L or large/moderate urine ketones; 
1032 
 Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
1033 
 Treatment provided in a health care facility 
1034 
 
1035 
When a hyperglycemia/ketotic event meets the above reporting requirements, a 
1036 
Hyperglycemia/DKA Form should be completed in addition to the Adverse Event Form. Events 
1037 
meeting DKA criteria should be considered to be serious adverse events with respect to reporting 
1038 
requirements. Hyperglycemia events not meeting criteria for DKA generally will not be 
1039 
considered as serious adverse events unless one of the SAE criteria in Section 8.2.1 is met. 
1040 
8.2.5 Relationship of Adverse Event to Study Device, Drug, or Procedure 
1041 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1042 
by determining if there is a reasonable possibility that the adverse event may have been caused 
1043 
by a study device, drug or procedure. 
1044 
 
1045 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1046 
following general guideline when determining whether an adverse event is related: 
1047 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 46 OF 64 
 
1048 
Yes 
1049 
There is a plausible temporal relationship between the onset of the adverse event and the study 
1050 
device, drug or procedure, and the adverse event cannot be readily explained by the participant’s 
1051 
clinical state, intercurrent illness, or concomitant therapies; and/or the adverse event follows a 
1052 
known pattern of response to the study device, drug or procedure; and/or the adverse event 
1053 
abates or resolves upon discontinuation of the study device, drug or procedure or dose reduction 
1054 
and, if applicable, reappears upon re-challenge. 
1055 
 
1056 
No 
1057 
Evidence exists that the adverse event has an etiology other than the study device, drug or 
1058 
procedure (e.g., preexisting medical condition, underlying disease, intercurrent illness, or 
1059 
concomitant medication); and/or the adverse event has no plausible temporal relationship to 
1060 
study device, drug or procedure. 
1061 
8.2.6 Severity (Intensity) of Adverse Events 
1062 
The severity (intensity) of an adverse event will be rated on a three point scale: (1) mild, (2) 
1063 
moderate, or (3) severe. A severity assessment is a clinical determination of the intensity of an 
1064 
event. Thus, a severe adverse event is not necessarily serious. For example, itching for several 
1065 
days may be rated as severe, but may not be clinically serious. 
1066 
 MILD: Usually transient, requires no special treatment, and does not interfere with the 
1067 
participant’s daily activities. 
1068 
 MODERATE: Usually causes a low level of inconvenience, discomfort or concern to the 
1069 
participant and may interfere with daily activities, but is usually ameliorated by simple 
1070 
therapeutic measures and participant is able to continue in study. 
1071 
 SEVERE: Interrupts a participant’s usual daily activities, causes severe discomfort, may 
1072 
cause discontinuation of study device, and generally requires systemic drug therapy or 
1073 
other treatment. 
1074 
8.2.7 Expectedness 
1075 
For a serious adverse event that is considered possibly related to study device or drug, the 
1076 
Medical Monitor will classify the event as unexpected if the nature, severity, or frequency of the 
1077 
event is not consistent with the known risk information. 
1078 
8.2.8 Coding of Adverse Events 
1079 
Adverse events will be coded using the MedDRA dictionary. To facilitate coding, the site will 
1080 
enter a preliminary MedDRA code which the Medical Monitor may accept or change (the 
1081 
Medical Monitor’s MedDRA coding will be used for all reporting). The Medical Monitor will 
1082 
review the investigator’s assessment of causality and may agree or disagree. Both the 
1083 
investigator’s and Medical Monitor’s assessments will be recorded. The Medical Monitor will 
1084 
have the final say in determining the, expectedness and causality as well as whether an event is 
1085 
classified as a serious adverse event and/or an unanticipated adverse device effect. 
1086 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 47 OF 64 
8.2.9 Outcome of Adverse Events 
1087 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
1088 
 RECOVERED/RESOLVED – The participant recovered from the AE/SAE without 
1089 
sequelae. Record the AE/SAE stop date. 
1090 
 RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had 
1091 
stabilized without change in the event anticipated. Record the AE/SAE stop date. 
1092 
 FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the event 
1093 
that was the cause of death should be reported as fatal. AEs/SAEs that were ongoing at 
1094 
the time of death; however, were not the cause of death, will be recorded as “resolved” at 
1095 
the time of death. 
1096 
 NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is defined 
1097 
as the event was ongoing with an undetermined outcome. 
1098 
 An ongoing outcome will require follow-up by the site in order to determine the 
1099 
final outcome of the AE/SAE. 
1100 
 The outcome of an ongoing event at the time of death that was not the cause of 
1101 
death, will be updated and recorded as “resolved” with the date of death recorded as 
1102 
the stop date. 
1103 
 UNKNOWN – An unknown outcome is defined as an inability to access the participant 
1104 
or the participant’s records to determine the outcome (for example, a participant that was 
1105 
lost to follow-up). 
1106 
 
1107 
If any reported adverse events are ongoing when a participant completes the study (or 
1108 
withdraws), adverse events classified UADEs will be followed until they are either resolved, or 
1109 
have no prospect of improvement or change, even after the participant has completed all 
1110 
applicable study visits/contacts. For all other adverse events, data collection will end at the time 
1111 
the participant completes the study. Note: participants should continue to receive appropriate 
1112 
medical care for an adverse event after their participation in the study ends.  
1113 
8.3 Reportable Device Issues 
1114 
All UADEs and ADEs as defined in Section 8.2.1 will be reported on both a device issue form 
1115 
and AE form, except for skin reactions from CGM sensor placement or pump infusion set 
1116 
placement that do not require pharmacologic treatment. As noted in Section 8.2.1, events that 
1117 
occur due to participant (user) error generally will not require completion of a device issue form. 
1118 
 
1119 
Device complaints and device malfunctions will be reported except in the following circumstances. 
1120 
These occurrences are expected and will not be reported on a Device Issue Form assuming criteria 
1121 
for a UADE or ADE have not been met: 
1122 
 CGM sensor lasting fewer days than expected per manufacturer 
1123 
 CGM tape adherence issues 
1124 
 Battery lifespan deficiency due to inadequate charging or extensive wireless 
1125 
communication 
1126 
 Intermittent device component disconnections/communication failures not requiring 
1127 
system replacement or workaround/resolution not specified in user guide/manual. 
1128 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 48 OF 64 
 Device issues clearly addressed in the user guide manual that do not require additional 
1129 
troubleshooting 
1130 
 Device issues in the non-HCL groups using commercially available Dexcom G6 CGMs if 
1131 
not associated with an adverse event. 
1132 
8.4 Timing of Event Reporting 
1133 
Serious AEs that are possibly related to a study device, drug or study participation must be 
1134 
reported to the Coordinating Center within 24 hours of the site becoming aware of the event. 
1135 
This can occur via phone or email, or by completion of the online serious adverse event form and 
1136 
device issue form if applicable. If the form is not initially completed, it should be competed as 
1137 
soon as possible after there is sufficient information to evaluate the event.  
1138 
 
1139 
All other reportable ADEs and other reportable AEs should be submitted by completion of an 
1140 
electronic case report form within 7 days of the site becoming aware of the event. 
1141 
 
1142 
The Coordinating Center will notify all participating investigators and the IRB of any adverse 
1143 
event that is serious, related, and unexpected. Notification will be made within 10 working days 
1144 
after the Coordinating Center becomes aware of the event and no later than seven calendar days 
1145 
where the event is fatal or life threatening.  
1146 
 
1147 
Upon receipt of a qualifying event, the Coordinating Center/Medical Monitor will investigate the 
1148 
event to determine if a UADE is confirmed, and if indicated, report the results of the 
1149 
investigation to the all overseeing IRBs and the FDA, within 10 working days of the 
1150 
Coordinating Center becoming aware of the UADE per 21CFR 812.46(b) (2). The Medical 
1151 
Monitor must determine if the UADE presents an unreasonable risk to participants. If so, the 
1152 
Coordinating Center must ensure that device use presenting that risk is terminated as soon as 
1153 
possible but no later than 5 working days after the Medical Monitor makes this determination 
1154 
and no later than 15 working days after first receipt notice of the UADE. 
1155 
 
1156 
Device malfunctions will be handled by the Coordinating Center as described below. In the case 
1157 
of a device malfunction related to a device that is donated to the study by the manufacturer, 
1158 
information may be forwarded to the manufacturer by the site personnel or the Coordinating 
1159 
Center. 
1160 
 
1161 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1162 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
1163 
Ethics Committee. When the JCHR IRB is the overseeing IRB, sites must report all serious, 
1164 
related adverse events regardless of whether they are expected/anticipated and regardless of 
1165 
whether they are fatal or life threatening within 7 calendar days. The Coordinating Center will be 
1166 
responsible for notifying the FDA of any unexpected fatal or life-threatening suspected adverse 
1167 
reaction as soon as possible, but in no case later than seven calendar days after initial receipt of 
1168 
the information. In addition, the Coordinating Center will notify FDA and all participating 
1169 
investigators of potential serious risks, from clinical trials or any other source, as soon as 
1170 
possible, but in no case later than 15 calendar days after the Sponsor determines that the 
1171 
information qualifies for reporting. 
1172 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 49 OF 64 
8.5 Independent Safety Oversight 
1173 
A Data and Safety Monitoring Board (DSMB) will review compiled safety data at periodic 
1174 
intervals (approximately every 6 months). SAEs, UADES, and any adverse events leading to 
1175 
study discontinuation will be reviewed immediately by the DSMB. The DSMB also will be 
1176 
informed of any ADEs not meeting criteria for a UADE if the Medical Monitor requests the 
1177 
DSMB review. The DSMB can request modifications to the study protocol or suspension or 
1178 
outright stoppage of the study if deemed necessary based on the totality of safety data available. 
1179 
Details regarding DSMB review will be documented in a separate DSMB document. 
1180 
8.6 Stopping Criteria Related to Study Devices or Drug 
1181 
8.6.1 Participant Discontinuation of Study Device 
1182 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or DKA 
1183 
event (or a malfunction that could have led to severe hypoglycemia or DKA), use of the HCL 
1184 
system will be suspended for all participants while the problem is diagnosed. The UADE will be 
1185 
reported to the IRB, DSMB, and FDA. After assessment of the problem and any correction, use 
1186 
of the system will not be restarted until approval is received from the IRB, DSMB, and FDA. 
1187 
In the absence of a device malfunction, use of the HCL system by a participant will be 
1188 
discontinued if any of the following occur: 
1189 
 The investigator believes it is unsafe for the participant to continue on the study device 
1190 
This could be due to the development of a new medical condition or worsening of an 
1191 
existing condition; or participant behavior contrary to the indications for use of the 
1192 
device that imposes on the participant’s safety 
1193 
 The participant requests that the treatment be stopped 
1194 
 Participant has two distinct severe hypoglycemia events as defined in Section 8.2.3  
1195 
 Participant has two distinct episodes of DKA as defined in Section 8.2.4 (not related to 
1196 
insulin set failure)  
1197 
 Participant pregnancy 
1198 
 Upon discovery of pregnancy, the use of closed loop will be stopped; however, the 
1199 
participant may continue use of the study pump and CGM in open loop until an 
1200 
alternative method for insulin delivery and glucose monitoring is in place. This is to 
1201 
ensure safety of the participant and unborn child.  
1202 
 
1203 
Each DKA or severe hypoglycemia event will be reviewed by the Medical Monitor and the 
1204 
DSMB with respect to determination of cause and whether the occurrence of the event can be 
1205 
attributed to use of the HCL system. 
1206 
An additional requirement for continued system use following a single DKA or severe 
1207 
hypoglycemia event will be that (1) the site investigator believes that the event is explainable, 
1208 
unlikely to recur, and that it is safe for the participant to continue to use the system and (2) the 
1209 
Medical Monitor and DSMB concur. If either the Medical Monitor or DSMB determines that the 
1210 
occurrence of the event indicates that it is not safe for the participant to continue to use the HCL 
1211 
system, use will be discontinued. 
1212 
 
1213 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 50 OF 64 
 
1214 
Participants who discontinue a study HCL system will remain in the study (unless the participant 
1215 
is pregnant, in which case the participant will be dropped from the study). Participants who 
1216 
discontinue a study HCL system and are not pregnant will remain in the study and be encouraged 
1217 
to use CGM and an insulin pump, which may be provided by the study.  
1218 
8.6.2 Participant Discontinuation of Study Drug 
1219 
Rules for discontinuing study drug use are described below. 
1220 
 The investigator believes it is unsafe for the participant to continue to receive the drug. 
1221 
This could be due to the development of a potential side effect of the drug, a new medical 
1222 
condition or worsening of an existing condition; or participant behavior contrary to the 
1223 
indications for use of the drug that imposes on the participant’s safety 
1224 
 The participant requests that the treatment be stopped 
1225 
 Participant pregnancy  
1226 
 
1227 
Even if the study drug is discontinued, the participant will be encouraged to remain in the study 
1228 
through the final study visit (unless the participant is pregnant, in which case the participant will 
1229 
be dropped from the study). 
1230 
8.6.3 Criteria for Suspending or Stopping Overall Study 
1231 
If any UADE occurs, the use of that study device may be suspended or stopped completely, 
1232 
pending Medical Monitor and DSMB review. If the study device in question is deemed to be 
1233 
unsafe, any participants currently using that device will be switched to a different HCL system, if 
1234 
possible. If there is not another FDA approved system, enrollment of the trial as a whole may be 
1235 
stopped until the issue is resolved.  
1236 
 
1237 
In addition, study activities could be suspended if the manufacturer of any constituent study 
1238 
device requires stoppage of device use for safety reasons (e.g., product recall). The affected 
1239 
study activities may continue if participants can switch to a different FDA approved HCL system 
1240 
or the underlying problem can be corrected by a protocol or system modification that will not 
1241 
invalidate the results obtained prior to suspension. 
1242 
 
1243 
If any death occurs in the study which is assessed as related to study treatment regimen by the 
1244 
study site investigator and Medical Monitor (but not limited to a specific study device that can be 
1245 
switched), enrollment in the trial will be halted, pending DSMB review. 
1246 
 
1247 
As part of their ongoing safety review, the DSMB will make independent judgments regarding 
1248 
other adverse events that may warrant trial interruption. 
1249 
 
1250 
The study Medical Monitor will review all adverse events and adverse device events that are 
1251 
reported during the study typically on a weekly basis and will review compiled safety data at 
1252 
periodic intervals (generally timed to the review of compiled safety data by the DSMB). The 
1253 
Medical Monitor may request suspension of study activities or stoppage of the study if deemed 
1254 
necessary based on the totality of safety data available. 
1255 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 51 OF 64 
8.7 Unmasking of Study Drug Due to Adverse Event 
1256 
Emergency unmasking criteria for an individual participant: 
1257 
 For the purpose of management of pregnancy as per the documentation and request of a 
1258 
treating physician, with PI approval. 
1259 
 For the occurrence of an adverse event that is assessed as serious, related and unexpected 
1260 
(SUSAR) by the Medical Monitor 
1261 
 A medical condition or surgery that is deemed necessary to unmask by the study PI and 
1262 
Medical Monitor 
1263 
The Investigator and Coordinating Center will document the unmasking, the reason for 
1264 
unmasking and the date and time of unmasking. The Investigator will be instructed to call the 
1265 
Medical Monitor prior to asking the Coordinating Center to break the blind. All instances of 
1266 
unmasking will be reported to the IRB, the Sponsor, the DSMB and the Protocol Chairs. 
1267 
 
1268 
Emergency unmasking criteria for the study: 
1269 
 A safety trend/pattern is detected during the conduct of a study that is deemed by the 
1270 
Medical Monitor and DSMB to be a safety concern for the continuation of the study. 
1271 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 52 OF 64 
Chapter 9: Miscellaneous Considerations 
1272 
9.1 Drugs Used as Part of the Protocol 
1273 
Participants in a HCL group will use an insulin approved for the pump. When transitioning from 
1274 
MDI to SAP therapy, total daily basal insulin dose will be decreased by 20%, divided by 24, and 
1275 
one basal rate will be set. When transitioning from SAP to HCL, CGM data will be used to guide 
1276 
device setting changes. If time spent < 70 is > 4%, carb ratios will be weakened by 10%.  
1277 
 
1278 
Participants in a non-HCL group will be prescribed insulin as part of usual diabetes management 
1279 
by their personal diabetes care provider. The study will not be providing insulin to participants in 
1280 
any group, unless the participant has no means of obtaining insulin. 
1281 
9.2 Collection of Medical Conditions and Medications 
1282 
Pre-Existing Condition: Any medical condition that is either present at Screening, a chronic 
1283 
disease, or a prior condition that could impact the participant’s health during the course of the 
1284 
study (e.g., prior myocardial infarction or stroke). 
1285 
 
1286 
Medications: All medications that the participant is currently taking at Screening and during the 
1287 
course of the study will be recorded. Nutraceuticals and preventative treatment also will be 
1288 
recorded. This will include the treatment of chronic pre-existing conditions, medical conditions 
1289 
that occur during the study, and/or adverse events. Medications only taken as needed either can 
1290 
be recorded when prescribed or only recorded if used during the study. Glucagon for treatment of 
1291 
severe hypoglycemia will only be recorded if used during the study. 
1292 
9.3 Prohibited Medications, Devices, Treatments, and Procedures 
1293 
Participants will be asked to consult with their study team, if possible, before starting any new 
1294 
prescription therapy unless it is medically urgent. If treatment with a beta blocker, seizure 
1295 
medication, other antihypertensive medications, HMG-CoA reductase inhibitors, lithium, 
1296 
theophylline, clonidine, or aspirin is required, participants in Cohort A may have study drug 
1297 
(verapamil/placebo) discontinued. 
1298 
 
1299 
Participants will be instructed, if possible, not to use systemic prednisone, other 
1300 
immunosuppressive agents, or chronic inhaled or nasal corticosteroids during this trial as these 
1301 
agents may accelerate ß-cell decline.  
1302 
 
1303 
Treatment with any non-insulin glucose-lowering agent (such as GLP-1 agonists, Symlin, DPP-4 
1304 
inhibitors, SGLT-2 inhibitors, biguanides, sulfonylureas) will not be permitted.  
1305 
 
1306 
Participants are not permitted to use diabetes management devices that are not FDA approved, 
1307 
outside of study devices (such as do-it-yourself closed-loop systems). 
1308 
 
1309 
Study devices (insulin pump, study CGM systems) must be removed before Magnetic Resonance 
1310 
Imaging (MRI), Computed Tomography (CT) or diathermy treatment.  
1311 
 
1312 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 53 OF 64 
For Medtronic HCL users, acetaminophen should be avoided. 
1313 
9.4 Rescue Medications, Treatments, and Procedures 
1314 
All participants will be required to have a commercially available glucagon (or glucagon analog) 
1315 
preparation for treatment as needed of severe hypoglycemia. The study will not be providing 
1316 
glucagon to participants in any group, unless the participant has no means of obtaining it. 
1317 
9.5 Pregnancy Reporting  
1318 
If pregnancy occurs, the participant will be dropped from the study, but information about the 
1319 
outcome of the pregnancy will be collected. Use of study devices and study drug will be stopped 
1320 
as detailed in Sections 8.6.1 and 8.6.2. The occurrence of pregnancy will be reported to the 
1321 
Coordinating Center and to the JCHR IRB as an Unanticipated Problem, both within seven 
1322 
calendar days. 
1323 
9.6 Participant Compensation 
1324 
Participant compensation will be specified in the informed consent form. 
1325 
9.7 Participant Withdrawal 
1326 
Participation in the study is voluntary, and a participant may withdraw at any time. For 
1327 
participants who withdraw, their data will be used up until the time of withdrawal. 
1328 
 
1329 
Participants who discontinue study treatment will be requested to remain in the study to at least 
1330 
return for the 52 week visit even if the participant is unwilling to return for all visits. 
1331 
9.8 Confidentiality 
1332 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
1333 
used instead of their name. Protected health information gathered for this study will be shared 
1334 
with the Coordinating Center, the Jaeb Center for Health Research in Tampa, FL. De-identified 
1335 
participant information may also be provided to research sites involved in the study. 
1336 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 54 OF 64 
Chapter 10: Statistical Considerations 
1337 
10.1 Statistical and Analytical Plans 
1338 
The approach to sample size and statistical analyses are summarized below and will be further 
1339 
detailed in the Statistical Analysis Plan.  
1340 
10.2 Statistical Hypotheses 
1341 
The primary outcome is the C-peptide area under the curve (AUC) in response to a 2-hour MMTT 
1342 
at 52 weeks. 
1343 
 
1344 
The study hypotheses can be stated as follows: 
1345 
 
1346 
HCL vs. non-HCL comparison: 
1347 
 Null Hypothesis: There is no difference in the C-peptide AUC in response to a 2-hour 
1348 
MMTT at 52 weeks between HCL with intensive care and non-HCL with standard care 
1349 
for the combined Cohort A and B population.  
1350 
 Alternative Hypothesis: There is a nonzero difference in the C-peptide AUC in response 
1351 
to a 2-hour MMTT at 52 weeks between HCL with intensive care and non-HCL with 
1352 
standard care for the combined Cohort A and Cohort B population. 
1353 
 
1354 
Verapamil vs. Placebo comparison: 
1355 
 Null Hypothesis: There is no difference in the C-peptide AUC in response to a 2-hour 
1356 
MMTT at 52 weeks between verapamil and placebo for the Cohort A population.  
1357 
 Alternative Hypothesis: There is a nonzero difference in the C-peptide AUC in response 
1358 
to a 2-hour MMTT at 52 weeks between verapamil and placebo for the Cohort A 
1359 
population. 
1360 
10.3 Sample Size 
1361 
The sample size calculation is detailed in a separate document and is summarized below. Sample 
1362 
size was driven by the verapamil vs. placebo comparison as the test only includes participants in 
1363 
Cohort A. The mean of the transformed C-peptide (log(AUC + 1)) and the root mean square 
1364 
error in the placebo group were assumed to be 0.315 and 0.18, respectively, based on 90% CIs 
1365 
from prior studies31. The corresponding geometric-like mean C-peptide value of 0.370 pmol/mL 
1366 
was calculated using the inverse transformation: exp(0.315) − 1. A recent randomized trial 29 
1367 
found a 62% increase in mean C-peptide in verapamil compared with placebo, although the total 
1368 
sample size was small (N=24) and confidence intervals were wide. Therefore, this study assumed 
1369 
a smaller, 50% increase in mean C-peptide using verapamil. The expected geometric-like mean 
1370 
C-peptide value in the verapamil arm was 0.370 · 1.50 = 0.555 pmol/mL. After a log(x+1) 
1371 
transformation, the mean values in the control and treatment groups are 0.315 and 0.441, 
1372 
respectively, giving a treatment effect of 0.441-0.315=0.126.  
1373 
 
1374 
With these estimates, a sample size of 88 participants in Cohort A was calculated to provide 90% 
1375 
power with a 5% two-sided type 1 error rate and a 1:1 treatment group allocation to detect a 
1376 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 55 OF 64 
verapamil vs. placebo treatment group difference assuming the true relative difference between 
1377 
groups was 50%. To account for a 10% dropout rate, the sample size in Cohort A will be 98 
1378 
participants. 
1379 
 
1380 
A sample size of 33 participants for Cohort B was selected based on convenience. Participants in 
1381 
Cohort B will be allocated to either HCL or non-HCL in a 2:1 treatment group allocation. Thus, 
1382 
we expect 131 participants in be enrolled in either Cohort A or Cohort B with approximately 71 
1383 
participants in HCL/intensive care and 60 participants in non-HCL/standard care arm. Assuming 
1384 
around a 10% dropout rate, an HCL/intensive care treatment effect of 50%, and an upper 
1385 
confidence limit estimate of 0.18 for the standard deviation (same presumed estimates for 
1386 
verapamil vs. placebo comparison), this study has 96% power to detect a significant 
1387 
HCL/intensive care vs. non-HCL/standard care treatment group difference with a type 1 error 
1388 
rate of 5%. 
1389 
10.4 Outcome Measures 
1390 
C-peptide 
1391 
The primary outcome is the C-peptide in response to a 2-hour MMTT at 52 weeks. This is 
1392 
measured as the area under the stimulated C-peptide curve (AUC). AUC is computed using a 
1393 
trapezoidal rule, which is a weighted sum of the C-peptide values over the 120 min. 
1394 
 
1395 
A variety of secondary C-peptide outcomes is planned, with randomization (±3 days) AUC as 
1396 
baseline, including the following: 
1397 
 C-peptide AUC 13, 26, and 39 weeks (52 weeks is primary outcome) 
1398 
 Peak C-peptide during a 2-hour MMTT at 13, 26, 39, and 52 weeks 
1399 
 
1400 
CGM Metrics 
1401 
CGM metrics from the Dexcom G6 and Medtronic Guardian Sensor 3 will be used to assess the 
1402 
level of glycemic control over the course of the study with respect to the study hypothesis that 
1403 
requires achieving near-normal glycemia in the intervention group and a separation between 
1404 
treatment groups in glycemic control. CGM metrics also will be used as secondary outcomes. 
1405 
 
1406 
CGM-derived indices will be computed over the study period for 24 hours, daytime (6AM to 
1407 
midnight) and nighttime (midnight to 6AM), and at 6, 13, 26, 39, and 52 weeks. 
1408 
 Mean glucose 
1409 
 Percentage of sensor glucose from 70 to 180 mg/dL 
1410 
 Percentage of sensor glucose >180 and >250 mg/dL 
1411 
 Percentage of sensor glucose <54 and <70 mg/dL 
1412 
 Coefficient of variation 
1413 
 
1414 
The Statistical Analysis Plan (SAP) will describe how CGM derived indices will be calculated. 
1415 
 
1416 
HbA1c 
1417 
HbA1c levels will be used as a measure of hyperglycemia. 
1418 
 
1419 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 56 OF 64 
HbA1c outcomes at 13, 26, 39, and 52 weeks will include the following: 
1420 
 Mean HbA1c  
1421 
 Percentage of patients with an HbA1c <7.0% and <6.5% 
1422 
 
1423 
10.5 Analysis Datasets 
1424 
The primary analysis will follow the intention-to-treat principle. It will include all randomized 
1425 
participants, and data will be analyzed based on the treatment assigned from randomization 
1426 
regardless of the actual treatment received.  
1427 
 
1428 
A per-protocol analysis that includes participants adhering to the protocol will be performed and 
1429 
detailed in the SAP. Sensitivity analyses on the primary outcome will be described in the SAP. 
1430 
 
1431 
All participants will be included in safety analyses.  
1432 
10.6 Analysis of the Primary Efficacy Endpoint 
1433 
Both primary analyses will follow the intention-to-treat principle.  
1434 
10.6.1 HCL vs. non-HCL Analysis 
1435 
The HCL/intensive care versus non-HCL/standard care comparison will combine participants 
1436 
from Cohort A and B. A constrained longitudinal analysis will be performed by fitting the 
1437 
baseline (randomization) and 52 week log(AUC+1) as the outcome and testing for device use 
1438 
indicator (randomized to HCL/intensive therapy or randomized to no HCL/standard therapy) 
1439 
controlling for age, time from diagnosis to randomization, and drug use indicator (verapamil, 
1440 
placebo, or no drug [Cohort B]). The log(AUC+1) transform is expected to make the residuals 
1441 
approximately normally distributed, but regression diagnostics will be performed to check the 
1442 
residuals and an appropriate alternative transformation or a nonparametric analysis based on 
1443 
ranks will be performed if the residuals have a skewed distribution. The primary analysis test 
1444 
assumes there is no interaction between device use and drug use; an analysis described below 
1445 
will assess possible treatment interactions. 
1446 
10.6.2 Verapamil vs. Placebo Analysis 
1447 
The verapamil vs. placebo comparison will only include participants in Cohort A. A similar 
1448 
constrained longitudinal analysis will be performed except testing for the drug use indicator 
1449 
(randomized to verapamil or randomized to placebo) and controlling for device use (HCL or no 
1450 
HCL). 
1451 
10.7 Analysis of the Secondary Endpoint 
1452 
Secondary analyses for HCL/intensive care vs. non-HCL/standard care and verapamil vs. placebo 
1453 
will be performed and described in the SAP. 
1454 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 57 OF 64 
10.8 Safety Analyses 
1455 
All adverse events will be listed by cohort. Events also will be listed separately for the HCL/intensive 
1456 
and non-HCL/standard care arms since differential reporting may occur due to the many additional 
1457 
study contacts occurring in HCL participants.  
1458 
 
1459 
In all safety analyses comparing the HCL/intensive to the non-HCL/standard care group, Cohorts 
1460 
A and B will be combined. 
1461 
 
1462 
For SH events, DKA events, and hospitalizations, the following outcomes will be compared 
1463 
between treatment groups if there are at least 5 events that occur during the study: 
1464 
 Number of events per participant 
1465 
 Number of participants with at least one event 
1466 
 Incidence rate per 100 person-years 
1467 
 
1468 
For the count outcomes and the incidence rates, a Poisson regression model will be used. All 
1469 
models will adjust for site as a random effect. Additionally, the models for the DKA outcomes 
1470 
will adjust for the presence or absence of a DKA event at diagnosis. 
1471 
 
1472 
For SH events, separate analyses also will be done for the outcomes listed above that will only 
1473 
include events that resulted in seizure or a loss of consciousness. 
1474 
10.9 Intervention Adherence 
1475 
HCL system use, verapamil, and placebo adherence will be tabulated at each time point and 
1476 
reported in a table.  
1477 
10.10 Protocol Adherence and Retention 
1478 
Tabulations and figures by treatment group to assess protocol adherence will include: 
1479 
 Flowchart accounting for all participants according to treatment group for all visits 
1480 
 Visit completion rates for each follow up visit 
1481 
 Protocol deviations 
1482 
 Numbers and reasons for unscheduled visits and phone calls 
1483 
10.11 Baseline Descriptive Statistics 
1484 
Baseline demographic and clinical characteristics will be tabulated overall, by cohort, and by 
1485 
treatment group.  
1486 
10.12 Device Issues 
1487 
All reportable device issues occurring during the study will be tabulated and reported in a table. 
1488 
10.13 Planned Interim Analyses 
1489 
No formal interim analyses or stopping guidelines are planned for this study. 
1490 
 
1491 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 58 OF 64 
The DSMB will review data for safety per the DSMB Standard Operating Procedures approximately 
1492 
every six months. The data to be reviewed will include information regarding adverse events, device 
1493 
issues, and protocol adherence/deviations as they may relate to participant safety. 
1494 
10.14 Interaction Analyses 
1495 
The primary outcome will also test for a possible device by drug interaction. The same model 
1496 
described above for the primary analysis will fit with the inclusion of a device by drug 
1497 
interaction. If the interaction is significant, a subgroup analysis of the effectiveness of 
1498 
HCL/intensive care will be assessed by drug use indicator (verapamil, placebo, or no drug 
1499 
[Cohort B]). Additionally, if the interaction is significant, a subgroup analysis of the 
1500 
effectiveness of verapamil will be assessed by device use indicator (HCL or no HCL). 
1501 
10.15 Subgroup Analyses 
1502 
Subgroup analyses of effect modification (interaction) will be performed separately for the 
1503 
HCL/intensive care vs. non-HCL/standard care and verapamil vs. placebo primary analyses. 
1504 
Subgroup analyses will assess the effectiveness of HCL/intensive care and the effectiveness of 
1505 
verapamil by various patient characteristics as described in the SAP. Interpretation of the 
1506 
analyses will be made with caution and tests only performed if the overall treatment effect is 
1507 
significant.  
1508 
10.16 Multiple Comparisons 
1509 
For the primary analysis, no adjustments for multiplicity will be made because two different 
1510 
interventions are being tested separately.  
1511 
 
1512 
For secondary analyses, Benjamini-Hochberg false discovery rate adjusted p-values will be 
1513 
calculated within several subcategories. The subcategories will be separate for each of the two 
1514 
interventions.  
1515 
10.17 Additional Analyses 
1516 
The relationship between C-peptide and glycemic outcomes (e.g., % time in range), pooled 
1517 
across all treatment groups, will be assessed and detailed in the SAP. Mechanistic studies may be 
1518 
performed, the exact nature of which will be determined at study end depending on study 
1519 
outcomes. 
1520 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 59 OF 64 
Chapter 11: Data Collection and Monitoring 
1521 
11.1 Case Report Forms and Device Data 
1522 
The main study data are collected through a combination of electronic case report forms (CRFs) 
1523 
and electronic device data files obtained from the study software and individual hardware 
1524 
components. These electronic device files and electronic CRFs from the study website are 
1525 
considered the primary source documentation. 
1526 
 
1527 
When data are directly collected in electronic case report forms, this will be considered the 
1528 
source data.  
1529 
11.2 Study Records Retention 
1530 
Study documents should be retained for a minimum of 3 years. These documents should be 
1531 
retained for a longer period, however, if required by local regulations. No records will be 
1532 
destroyed without the written consent of the Coordinating Center, if applicable. It is the 
1533 
responsibility of the Coordinating Center to inform the investigator when these documents no 
1534 
longer need to be retained.  
1535 
 
1536 
Auto-antibody and HbA1c results from the central labs may be returned to clinical sites during 
1537 
the study. C-peptide results from the central lab will not be returned to sites until study 
1538 
completion. Results from other samples sent to central labs will not be returned to sites.  
1539 
 
1540 
Each participating site will maintain appropriate medical and research records for this trial, in 
1541 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1542 
confidentiality of participants. 
1543 
11.3 Quality Assurance and Monitoring 
1544 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1545 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1546 
conducted and data are generated, documented and reported in compliance with the protocol, 
1547 
Good Clinical Practice (GCP) and the applicable regulatory requirements. Adverse events will be 
1548 
prioritized for monitoring. 
1549 
 
1550 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1551 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
1552 
Investigations — A Risk-Based Approach to Monitoring” (August 2013). Study conduct and 
1553 
monitoring will conform with 21 Code of Federal Regulations (CFR) 812. 
1554 
 
1555 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1556 
events. Therefore, the RBM plan will focus on these areas. As much as possible, remote 
1557 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1558 
verity and completeness of the key site data. Elements of the RBM may include: 
1559 
 Qualification assessment, training, and certification for sites and site personnel 
1560 
 Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
1561 


 
 
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 Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1562 
review of entered data and edits, statistical monitoring, study closeout 
1563 
 On-site monitoring (site visits): source data verification, site visit report 
1564 
 Agent/Device accountability 
1565 
 Communications with site staff 
1566 
 Patient retention and visit completion 
1567 
 Quality control reports 
1568 
 Management of noncompliance 
1569 
 Documenting monitoring activities 
1570 
 Adverse event reporting and monitoring 
1571 
 
1572 
Coordinating Center representatives or their designees may visit the study facilities at any time in 
1573 
order to maintain current and personal knowledge of the study through review of the records, 
1574 
comparison with source documents, observation and discussion of the conduct and progress of 
1575 
the study. 
1576 
11.4 Protocol Deviations 
1577 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1578 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
1579 
the study site staff. As a result of deviations, corrective actions are to be developed by the site 
1580 
and implemented promptly. 
1581 
 
1582 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements. 
1583 
Further details about the handling of protocol deviations will be included in the monitoring plan. 
1584 


 
 
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Chapter 12: Ethics/Protection of Human Participants 
1585 
12.1 Ethical Standard 
1586 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1587 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1588 
21 CFR Part 56, and/or the ICH E6. 
1589 
12.2 Institutional Review Boards 
1590 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1591 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
1592 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
1593 
require review and approval by the IRB before the changes are implemented to the study. All 
1594 
changes to the consent form will be IRB approved; a determination will be made regarding 
1595 
whether previously consented participants need to be re-consented. 
1596 
12.3 Informed Consent Process 
1597 
12.3.1 Consent Procedures and Documentation 
1598 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the 
1599 
study and continues throughout the individual’s study participation. Extensive discussion of risks 
1600 
and possible benefits of participation will be provided to the participants and their families. 
1601 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
1602 
document. The investigator will explain the research study to the participant and answer any 
1603 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
1604 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
1605 
research participants. Participants will have the opportunity to carefully review the written 
1606 
consent form and ask questions prior to signing. 
1607 
 
1608 
The participants should have the opportunity to discuss the study with their surrogates or think 
1609 
about it prior to agreeing to participate. The participant will sign the informed consent document 
1610 
prior to any procedures being done specifically for the study. The participants may withdraw 
1611 
consent at any time throughout the course of the trial. A copy of the informed consent document 
1612 
will be given to the participants for their records. The rights and welfare of the participants will 
1613 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
1614 
affected if they decline to participate in this study. 
1615 
12.3.2 Participant and Data Confidentiality 
1616 
 Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1617 
and the Coordinating Center and their agents. This confidentiality is extended to cover testing of 
1618 
biological samples and genetic tests in addition to the clinical information relating to 
1619 
participants. Therefore, the study protocol, documentation, data, and all other information 
1620 
generated will be held in strict confidence. No information concerning the study or the data will 
1621 
be released to any unauthorized third party without prior written approval of the Coordinating 
1622 
Center. 
1623 
 
1624 


 
 
CLVER PROTOCOL V5.2 01MAR2022 
PAGE 62 OF 64 
The study monitor, other authorized representatives of the Coordinating Center, representatives 
1625 
of the IRB or pharmaceutical company supplying study product may inspect all documents and 
1626 
records required to be maintained by the investigator, including but not limited to, medical 
1627 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
1628 
clinical study site will permit access to such records. 
1629 
 
1630 
The study participant’s contact information will be securely stored at each clinical site for 
1631 
internal use during the study. At the end of the study, all records will continue to be kept in a 
1632 
secure location for as long a period as dictated by local IRB and Institutional regulations. 
1633 
 
1634 
Study participant research data, which is for purposes of statistical analysis and scientific 
1635 
reporting, will be transmitted to and stored at the Jaeb Center for Health Research (JCHR). This 
1636 
will not include the participant’s contact or identifying information, unless otherwise specified in 
1637 
the informed consent form. Rather, individual participants and their research data will be 
1638 
identified by a unique study identification number. The study data entry and study management 
1639 
systems used by clinical sites and by JCHR research staff will be secured and password 
1640 
protected. At the end of the study, all study databases will be de-identified and archived at the 
1641 
JCHR. 
1642 
12.3.3 Future Use of Stored Specimens 
1643 
Permission to collect and store blood samples for future use will be included in the informed 
1644 
consent. With the participant’s approval, blood specimens will be labeled by study ID and stored 
1645 
at Indiana University and the University of Minnesota for use by researchers, including those 
1646 
outside of the study. 
1647 
 
1648 
These samples could be utilized to learn more about causes of T1D, its complications (such as 
1649 
eye, nerve, and kidney damage) and other conditions for which individuals with diabetes are at 
1650 
increased risk, and how to improve treatment. 
1651 
 
1652 
All studies will be performed after a written protocol for testing and analysis are approved by 
1653 
local IRB(s). Specimens will be transferred to research labs at research institutions as needed to 
1654 
perform the approved investigations. 
1655 
 
1656 
The labs will be provided with a code-link for each participant that will allow linking the 
1657 
biological specimens with the clinical information collected during the trial, maintaining the 
1658 
masking of the identity of the participant. 
1659 
 
1660 
During the conduct of the study, an individual participant can choose to withdraw consent to 
1661 
have biological specimens stored for future research. However, withdrawal of consent with 
1662 
regard to biosample storage may not be possible after the study is completed. 
1663 


 
 
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Chapter 13: References 
1664 
1. 
Dabelea D, Mayer-Davis DJ, Saydah S, et al. SEARCH for Diabetes in Youth Study. Prevalence of 
1665 
type 1 and type 2 diabetes among children and adolescents form 2001-2009. JAMA. 
1666 
2014;311:1778-1786. 
1667 
2. 
Chiang JL, Maahs DM, Garvey KC, et al. Diabetes in Children and Adolescents: A Position 
1668 
Statement by the American Diabetes Association. . Diabetes Care. 2018;41:2026-2044. 
1669 
3. 
Miller KM, Forster NC, Beck RW, et al. for the T1D Exchange Clinic Network. Current state of 
1670 
type 1 diabetes treatment in the US: updated data from The T1D Exchange Clinic Registry. 
1671 
Diabetes Care. 2015;38:971-978. 
1672 
4. 
Wood JR, Miller KM, Maahs DM, et al. Most youth with type 1 diabetes in the T1D Exchange 
1673 
Clinic Registry do not meet American Diabetes Association or International Society for Pediatric 
1674 
and Adolescent Diabetes Clinical Guidelines. Diabetes Care. 2013;36:2035-2037. 
1675 
5. 
Beck RW, Tamborlane WV, Bergenstal RM, Miller KM, DuBose SM, Hall CA. The T1D Exchange 
1676 
clinic registry. . J Clin Endocrinol Metab. 2012;97:4383-4389. 
1677 
6. 
Greenbaum C, Beam CA, Boulware D, et al. Fall in C-peptide during frist 2 years from diagnosis: 
1678 
evidence of at least two distinct phases form composite type 1 diabetes TrialNet Data. Diabetes. 
1679 
2012;61:2066-2073. 
1680 
7. 
Karjalainen J, Salmela P, Ilonen J, Surcel HM, Knip M. A comparison of childhood and adult type I 
1681 
diabetes mellitus. N Eng J Med. 1989;320:881-886. 
1682 
8. 
von Herrath M, Sanda S, Herold K. Type 1 diabetes as a relapsing-remitting disease? Nature 
1683 
Reviews Immunology. 2007;7:988-994. 
1684 
9. 
Bonfanti R, Bazzigaluppi E, Calori G. Parameters associated with residual insulin secretion during 
1685 
the first year of disease in children and adolescents with Type 1 diabetes mellitus. Diabetic 
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Medicine : A journal of the British Diabetic Association. 1998;15:844-850. 
1687 
10. 
Sildorf SM, Hertel NT, Thomsen J, et al. Treatment intensification without improved HbA1c 
1688 
levels in children and adolescents with Type 1 diabetes mellitus. Diabetic Medicine. 
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2016;33:515-522. 
1690 
11. 
Shah SC, Malone JI, Simposn NE. A randomized trial of intensive insulin therapy in newly 
1691 
diagnosed insulin-dependent diabetes. . N Eng J Med. 1989;350:550-555. 
1692 
12. 
Perlman K, Ehrlich M, Filler RM, Albisser AM. Sustained normoglycemia in newly diagnosed type 
1693 
1 diabetic subjects. Short-term and one-year follow up. Diabetes. 1984;33:995-1001. 
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13. 
The DCCT Research Group. Effect of intensive therapy on residual β-cell function in patients with 
1695 
type I diabetes in the Diabetes Control and Complications Trial. . Ann Intern Med. 1998;128:517-
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523. 
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14. 
Bergenstal RM, Tamborlane WV, Ahmann A, et al. Effectiveness of sensor-augmented insulin-
1698 
pump therapy in type 1 diabetes. N Engl J Med. 2010;363:310-320. 
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15. 
Kordonouri O, Pankowska E, Rami B, et al. Sensor-augmented pumptherapy from the diagnosis 
1700 
of childhood type 1 diabetes: results fo the Paediatric Onset Study (ONSET) after 12 months of 
1701 
treatment. Diabetologia. 2010;53:2487-2495. 
1702 
16. 
Buckingham B, Beck RW, Ruedy KJ, et al. Diabetes Care. 2013;36:4030-4035. 
1703 
17. 
Miller KM, Foster NC, Beck RW, et al. Current state of type 1 diabetes treatment in the U.S.: 
1704 
updated data from the T1D Exchange clinic registry. Diabetes Care. 2015;38:971-978. 
1705 
18. 
Steffes MW, Sibley S, Jackson M, Thomas W. Beta-cell function and the development of 
1706 
diabetes-related complications in the diabetes control and complications trial. Diabetes Care. 
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2003;26:832-836. 
1708 


 
 
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19. 
Gregg EW, Li Y, J. W, et al. Changes in diabetes-related complications in the United States, 1990-
1709 
2010. N Eng J Med. 2014;370:1514-1523. 
1710 
20. 
Secrest AM, Becker DJ, Kelsey SF, Laporte RE, Orchard TJ. Cause-specific mortality trends in a 
1711 
large population-based cohort with long-standing childhood-onset type 1 diabetes. Diabetes. 
1712 
2010;59:3216-3222. 
1713 
21. 
Garg SK, Weinzimer SA, Tamborlane WV, et al. Glucose outcomes with the in-home use of a 
1714 
hybrid closed-loop insulin delivery system in adolescents and adults with type 1 diabetes. 
1715 
Diabetes Technology and Therapeutics. 2017;19:DOI: 10.1089/dia.2016.0421DOI: 
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1010.1089/dia.2016.0421. 
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22. 
Pinckney A, Rigb yMR, Keyes-Elstein L, Soppe CL, Nepom GT, Ehlers MR. Correlation Between 
1718 
Hypoglycemia, Glycemic Variability and C-Peptide Preservation After Alefacept Therapy in 
1719 
Patients with Type 1 Diabetes: Analysis of Data from the ITN T1DAL Trial. . Clin Ther. 
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2016;38:1327-1339. 
1721 
23. 
Agrawal P, Stone MD, Cordero T, Lee SW, Shin J, Kaufman. Real-world use of the Minimed 670G 
1722 
hydrid-closed-loop system. 2018;ATTD Oral Abstracts:038. 
1723 
24. 
Atkinson MA, Roep BO, Posgai A, Wheeler DCS, Peakman M. The challenge of modulating beta-
1724 
cell autoimmunity in type 1 diabetes. The lancet Diabetes & endocrinology. 2019;7(1):52-64. 
1725 
25. 
Xu G, Chen J, Jing G, Shalev A. Preventing beta-cell loss and diabetes with calcium channel 
1726 
blockers. Diabetes. 2012;61(4):848-856. 
1727 
26. 
Chen J, Saxena G, Mungrue IN, Lusis AJ, Shalev A. Thioredoxin-interacting protein: a critical link 
1728 
between glucose toxicity and beta-cell apoptosis. Diabetes. 2008;57(4):938-944. 
1729 
27. 
Chen J, Hui ST, Couto FM, et al. Thioredoxin-interacting protein deficiency induces Akt/Bcl-xL 
1730 
signaling and pancreatic beta-cell mass and protects against diabetes. FASEB journal : official 
1731 
publication of the Federation of American Societies for Experimental Biology. 2008;22(10):3581-
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3594. 
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28. 
Chen J, Cha-Molstad H, Szabo A, Shalev A. Diabetes induces and calcium channel blockers 
1734 
prevent cardiac expression of proapoptotic thioredoxin-interacting protein. American journal of 
1735 
physiology Endocrinology and metabolism. 2009;296(5):E1133-1139. 
1736 
29. 
Ovalle F, Grimes T, Xu G, et al. Verapamil and beta cell function in adults with recent-onset type 
1737 
1 diabetes. Nature medicine. 2018;24(8):1108-1112. 
1738 
30. 
Sherr JL. Closing the loop on managing youth with type 1 diabetes: children are not just small 
1739 
adults. Diabetes Care. 2018;41:1572-1578. 
1740 
31. 
Lachin JM, McGee PL, Greenbaum CJ, et al. Sample size requirements for studies of treatment 
1741 
effects on beta-cell function in newly diagnosed type 1 diabetes. PLoS One. 2011;6(11):e26471. 
1742 
 
1743 

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