Comparing the Effectiveness of Two Approaches to Preventing Severe Hypoglycemia
Phase: NA
Conditions: Severe Hypoglycemia
Sponsor: Kaiser Permanente

Protocol:  ClinicalTrials.gov #NCT0486387, Comparing the Effectiveness of Two Approaches 
 
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Comparing the Effectiveness of Two Approaches to 
Preventing Severe Hypoglycemia 
 
STUDY PROTOCOL 
 
 
Issue date:  07-01-2022 
Protocol amendment number: 04 
Authors: JR, KE 
 
Revision chronology: 
04/29/2021 Original 
06/04/2021 Version 2 
10/29/2021 Version 3 
07/01/2022 Version 4 
11/29/2023 Version 5 
11/27/2024 Version 6 
04-14-2025 Version 7 
 
 
Funding: 
Patient-Centered Outcomes Research Institute (PCORI) 
Contract # IHS-2019C3-17789 
This funding source had no role in the design of this study and will not have any role during its 
execution, analyses, interpretation of the data, or decision to submit results. 
 
 
 

Protocol:  ClinicalTrials.gov #NCT0486387, Comparing the Effectiveness of Two Approaches 
 
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Trial Registration Data 
Data Category 
Information 
Primary registry and trial 
identifying number 
ClinicalTrials.gov, NCT0486387 
Date of registration in primary 
registry 
04-26-2021 
Secondary identifying numbers 
Not applicable 
Source(s) of monetary or 
material support 
Patient-Centered Outcomes Research Institute 
Primary sponsor 
Kaiser Permanente Washington Health Research Institute 
Secondary sponsor(s) 
Not applicable  
Contact for public inquiries 
James Ralston, MD, MPH; James.D.Ralston@kp.org 
Contact for Scientific inquiries 
James Ralston, MD, MPH; James.D.Ralston@kp.org 
Public title 
Comparing the Effectiveness of Two Approaches to Preventing Severe Hypoglycemia 
Scientific title 
Comparing the Effectiveness of Two Approaches to Preventing Severe Hypoglycemia 
Countries of recruitment 
United States of America 
Health condition(s) or problem(s) 
studied 
Severe hypoglycemia in persons with Type 2 diabetes 
Intervention(s) 
Usual care comparator: Proactive care management (nurse outreach with follow up as 
necessary) 
 
Active comparator: Proactive care management (nurse outreach with follow up as 
necessary) plus structured MyHC-T2D educational program, designed to improve 
hypoglycemia awareness and reduce severe hypoglycemia 
Key inclusion and exclusion 
criteria 
Ages eligible for study: ≥18 years; Sexes eligible for study: all 
Inclusion criteria: Age ≥18 years; diagnosed with type 2 diabetes; receiving primary care 
at Kaiser Permanente Washington (KPWA); enrolled at KPWAat baseline; planning to 
stay with a KPWA health plan for the next 6 months; at intermediate to high risk for 
severe hypoglycemia; and with history of severe hypoglycemia in the prior 12 months 
or impaired awareness of hypoglycemia. 
Exclusion criteria: Inability to give informed consent; unable to speak or read English; 
inability or unwillingness to attend online or telephone educational sessions, follow up 
calls, or to complete outcome assessments; prior diagnosis of dementia, severe 
psychiatric condition with psychosis, severe cognitive impairment; currently living in 
nursing home or hospice care, current use at baseline of Continuous Glucose Monitor, 
pregnant or planning to become pregnant. 
Study type 
Interventional 
Allocation: individually randomized; Interventional model: parallel assignment; Masking: 
single blind (outcome assessors will be blinded; participants will not be blinded) 
Primary purpose: Prevention 
Phase III 
Date of first enrollment 
01-26-2022 
Target sample size 
256 
Recruitment status 
Complete 
Primary outcome(s) 
Self-reported severe hypoglycemia in prior 12 months.  
Secondary outcome(s) 
All secondary outcomes 
assessed 14 months after 
baseline. In MyHC-T2D 
intervention arm, 14 months post 
baseline corresponds to 
approximately 12 months after 
the main component of the 
MyHC-T2D intervention. 
Measures using Continuous Glucose Monitoring (CGM)  
Hypoglycemia: % time glucose <54mg/dL, % time glucose <70 mg/dL, # of events 
> 15 minutes glucose 54-69 mg/dL, # events > 15 minutes glucose <54 mg/dL, # of 
events > 15 minutes glucose <70 mg/dL between 12 AM and 6AM 
Hyperglycemia: % time glucose >180 mg/dL, % time glucose > 250 mg/dL 
Time in range: % time between 70 to 180 mg/dL 
Glucose Management Indicator 
Average glucose 
Glucose variation: coefficient of variation, standard deviation 
Self-reported measures: # of severe hypoglycemic events in prior 4 months: # of 
moderate hypoglycemia events in past 4 weeks; # of nocturnal hypoglycemic events in 
past 6 months; hypoglycemia unawareness; fear of hypoglycemia; diabetes knowledge; 
diabetes self-efficacy  
Hemoglobin A1c 
Hypoglycemia-related healthcare utilization: total number of urgent care, emergency 
department and inpatient visits for hypoglycemia as primary or principal diagnosis 
collected from the electronic health record (EHR) 

Protocol:  ClinicalTrials.gov #NCT0486387, Comparing the Effectiveness of Two Approaches 
 
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Roles and Responsibilities 
James Ralston, MD, MPH 
Principal investigator and research physician 
• 
Design and conduct of the study 
• 
Preparation of protocol and revisions 
• 
Overseeing and directing the study team and all implementation and data collection 
• 
Leading Stakeholder Advisory Committee meetings 
• 
Leading analyses and publication of study reports 
Study Team: 
Name, degree(s) 
Role 
Melissa Anderson, MS  
Biostatistician 
Ayat Bashir, MBBS, MRCP (UK) 
Consultant 
Kelly Ehrlich, MS 
Project Manager 
Laurel Hansell, MA, MPH 
Qualitative Research Associate 
Dena Burns-Hunt 
Patient partner and Co-Investigator 
Helen Hunt 
Family member partner and Co-Investigator 
Clarissa Hsu, PhD  
Qualitative Lead and Co-Investigator 
Andrew Karter, PhD 
Co-Investigator 
Evette Ludman, PhD 
Co-Investigator 
Lawrence Madziwa, MS 
Programmer Analyst 
Janet Ng, PhD 
Implementation Lead and Co-Investigator 
Emily Omura, MD 
Endocrinologist 
James Shaw, BSc (Hons Biochem), MB ChB, 
PhD, FRCP (Ed) 
Consultant 
Susan Shortreed, PhD 
Biostatistician and Co-Investigator 
Jane Speight, PhD CPsychol FBPsS 
Consultant 
Katherine Purwin-Tschernisch 
Family member partner and Co-Investigator 
Sergei Tschernisch, MFA 
Patient partner and Co-Investigator 
Study team responsibilities: 
• 
Agreement of final Study Protocol (All) 
• 
Adaptation of MyHC-T2D; development and oversight of interventions (EL, JN) 
• 
Development of data collection instruments and protocols (All) 
• 
Development and oversight of allocation procedures (MA, SS) 
• 
Oversight of study recruitment, implementation of interventions and all data collection (All) 
• 
Reviewing of study progress, as necessary agreeing changes to the protocol to facilitate the 
smooth running of the study (All) 
• 
Data cleaning and analysis (MA, SS, LM) 
• 
Presentation and publication of study results (All) 
• 
Preparing reports for the Data and Safety Monitoring Board (MA, SS, JR, KE) 
• 
Organization and conduct of Stakeholder Advisory Committee meetings (JR, KE) 
• 
Developing and managing timeline, maintaining trial master files (KE) 
• 
Preparing submissions to the Institutional Review Board, registering with ClinicalTrials.gov (KE) 
• 
Budget administration and contractual management (KE) 
 
Authors’ contributions 
JR and AK conceived of the study. JR, AB, CH, DBH, HH, AK, EL, JN, JSh, JSp, KPT, and ST led the 
design of the study and KE, LH and LM helped with implementation. JR is Lead Investigator on the 
contract. MA and SS provided statistical expertise in clinical trial design and MA is conducting the 
primary statistical analysis. All authors contributed to refinement of the study protocol. 

Protocol:  ClinicalTrials.gov #NCT0486387, Comparing the Effectiveness of Two Approaches 
 
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Protocol Amendment History 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a description 
of the change and rationale. 
Version 
Date 
Description of Change  
Brief Rationale 
02 
06/04/2021 
New exclusion: use of CGM at 
baseline 
Direct and real time feedback of glucose levels to 
participants could 1) impact the study’s outcome 
of severe hypoglycemia and 2) interact in 
uncertain ways in the two comparison 
interventions. 
03 
10/29/2021 
Revised inclusion: removed 
requirement for 24 months of 
continuous enrollment in the 
health plan at baseline, now only 
1 month prior enrollment at 
baseline 
Requirement for 24 months unnecessarily 
restricts sample pool. 
03 
10/29/2021 
New exclusion: pregnant or 
planning to become pregnant 
Per manufacturer’s instructions, use of the CGM 
(required for study data collection) not 
recommended for women who are pregnant or 
planning to become pregnant. 
03 
10/29/2021 
Collection of HbA1c test at 14 
months, if the participant has not 
had one within the past 3 months. 
Addition of $25 incentive for those 
who have this test. 
Added to ensure a 14-month measure to 
compare to baseline. 
03 
10/29/2021 
Revised randomization method: 
covariate constrained 
randomization instead of matched 
pair 
Allows balance on a greater number of cluster 
characteristics than matched pair, allows an odd 
number of clusters. 
03 
10/29/2021 
Self-report data collection will use 
telephone surveys at all 
timepoints, not just baseline.  
There will be no web-based 
survey collection. 
Changed to keep mode consistent, avoid 
potential mode differences 
03 
10/29/2021 
Revised consent procedures: 
addition of signed e- or paper 
consent for participation in the 
trial 
Signed consent required by our Institutional 
Review Board 
04 
07/01/2022 
Change from cluster to individual 
randomization 
Changes in health care delivery system now 
allow individual randomization. Individual 
randomization yields yields more assurance of 
comparable balance between study arms and 
higher likelihood of balanced sample size by arm  
04 
07/01/2022 
Revised inclusion: expand age 
from >50 to >18 
Expands sample to help meet enrollment targets 
04 
07/01/2022 
Expanded recruitment pool to 
include individuals with type 2 
diabetes with current prescription 
for insulin regardless of Karter 
risk stratification 
Expands screening to help meet enrollment 
targets.  No change to requirement for severe 
hypoglycemia in past 12 months or current 
impaired awareness of hypoglycemia. 
04 
07/01/2022 
Update to Study Team: 
replacement Dr. Avantika Waring 
with Dr. Emily Omura 
Administrative change: Dr. Waring has left Kaiser 
Permanente Washington 
05 
11/29/2023 
Addition of new secondary 
outcomes of glycemic control 
New outcomes consistent with International 
Consensus on Use of Continuous Glucose 
Monitoring.  Will be Important to assess potential 

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from Continuous Glucose 
Monitoring (CGM) data 
intervention effects on frequency of high blood 
sugars and variability of blood glucose levels 
05 
11/29/2023 
Revised plan for mediation 
analysis 
Revised mediation analysis to reflect an updated 
approach using the causal mediation framework 
instead of the Baron and Kenney framework 
05 
11/29/2023 
Revised analysis plan for 
handling missing data 
Lowered the threshold for attrition that would 
trigger use of missing data methods to account 
for possible selection bias (from 15% to 10%). 
Other editorial changes to analysis plan were 
made for clarity, but were not substantive. 
06 
11/27/2024 
Clarified clustering level for 
analysis 
Revised analysis plan to account for patient 
clustering in the intervention arm within group 
training session cohorts rather than within clinic.  
06 
11/27/2024 
Corrected Figure 4 to remove 
reference to randomization by 
clinic and add individual 
randomization 
Figure 4 was incorrect, not updated per change 
in Protocol Version 04, see below.  Now 
corrected in the Figure as well as the text. 
06 
11/27/2024 
Changed references to “my hypo 
compass” intervention protocol to 
“MyHC-TD2” 
Name changed per the now executed copyright 
license agreement with the original developers of 
my hypo compass.  The study intervention is an 
adaptation of the original my hypo compass, 
which was developed and tested in persons with 
type 1 diabetes and was adapted in this study for 
use by persons with type 2 diabetes. 
07 
04/14/2025 
Changed references to “MyHC-
TD2” intervention protocol to 
“MyHC-T2D” (reverse order of 
last two characters) 
The reference ending “…TD2” was incorrect.  
The name of the adapted intervention should 
have been MyHC-T2D. 

Protocol:  ClinicalTrials.gov #NCT0486387, Comparing the Effectiveness of Two Approaches 
 
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Table of Contents 
 
Contents 
1. Introduction ................................................................................................................................. 7 
1a. Background and rationale ................................................................................................... 7 
1b. Objectives: ......................................................................................................................... 7 
1c. Trial design ......................................................................................................................... 8 
2. Methods: Participants, interventions and outcomes ..................................................................... 8 
2a. Study setting ...................................................................................................................... 8 
2b. Eligibility criteria .................................................................................................................. 8 
2c. Interventions ....................................................................................................................... 9 
2d. Outcomes ......................................................................................................................... 11 
2e. Participant timeline ........................................................................................................... 13 
2f. Sample size ....................................................................................................................... 14 
2g. Recruitment ...................................................................................................................... 15 
3. Methods: Assignment of interventions ....................................................................................... 15 
3a. Allocation .......................................................................................................................... 15 
3b. Blinding (masking) ............................................................................................................ 15 
4. Methods: Data collection, management, and analysis ............................................................... 16 
4a. Data collection methods ................................................................................................... 16 
4b. Data management ............................................................................................................ 18 
4c. Statistical methods ........................................................................................................... 19 
4d. Trial monitoring................................................................................................................. 20 
5. Ethics and dissemination ........................................................................................................... 22 
5a. Research ethics approval ................................................................................................. 22 
5b. Protocol amendments....................................................................................................... 22 
5c. Consent ............................................................................................................................ 23 
5d. Confidentiality ................................................................................................................... 23 
5e. Declaration of interests ..................................................................................................... 24 
5f. Access to data ................................................................................................................... 24 
5g. Ancillary and post-trial care .............................................................................................. 24 
5h. Dissemination policy ......................................................................................................... 24 
 
 
 

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1. Introduction 
1a. Background and rationale 
Severe hypoglycemia is the most feared complication of glucose-lowering medications used to treat people with 
diabetes. Severe hypoglycemia, defined as a blood sugar low enough to require assistance, is associated with 
accidents,1 falls,2,3 motor vehicle accidents,1 poor health-related quality of life,4,5 emotional and interpersonal 
challenges,6 chronic and acute cardiovascular disease,7-12 dementia,13-15 and death.16-19 Older adults with type 2 
diabetes on glucose-lowering medications are particularly vulnerable to the complications of severe 
hypoglycemia.20 Severe hypoglycemia is also linked to hospitalization: of all emergency hospitalizations of older 
Americans for adverse drug events, an estimated 14% implicate insulin and 11% implicate oral hypoglycemic 
agents.21 One in four diabetes-related hospital admissions is due to hypoglycemia.22 Each year, about 11% of 
patients with type 2 diabetes self-report severe hypoglycemia.23 
Preventing severe hypoglycemia requires patients to recognize when hypoglycemia is imminent and act to 
prevent it. Many patients who are at risk for severe hypoglycemia, though, have lost the hormonal response and 
associated symptoms that would usually alert them to low blood sugar. Impaired awareness of hypoglycemia is 
acquired over time through repeated exposure to hypoglycemia. Severe hypoglycemia is 17 times more 
common in individuals with impaired awareness of hypoglycemia.24 Current type 2 diabetes self-management 
training does not address impaired awareness of hypoglycemia and provides limited coaching on when and how 
to avoid severe hypoglycemia. Recently developed interventions can restore hypoglycemia awareness, enabling 
immediate action to reverse hypoglycemia and reduce severe hypoglycemia in patients with type 1 diabetes.25-29 
We do not know if these interventions work in patients with type 2 diabetes. 
The goal of this study is to compare the effectiveness of two evidence-based approaches for preventing severe 
hypoglycemia among patients with type 2 diabetes who are at high risk for severe hypoglycemia, defined as 
experiencing one or more severe hypoglycemic events in prior 12 months or having impaired awareness of 
hypoglycemia. 
 
1b. Objectives: 
1b.1 Primary objective 
To determine if proactive care management plus MyHC-T2D is superior to proactive care management alone at 
preventing self-reported severe hypoglycemia in adults with type 2 diabetes at high risk for severe 
hypoglycemia. The primary outcome will be assessed through self-report via study survey at 14-months post 
baseline. 
1b.2 Secondary objectives 
1b.2.a Key secondary objectives 
Key secondary outcomes will be assessed at 14-months post baseline through self-report in study survey (SR), 
continuous glucose monitors (CGMs; study participants will wear CGMs for 10 days), and electronic health 
records (EHRs). 
1.  To determine if proactive care management plus MyHC-T2D is superior to proactive care management 
alone in adults at high risk for severe hypoglycemia for the following: 
• 
Reducing percentage time with biochemical hypoglycemia (CGM assessed) 
• 
Reducing biochemical hypoglycemic events (CGM assessed) 
• 
Reducing the frequency of high blood sugars and reducing variability of blood glucose levels 
(CGM assessed) 
• 
Reducing number of severe hypoglycemic events in prior 4 months (SR assessed) 
• 
Reducing hypoglycemia unawareness (SR assessed) 
• 
Reducing number of self-reported moderate hypoglycemic events (SR assessed) 

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• 
Reducing fear of hypoglycemia (SR assessed) 
• 
Reducing frequency of nocturnal hypoglycemia (SR assessed) 
• 
Improving diabetes and hypoglycemia knowledge (SR assessed) 
• 
Improving diabetes self-efficacy (SR assessed) 
• 
Reducing hypoglycemia related healthcare utilization, including urgent care, Emergency 
Department and inpatient visits related to hypoglycemia (EHR assessed) 
2. To assess differences in glycemic control, indicated by Hemoglobin A1c, between study participants in 
the proactive care management plus MyHC-T2D group and the proactive care management alone group. 
1b.2.b Other secondary Objectives 
Conduct a mixed methods process evaluation to evaluate the fidelity of implementation of intervention 
components, and clarify the causal pathway if intervention effects are found. 
 
1c. Trial design 
This study is an individually randomized controlled trial (RCT) comparing proactive care  management30,31 to 
proactive care management plus MyHC-T2D.25,32  
 
2. Methods: Participants, interventions and outcomes 
2a. Study setting 
The study will be at Kaiser Permanente Washington (KPWA), an integrated care and coverage system with 34 
owned-and-operated clinics for nearly 700,000 members. We will recruit and retain a representative population 
in the study in two steps from KPWA clinics. 
 
2b. Eligibility criteria 
Inclusion criteria 
Participants eligible for the trial must meet all the following inclusion criteria at baseline  
• 
Age ≥18 years; 
• 
Diagnosed with type 2 diabetes; 
• 
Receiving primary care at KPWA; 
• 
Enrollment at KPWA at baseline; 
• 
Planning to stay with a KPWA health plan for the next 6 months; 
• 
Current prescription for insulin or at intermediate to high risk for a severe hypoglycemia episode using 
the hypoglycemia risk-stratification tool developed by Karter et al and validated in the KPWA patient 
population;33,34 and 
• 
Have history of a severe hypoglycemia episode in the prior 12 months or impaired awareness of 
hypoglycemia based on Gold score.35,36 
Exclusion criteria 
Any of the following criteria at baseline exclude participation in the study:  
• 
Unable to give informed consent; 
• 
Unable to speak or read English; 
• 
Unable or unwilling to attend online or telephone educational sessions, follow up calls, or to complete 
outcome assessments; 
• 
Prior diagnosis of dementia, severe psychiatric conditions with psychosis, severe cognitive impairment; 
• 
Currently living in nursing home or under hospice care; 
• 
Current use at baseline of Continuous Glucose Monitor; 
• 
Pregnant or planning to become pregnant. 
 

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2c. Interventions 
Randomization will be at the individual level. Participants will be assigned to one of the two following 
interventions. 
2c.1. Proactive care management 
Population care management nurses trained in diabetes care will deliver evidence-based care to prevent 
hypoglycemia based on ADA guidelines.30,31 They will use existing standard training, tools and workflows already 
in use at KPWA. The study will provide a continuing nurse education training covering these materials for nurses 
delivering proactive care management in both study arms prior to enrolling the first study participant. Care for 
this group will be similar to care usually received from KPWA nurses after a recent severe hypoglycemic event. 
Current practices include the following: for participants with overly aggressive glucose targets or impaired 
awareness of hypoglycemia, nurses work with the participant’s primary care provider to personalize a care plan 
that may include adjusting glucose targets, de-intensifying hypoglycemic medications, enhancing self-monitoring 
of blood glucose, providing glucagon kits and training, or referring for consideration of Continuous Glucose 
Monitoring (CGM).37,38 For participants on glucose-lowering agents who need help with self-monitoring, nurses 
provide basic coaching on hypoglycemia signs, symptoms, and actions such as how to safely raise blood sugar 
and refer to dieticians as needed.31,39 Nurses also ensure standard primary care at KPWA including regular 
assessment and follow-up for mental health and social needs that may contribute severe hypoglycemia risk.40 
Outreach for care will include one standardized outreach call followed by additional calls or other follow up as 
indicated to meet current standard of care. 
 
2c.2 Proactive care management plus MyHC-TD2 education 
Participants in this group will receive the same proactive care management as described above, plus MyHC-T2D, 
an adapted version of the my hypo compass protocol which was developed and tested in patients with type 1 
diabetes. The MyHC-T2D curriculum uses standardized Facilitator and Participant handbooks and behavioral 
intervention techniques to facilitate discussions on strict avoidance of hypoglycemia using four key principles 
around compass points: 1) Never delay appropriate treatment of hypoglycemia; 2) Establish times of Extra risk; 
recognize hypoglycemia by 3) Subtle symptoms; and 4) being Watchful to detect and prevent hypoglycemia, 
particularly asymptomatic nocturnal hypoglycemia. The MyHC-T2D protocol for this study will consist of the 
following activities: 
• 
Baseline outreach and engagement in structured educational sessions: KPWA nurses specializing in diabetes 
will call participants and coordinate care for severe hypoglycemia risk factors as in the proactive care group. 
Nurses will elicit and address barriers for attending MyHC-T2D training.41-43 Participants will be mailed the 
MyHC-T2D Glucose/Hypo diary and Participant Handbook in preparation for structured educational sessions. 
They will have the same nurse care manager throughout the intervention. 
• 
Structured 
Educational Session 
1: Two diabetes 
nurse educators 
trained on the 
MyHC-T2D protocol 
will lead online 
virtual group 
sessions (Figure 1). The 
sessions will include 8 participants and will be conducted based on the Facilitator Guide and Participant 
Handbooks (Appendix B). Educational session #1 will be approximately 3 hours. Nurse educators will 
encourage participants to reflect on personal hypoglycemia events using the Glucose/Hypo diary. The 
Figure 1: MyHC-T2D Education Activities 

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session will promote patient understanding and self-management strategies by group discussion of the 
MyHC-T2D compass points. Diaries will be completed over the first 4 weeks of the study. Daily 4-point and 
weekly 8-point blood glucose profiles will be done to determine times of increased hypoglycemia risk 
including at night and allow reflection on possible prevention strategies. 
• 
Telephone Review: Approximately 2 weeks after the first educational session, nurse care managers 
will call participants for a 10- to 15-minute review. Nurses will discuss progress and review the 
Glucose/Hypo diary. They will encourage reflection on any hypoglycemia events and self-
management strategies. 
• 
Structured Educational Session 2: A diabetes nurse educator will lead an online virtual follow-up 
session with participants in their original groups. This 60-minute session, led by the same diabetes 
nurse educator as the first session, will facilitate discussion on progress with reference to the 4 
points of hypo compass. Participants will be encouraged to reflect on hypoglycemia symptoms 
experienced during each event including subtle symptoms with review and discussion of the 
treatments implemented. 
• 
Telephone Booster: Approximately 3 months after intervention start or 2 months after the second 
educational session, nurse care managers will call participants for a 10- to 15-minute review and 
booster call. Nurses and participants will reflect on any hypoglycemia events and review self-
management strategies.  
 
2c.3. Training and monitoring intervention fidelity. 
We will ensure maximum generalizability and relevance to providers and healthcare systems by applying the 
Treatment Fidelity Workgroup of the NIH Behavioral Change Consortium framework to ensure interventions are 
delivered as intended.44 
Training 
• 
Proactive care management:  All intervention nurses will use existing standard training, tools and workflows 
which are already in use at KPWA to provide the proactive care management part of both interventions. All 
KPWA nurses are trained in these protocols. The study will provide a continuing nurse education training to 
refresh nurses in these standard protocols for all nurses prior to enrolling the first study participant 
• 
MyHC-T2D protocol:  Study intervention leads will train the diabetes nurse educators in delivery of the 
MyHC-T2D protocol with input and assistance from the program originators. The diabetes nurse educators 
will conduct all online virtual educational sessions. These will be recorded for fidelity monitoring, and for 
qualitative assessment per Aim 2. The study intervention leads and the diabetes nurse educators will train 
the MyHC-T2D intervention nurses for telephone review and booster follow up calls. 
Fidelity 
We will maintain and assess fidelity through four proactive strategies: 
• 
Use of standardized written nurse and participant materials. Study intervention leads and diabetes nurse 
educators and population care nurses will meet regularly to ensure protocol clarity and treatment integrity 
and fidelity. 
• 
Observation of nurses delivering the proactive care management and MyHC-T2D activities by a supervising 
RN for the first two intervention months. 
• 
Use of fidelity assurance checklists for protocol integrity and skills to be covered in each educational session. 
After each session, the nurse will check each point that was covered. If a point was not covered, the nurse 
will plan for follow-up. This checklist will also permit calculation of the percentage of points covered. An 
independent Fidelity Monitoring Research Associate will review completed checklists using a standard 
protocol to document adherence and give formative feedback. 

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• 
Monitoring for potential drift through audio recording sessions. After 2 months of observation, the Fidelity 
Monitoring Research Associate will randomly review 10% of sessions, coding for intervention adherence and 
returning results to be reviewed in weekly supervision meetings. If nurses “drift” from protocols, we will add 
training and supervision and monitor until fidelity is established. 
 
2d. Outcomes 
2d.1 Primary outcome measure 
We will measure number of self-reported severe hypoglycemia episodes in the past 12 months at baseline and 
14 months after the baseline. We assess the primary outcome 14-months after baseline, to allow 2 months for 
baseline collection of CGM and intervention activities prior to the 12-month outcome window (Figure 2). This 
timing is consistent with prior studies showing that symptoms of hypoglycemia return after 3 to 4 weeks of 
avoiding hypoglycemia45 and early impacts of the MyHC-T2D intervention on the percent time with glucose less 
< 54 mg/dL in patients with type 1 diabetes. 25  
• 
Planned primary outcome: Self-report of any severe hypoglycemia episode (yes/no) in the prior 12 months 
assessed 14 months after baseline using a validated question from the Diabetes Care Profile: "In the past 
year, how many times have you had a severe low blood sugar reaction such as passing out or needing help 
to treat the reaction?”46,47. 
• 
Alternative primary outcome: Count of the number of self-report severe hypoglycemia episodes in the prior 
12 months assessed 14 months after baseline using the validated question from the Diabetes Care Profile. 
We will evaluate the distribution of number of severe hypoglycemia events in the prior 12 months assessed 
on all participants at the baseline survey. If more than 60% of respondents report having had 2 or more 
severe hypoglycemia events in the prior 12 months, we will change our primary outcome to be a count of 
the number of severe hypoglycemia events in the prior 12 months. 
 
2d.2 Secondary outcome measures 
• 
Outcomes measured by Continuous Glucose Monitor, over 10 days, at baseline and 14-month assessment: 
o Percent time with biochemical hypoglycemia (<54 mg/dL); 
o Number of Level 2 biochemical hypoglycemic events (15 or more minutes <54 mg/dL). 
o Percent time biochemical hypoglycemia (< 70 mg/dL) 
o Number of level 1 hypoglycemic eventss (≥ 15 minutes at 54 - 69 mg/dL) 
o Number of nocturnal hypoglycemic events (≥ 15 minutes < 70 mg/dL between midnight and 6 am) 
o Percent time 70 to 180 mg/dL 
o Percent time above 180 mg/dL 
o Percent time above 250 mg/dL 
o Average blood glucoses, mg/dL 
o Standard deviation of glucose 
o Coefficient of variation for glucose (%CV) 
o Glucose management indicator 
• 
Outcomes measured by self-report survey at baseline, 6, 10, and 14 months: 
o Number of severe hypoglycemic events in prior 4 months; 
o Hypoglycemia unawareness measured by the single item Gold survey;35,36 
o Number of symptomatic48 hypoglycemic events in the prior 4 weeks;46 
o Fear of hypoglycemia using the Hypoglycemia Fear Survey-II;49 
o Numberof nocturnal hypoglycemia events (defined as “during sleep”) during past 6 months;50 
o Diabetes and hypoglycemia knowledge with the revised Diabetes Knowledge Test;51 
o Diabetes self-efficacy using the 8-item Diabetes Self-Efficacy scale.52 

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• 
Outcomes defined based on data collected from the EHR: 
o Hemoglobin A1c (HbA1c).  The most recent HbA1c measures in the 12 months before baseline will be 
used for the baseline measure. Most recent measures within the past 3 months will be collected at 14 
months. If the participant has not had an HbA1c within the past 3 months at 14 months, they will be 
asked to have one for the study. 
o Hypoglycemia-related healthcare utilization: total number urgent care, emergency department and 
inpatient visits for hypoglycemia as primary or principal diagnosis. 
Figure 2 shows the relationship between outcome measures and study activities. Due to cost and participant 
burden, we will collect CGM measures only at baseline and at 14 months. We will measure all secondary 
outcomes including potential mediators of the intervention, at 6, 10 and 14 months after baseline assessment to 
identify potential early vs. later effects of the intervention.32 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2: Outcome measures and study activities 

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2e. Participant timeline 
Figure 3 shows the study flow diagram 
and Figure 4 the schedule of 
enrollment, interventions and 
assessments. Participants in the 
proactive care management group will 
receive one standardized proactive 
outreach call from KPWA nursing 
staff, with follow up as indicated by 
the participant’s needs. Participants in 
the proactive care management + 
MyHC-T2D group will receive the 
same standardized proactive outreach 
call in addition the standardized 
MyHC-T2D educational intervention, 
delivered over approximately three 
months. As described above, self-
report data will be collected at 
baseline, 6- ,10- and 14 months, and 
CGM and EHR data at baseline and 14 
months.  Duration of participation for 
an individual participant will be 14 
months from baseline data collection. 
 
 
 
 
 
 
Figure 3: Study Flow 

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Figure 4.  Schedule of enrollment, interventions, and assessments 
 
 
 
STUDY PERIOD 
 
Allocation 
Enrollment 
Post-Enrollment 
Close-out 
TIMEPOINT 
Pre-
enrollment 
Pre-
enrollment 
Baseline 
6 month 
10 months 
14 months 
 
 
 
 
 
 
 
ENROLLMENT: 
 
 
 
 
 
 
Identification 
 
X 
 
 
 
 
Telephone screen 
 
 
X 
 
 
 
Informed Consent 
 
 
X 
 
 
 
Individual randomization 
 
 
X 
 
 
 
INTERVENTIONS: 
 
 
 
 
 
 
Proactive care management 
 
 
 
 
 
 
Proactive care management + 
MyHC-T2D 
 
 
 
 
 
 
ASSESSMENTS: 
 
 
 
 
 
 
Primary Outcome: 
Self-report severe hypoglycemia 
events 
 
 
X 
X 
X 
X 
Secondary outcomes: 
 
 
 
 
 
X 
Self report measures 
 
 
X 
X 
X 
X 
CGM Measures 
 
 
X 
 
 
X 
EHR measures 
 
 
X 
 
 
X 
Process Measures 
 
 
 
 
 
X 
Qualitative Assessments 
 
X 
X 
X 
X 
X 
 
2f. Sample size 
We estimate 256 patients (128 randomized to proactive care management, and 128 randomized to MyHC-T2D) 
will consent and complete the baseline survey. To account for loss to follow-up, we assume an 80% response 
rate for the primary outcome measured at 14-months, for an analytic sample size of 204 (102 per group). Power 
calculations for comparing two independent proportions and assumed a 0.05 type I error rate. Assuming 60% of 
patients in the proactive care management group will self-report having had a severe hypoglycemia event in 12-
month look back (yes/no), we have 90% power to detect a 22.6% absolute difference between groups (i.e. 
37.4% severe hypoglycemia rate in MyHC-T2D arm) for the primary outcome. We have 80% power to detect an 
absolute difference of 19.7% between groups. Our study has power to detect a meaningful difference (30% or 
more reduction in frequency of self-reported severe hypoglycemia events).54 Other studies including for the 
original my hypo compass have similar or larger effects on severe hypoglycemia reductions.25-29 We also have 
80% power to detect a 1.4% difference and 90% power to detect a 1.6% difference between groups in the 
secondary outcome of the percent time with biochemical hypoglycemia (<54 mg/dL); this difference is 
consistent with the effect seen with the original my hypo compass.25,32 
 
 
 

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2g. Recruitment 
We will recruit the study population in two steps. 
Step 1, Automated risk stratification: We will identify a cohort of adults (≥18 years) with T2D receiving primary 
care at KPWA. We will identify all individuals with either a current prescription for insulin or who have 
intermediate-to-high risk for a SH event based on our hypoglycemia risk-stratification tool.  
Step 2, Phone screening for verbal consent and to identify patients at highest SH risk: We will mail eligible 
participants an invitation with study brochure and notification that staff will call them about the study. KPWHRI 
Survey Research Program (SRP) members will then call the potential participant to explain the study, assess 
eligibility and interest, and conduct informed verbal consent with those who are eligible and interested. We 
expect 1001 eligible. Based on a similar recruitment55 and participation in other diabetes education trials, we 
anticipate at least 25% will consent and complete baseline data collection.56 
To retain participants and minimize data loss, we will provide $100 incentive for completing data collection at 
baseline and 14 months ($30 for the survey and $70 for CGM at each time point) and $30 for self-report-only 
measures at 6 and 10 months.  Participants who agree to have an HbA1c test for the study at months will 
receive an additional $25. 
 
3. Methods: Assignment of interventions 
3a. Allocation 
After identifying potentially eligible patients based on EHR data, and verify eligibility, documenting verbal 
consent, collecting baseline data by phone, and receiving written consent, we will randomize study participants 
to one of our two intervention arms using a 1:1 allocation ratio. Randomization will occur by selecting sequential 
assignments from randomization sequences generated by the study biostatistician, and stored on a computer 
inaccessible to study staff.  The randomization list will use permuted blocks of randomized size 4 or 8.  
Randomization will be stratified by age (18-74 versus 75+ years) and risk score for severe hypoglycemia 
(moderate versus high risk), to ensure balance of these important risk factors of SH events across intervention 
arms.  Individuals with low risk but using insulin will be randomized in the moderate risk strata.  Randomization 
assignment will be concealed from the study staff verifying eligibility and will only be revealed after baseline 
data has been collected, and the next sequential randomization assignment has been requested. Outcomes will 
be measured and analyzed at the participant level. 
 
3b. Blinding (masking) 
Blinding or masking will be maintained for research staff collecting outcomes, including those collecting self-
report and CGM data. However, participants, nurses, and providers engaged in the interventions cannot 
reasonably be masked to the study groups, nor can study staff conducting fidelity monitoring or those collecting 
qualitative data. 
The study programmer and biostatisticians will have access to unblinded data to conduct data summaries by 
intervention group as necessary for reporting to the Data and Safety Monitoring Board (DSMB). The Principal 
Investigator and other study investigators will remain blinded until all study data for the relevant analyses is 
collected. 
 
 

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4. Methods: Data collection, management, and analysis 
4a. Data collection methods 
Study data will be collected using self-report surveys at baseline, 6, 10- and 14-months; biochemical measures of 
percent time with hypoglycemia and number of biochemical hypoglycemic events using CGM at baseline and 14 
months; and data extracted from the EHR for Hemoglobin A1c and hypoglycemia-related healthcare utilization 
at baseline and 14 months. The outcomes are described in section 2d, above. 
 
4a.1 Self-report measures: 
All self-report instruments are included in Appendix C.  Survey questions will be administered at baseline and all 
follow up time points (6, 10 and 14 months) by telephone by trained KPWHRI survey research program (SRP) 
staff. Telephone data collection will be performed using Sawtooth Ci3 and WinCATI computer-assisted 
telephone interviewing (CATI) software. SRP Interviewers are trained in standardized survey interviewing 
techniques, use of the CATI system, and will be trained in project-specific procedures including item-by-item 
specifications for each questionnaire. Interviewers' phone performance, productivity, and response rates are 
routinely monitored; corrective or remedial training is provided if necessary. Interview quality is continuously 
assessed using silent monitors installed on all telephones; completed interviews are edited and coded within 
48 hours, and interviewer feedback occurs on a regular basis. SRP Interviewers are certified in NIH Human 
Subjects Protections. 
 
4a.2. CGM data: 
CGM data will be collected at baseline and 14 months using the Dexcom 6G Pro CGM integrated sensors and 
transmitters in blinded mode. We chose Dexcom sensors because of validity, reliability, ability to record glucose 
measurements blinded to the participant; and the ability to store up to 10 days of data. At both timepoints we 
will collect 10 days of CGM readings. The readings will be blinded at the time of data collection but shared with 
the participant at the end of the study. 
Baseline CGM data will be collected after collection of baseline self-report data but before beginning any 
intervention activities. CGM data at 14-months will be collected at the same time as outreach for 14-month 
follow up self-report.  In both cases the process will be the same: 
The study nurse or medical assistant (MA) will telephone the participant and schedule a CGM virtual visit. S/he 
will then mail the sensor-transmitter unit (programmed to keep glucose readings blinded from the participant) 
and instructions to the participant, along with postage-paid packaging to return at the end of the 10-day 
recording period. At the virtual visit, the nurse or MA will walk the participant through placing the device, will 
answer any questions and will provide a telephone number that the participant can call for questions or issues 
that may come up. The participant will then wear the device for 10 days with readings stored on the unit. The 
study nurse or MA will make one follow up call near the end of the 10 days, to check in, answer questions and 
confirm that the participant will remove and mail back the single use sensor-transmitter on the planned date. At 
the end of the recording period the participant will remove and mail back the device using the provided mailing 
materials.  The data will then be read or downloaded from the sensor-transmitter using the DexCom 6G Pro 
reader/receiver. 
 
4a.3 EHR data: 
The study programmer will extract data from the EHR to assess study eligibility for recruitment and collect 
outcome measures including HbA1c and hypoglycemia related health care utilization, including emergency 
department and urgent care visits and hospitalizations.  If participants are asked to have an HbA1c at 14 months, 
the results will be collected from the medical record in the same way as other HbA1cs. 

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4a.4 Data collection incentives: 
Participants will be mailed $100 for completion of baseline and 14-month follow up study measures ($30 for the 
survey and $70 for CGM at each time point). They will be mailed $30 for completion of self-report-only 
measures at 6- and 10-month follow up.   Participants who agree to have an HbA1c test for the study at months 
will be mailed an additional $25. 
 
4a.5 Procedures for participants not completing study activities, or withdrawing consent 
Participation in this study is voluntary. Even after consent, participants may choose to not do specific study 
components such as CGM data collection. They may decline survey questions or choose not to participate in 
intervention activities. Participants will not be considered withdrawn from the study unless they state clearly 
that they wish to withdraw. For participants who do not complete specific activities but do not withdraw 
consent, we will continue to use what information they have provided and will extract and use EHR data as 
described in the consent process. If participants withdraw their consent, we may still use information collected 
before withdrawal, but will not collect any additional information and will destroy any record of their name or 
other information that may identify them. This will be clearly stated in the consent materials and reviewed as 
part of the informed consent process. 
 
4a.6. Process evaluation 
In addition to collection of data for primary and secondary outcomes described above, we will conduct a process 
evaluation to assess whether the interventions were implemented as planned and to test and refine the 
hypothesized causal pathways (Figure 5). These results will be essential to ensure future implementations of 
severe hypoglycemia prevention are centered on patient needs and are feasible and acceptable for healthcare 
providers and systems. 
We will use qualitative and quantitative methods for assessing the fidelity, dose and mechanism of the 
intervention. 
Qualitative assessments: To 
assess delivery fidelity and 
dose to clusters and 
individuals, we will observe 
nurse care managers and 
diabetes nurse educators 
working with participants and 
interview them after 
interventions.57 For 
observations of nurse care 
managers, we will develop a 
tool to capture information on 
protocol integrity for outreach 
calls to patients in both 
comparator groups. We will 
do observations in the last 2 months of intervention implementation to separate evaluation from earlier fidelity 
monitoring and feedback training to nurses conducted by the intervention team. We will observe nurses on 
initial proactive care management outreach calls in each comparator group. We will observe nurses on the two 
follow-up educational calls in the MyHC-T2D group. We will also observe selected MyHC-T2D group educational 
sessions facilitated by the diabetes nurse educators. 
After the intervention and collection of outcomes, we will conduct interviews with participants, diabetes nurse 
educators and clinic nurse care managers. We will ask participants to reflect on their experiences with the 
Figure 5: Study Model 

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intervention and the impact of the intervention on care including unintended consequences. We will interview 
participants in each comparator group, diabetes nurse educators delivering the in-person education sessions 
and nurse care managers in each comparator group. We will purposively sample participants to ensure robust 
representation based on race/ethnicity, gender, and educational attainment. For evaluating intervention 
context, we will also interview the healthcare system’s stakeholders, examples of which may include directors of 
nursing, endocrinology, primary care, quality and health plan representatives. We will analyze interview and 
observational data using a template analysis approach based on a code manual from our conceptual model and 
emergent themes. Atlas.ti will be used to organize and manage the data. model and the intervention.58 59  
Quantitative data for process evaluation will include process data such as number and type of participant 
contacts, data collected for fidelity monitoring, and outcome data such as number of self-reported severe 
hypoglycemia episodes.  Table 1 describes how these data will be used, with results from the qualitative 
assessments. We will collect quantitative data as follows: 
• 
Fidelity checklists filled out by study 
nurses 
• 
Participant contacts collected from EHR 
data and 
• 
Variables for mediation analysis collected 
from combination of self-report and EHR 
data.   
Integrating results: We will do a concurrent 
triangulation mixed methods design, where 
qualitative and quantitative data will be 
collected at the same time and used to 
validate and/or add detail and depth to the 
data from two data collection approaches.57 
 
4b. Data management 
Data for this study will be captured from 
telephone surveys, capture by CGM monitoring devices (baseline and 14 months) and extraction from EHR 
databases. If a participant is asked to have an HbA1c test at 14 months for the study, this will be done by the 
healthcare system, paid for by the study, and results collected from the medical record. 
• 
Telephone surveys will be administered by the KPWHRI SRP. Staff will be trained and quality monitored 
as described in Section 2.c.1, Data Collection Methods, Self-Report data, above. Instruments will be 
programmed with skip patterns and range checks. KPWHRI, and specifically SRP, maintain a HIPAA-
compliant environment. Data in DatStat Illume, which will be used for survey data, is encrypted at all 
times. Other protections include real-time scanning for viruses and malware, and scanning and 
blacklisting of suspicious incoming email and web traffic. Multiple real-time systems monitor internal 
activity including movement of data between internal systems. Data collected through DatStat Illume 
are stored on Microsoft SQL Server systems located behind the Kaiser Permanente firewall. Access to 
both the DatStat web server and the database servers is restricted to IT Operations staff. Access to data 
collected through DatStat is limited to Kaiser Permanente Washington employees with a need for 
access. 
• 
Data collected via CGM: Study staff will download data from each participant’s CGM sensor transmitter 
unit using the Dexcom receiver. The receiver will transmit this data to the Dexcom CLARITY server from 
which data and reports will be retrieved. Data for individuals will be identified only by a device ID, which 
will be linked to study ID using crosswalks kept only at KPWHRI. 
Table 1: Process Assessment: Domains, Question, Methods 60 
Evaluation 
Domain 
Research Questions 
Research Methods 
Fidelity 
Is the intended 
intervention delivered at 
the cluster level? 
individual level? 
Qualitative analysis of nurse and 
patient interviews, nurse observations  
-Quantitative analysis of fidelity 
checklists and participant contacts 
Dose 
Is the intended amount of 
the intervention delivered 
at the cluster level? 
Individual level?  
-Qualitative analysis of nurse and 
patient interviews, nurse observations 
-Quantitative analysis of fidelity -
checklists and participant contacts 
Mechanism  
Why and how did the 
intervention work?   
-Quantitative mediation analysis of 
causal pathway 
-Qualitative analysis of patient and 
nurse interviews 
Reach 
Did the intended 
populations receive the 
intervention? 
Quantitative descriptive analysis of 
clusters and individuals using 
administrative and EHR data 
Context  
What clinic, institutional, 
state and national factors 
may moderate 
intervention? 
-Qualitative analysis of interviews with 
stakeholders 
 

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• 
EHR data will be extracted by the study programmer from automated administrative and EHR data 
sources, including the KPWHRI Data Warehouse, a research-centric repository of datasets maintained by 
the Research Institute. Data are stored in Teradata, SQL Server, and SAS format and cover enrollment, 
demographics, diagnoses and procedures, vital signs, pharmacy, lab tests, costs. A rich collection of 
powerful SAS macros can be used in conjunction with the KPWHRI data. KPWHRI data warehouse 
content and usage are documented by a wiki-based system authored by the data warehouse’s 
architects, managers, and users. Access and security for electronic data sources are described below in 
Section 3. Ethics and Dissemination, Confidentiality. 
 
4c. Statistical methods 
Comparative effectiveness analyses will apply intent-to-treat principles, with study participants analyzed based 
on randomization group, regardless of intervention received. To assess comparability across study groups, we 
will summarize demographic characteristics and responses to baseline surveys in the two comparison groups. 
The preliminary analysis plan defines the primary outcome as a binary indicator for whether or not (yes/no) the 
participant self-reported having had a severe hypoglycemia event in the prior 12-months, assessed 14 months 
after baseline. We will estimate relative risk of severe hypoglycemia in the MyHC-T2D group vs. proactive care 
management group by fitting a modified Poisson regression model with the binary self-report measure as the 
dependent variable and randomization group as the independent variable. Models will adjust for age, sex, risk 
score, and the number of self-reported severe hypoglycemic events in the 12 months prior to baseline. 
Modelswill be fit using generalized estimating equations (GEE) and robust variance estimation to account for 
correlation due to patient clustering in the intervention arm within group training session cohorts, and the 
misspecified mean-variance relationship in using Poisson regression for a binary outcome.  
 
Prior to conducting analysis of 14-month outcomes, we will look at the baseline distribution of the self-reported 
number of severe hypoglycemic events in the prior 12-months collected at baseline. If more than 60% of 
enrolled patients report 2 or more events, we will revise the primary outcome to be defined as the self-reported 
number of severe hypoglycemic events in the past 12-months, measured at 14-months post baseline (a count 
rather than a binary outcome and fit a Poisson regression model to estimate the rate ratio for severe 
hypoglycemia events for the MyHC-T2D group relative to the care management group.  We will assess model fit, 
and consider zero-inflated models as an alternative, if the number of participants reporting zero events violates 
distributional assumptions of the Poisson model. If primary analyses use the binary outcome measure (i.e. fewer 
than 60% of patients report 2 or more events in the 12-months prior to baseline), but 40% or more of 
respondents report 2 or more events at 14-months, we will do a secondary analysis with the count variable as 
the outcome. 
Generalized linear regression models estimated with GEE and robust sandwich errors will also be used to 
estimate intervention effects on secondary outcomes, with link function and error distribution appropriate for 
each outcome. For secondary outcomes measured at multiple follow-up time points (6-, 10- and 14-months 
post-baseline), we will fit a single regression model that includes outcome measures from all follow-up time 
points. Models will include indicator variables for time, intervention group, and interaction terms between these 
variables, to estimate intervention effects at each time point. Models will adjust for age, sex, risk score and the 
baseline measure of the outcome. For hypoglycemia-related health care utilization (urgent care and emergency 
department visits, hospital admits), we will follow a similar analytic plan as the primary outcome, including the 
process to determine whether to model these outcomes as binary or count variables. 
Standards for Preventing and Handling Missing Data. Outreach with repeated calls will maximize response rates 
of follow-up phone surveys. Response rates and data collection will be monitored and if attrition is greater than 
10%, statistical methods will account for potential selection bias. We will compare baseline characteristics of 
responders and non-responders and consider multiple imputation or inverse probability weighting (IPW) to 
account for potential bias due to missing data. 

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Addressing HTE standards.  
Exploratory analyses will assess whether treatment effects vary by patient characteristics including age (under 
75 years vs. 75 years and older), sex, race/ethnicity, comorbidities, insulin use and/or sulfonylurea use, baseline 
IAH presence, and baseline SH history. We will include interaction terms between randomization group and 
these characteristics in the primary and secondary outcome models to estimate comparative effectiveness by 
subgroup. 
 
We provide a brief description of the power we estimate we will have for some subgroup analyses. For those 
with minority racial and ethnic backgrounds (approximately 30% of participants), we will have 90% power to 
detect a 39% difference and 80% power to detect a 35% difference in the rate of severe hypoglycemia between 
comparators for this subgroup. For females (approximately 50% of participants) and those the 65 years of age or 
older (approximately 50% of participants), we will have 90% power to detect a 31% difference in the rate of 
severe hypoglycemia and 80% power to detect 27% difference. All of these effect sizes are smaller than those in 
the MyHC-T2D study in patients with type 1 diabetes.34 
 
Process Evaluation: We will use descriptive analysis to assess intervention recruitment, reach and delivery. If 
significant differences (p<0.05) between intervention groups are found for the primary outcome, we will 
perform mediation analysis to test the hypothesis that the possible causal pathway for reducing the occurrence 
of severe hypoglycemia is through improvements in hypoglycemia knowledge, hypoglycemia awareness, self-
efficacy of hypoglycemia management, blood glucose testing, and hypoglycemic medication adjustment and 
other factors in causal pathway in Figure 2. Mediation analysis will use a regression-based approach within the 
causal mediation framework,53 separating the total intervention effect into a natural indirect effect (effect 
occurring through the mediator), and a natural direct effect (effect through all other pathways). To estimate 
these effects, we will use either a log-linear or Poisson model for the outcome model (depending on whether 
the primary outcome is defined as a binary or count variable), and linear regression for the mediator model. The 
effect of each mediator will be estimated in separate models.  
 
4d. Trial monitoring 
4d.1 Data monitoring 
This study will have a Data Safety Monitoring Board (DSMB) to ensure safety of research participants. The DSMB 
will include an external researcher with prior DSMB experience (the chair), and two clinicians with expertise in 
type 2 diabetes and in the treatment and care for patients with severe hypoglycemia and impaired 
hypoglycemia awareness. The DSMB will meet once in the first 6 months after study funding and prior to patient 
enrollment to review study protocols and plans for study reports (enrollment, completion, and adverse event-
reporting tables by study group) and recommend changes. The study team will track participant-reported 
serious adverse events whether related or not to study participation. The team will provide ongoing reports to 
the DSMB and the Institutional Review Board. The DSMB will meet twice per year, in person or by phone, as 
directed by the committee. The study Principal Investigator, biostatisticians, and project manager will attend all 
open portions of DSMB meetings. 
The DSMB will receive ongoing reports to ensure data validity and integrity, including recruitment reports, 
participant characteristics by study arm to ensure adequacy of randomization and balanced enrollment, 
participant completion of study visits, and completeness of study data collection. The DSMB may also choose to 
see outcome data, with this data blinded except to the study biostatisticians. If the DSMB deems it necessary to 
unblind themselves to interim trial reporting this may occur, similarity the DSMB may decide to unblind the 
study Principal Investigator if patient safety is a concern. 
We do not propose interim analyses or stopping guidelines. The assessment of the primary outcome requires 14 
months of follow-up from baseline; the study enrollment period is only 8 months long, therefore enrollment 
(and likely study interventions) will be complete for all participants before primary outcome data is available on 

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any participants. We cannot feasibly stop the trial for futility or harms seen on the primary outcome before the 
end of enrollment. 
 
4d.2 Harms 
Adverse events:  For this study an adverse event will be defined using the definition from 21 CFR 312.32 (a) as any 
untoward medical occurrence in a participant without regard to the possibility of a causal relationship. Adverse 
events will be collected after the participant has provided consent and enrolled in the study and through 14-month 
follow up. 
Adverse events will be collected using self-report open-ended survey questions at all follow up data collection 
timepoints, including 6-month, 10-month and 14-month follow ups. Adverse events will be classified as to whether 
they are:  
1. Expected or unexpected in nature, severity, or frequency for the population under study (i.e. not 
mentioned in study documents or consent); 
2. Related or possibly related to the study procedures or participation in the research; and 
3. Serious adverse events (SAE) or not. 
Expected adverse events are those which could be anticipated for the population under study. These will be listed 
and discussed as part of informed consent. For this study, severe hypoglycemic events are a risk for this population 
and indeed a planned outcome measure, thus an expected adverse event. However, we do not anticipate that 
the study intervention will provide additional risk. The intervention is an adjunct to usual care aimed at 
preventing severe hypoglycemia for this high-risk population. Other expected adverse events could include 
complications of CGM data collection. It is uncommon, but inserting the CGM monitoring sensor could cause 
infection, bleeding, or pain, and wearing the adhesive patch could irritate the skin. Only a few patients in the 
CGM G6 clinical studies got slight redness and swelling. No sensor wires broke in the clinical studies; however, 
there is a remote chance a sensor wire could break or detach and remain under the skin. Such sterile broken 
sensor wires do not usually pose a significant medical risk. Participants will be fully informed of these risks 
before consenting to the study. If they experience any adverse events with the CGM monitor, participants will 
be instructed to contact the KPWA Endocrinology service which provides support for all KPWA patients who use 
continuous glucose monitors and who will provide medically appropriate advice and care as necessary. If the 
participant has blood drawn for an HbA1c test, having blood drawn can be uncomfortable and can cause a 
bruise. Some people may feel nervous or get dizzy. In rare cases, it can cause people to faint. Participants can 
choose not to have this test and still participate in the study. The informed consent process will include a 
discussion of risks and the release of information to their medical team and coordination of care as needed. 
Relation to the study intervention or data collection will be assessed by an independent physician reviewer as: 
• 
Definitely related – There is clear evidence to suggest a causal relationship. The clinical event, including 
an abnormal laboratory test result, occurs in a plausible time relationship to study procedures and 
cannot be explained by concurrent disease or other factors. 
• 
Probably related – There is evidence to suggest a causal relationship, and the influence of other factors 
is unlikely. 
• 
Possibly related – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of study procedures). However, other factors may have 
contributed to the event (e.g., the participant’s clinical condition, other concomitant events). Although 
an adverse event may rate only as “possibly related” soon after discovery, it can be flagged as requiring 
more information and later be upgraded to “probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study procedures or administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the study procedures) and in which 

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other factors or underlying disease provides more plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• 
Not related – The adverse event is completely independent of study procedures administration, and/or 
evidence exists that the event is definitely related to another etiology. 
A serious adverse event (SAE) will be defined as harm experienced by the study participant that resulted in any of 
the following: 
• 
Death; 
• 
A life-threatening situation (from the event as it occurred) that placed the participant at risk of death; 
• 
Inpatient hospitalization or prolongation of existing hospitalization; 
• 
A persistent or significant disability, incapacity, or condition requiring treatment or impairing subject 
ability to carry out normal daily activities; 
• 
A congenital anomaly/birth defect; or 
• 
Any other adverse event that, based upon appropriate medical judgment, may jeopardize the subject’s 
health or wellbeing and may require medical or surgical intervention or procedural modifications (that 
are not minor) to prevent one of the other outcomes listed in the bullets above. 
All adverse events will be reported to our Institutional Review Board (IRB) on at least an annual basis following the 
standard practice of our institution, and to the DSMB at all DSMB meetings and at additional timepoints if 
requested. 
In addition, adverse events will be reported on an expedited basis that are: (1) unexpected; and (2) related or 
possibly related to study procedures or participation in the research; and (3) suggests that the research places 
subjects or others at a greater risk of harm than was previously known or resulted in a serious adverse event 
(SAE).  Per institutional reporting requirements these events will be reported within 1 business day of discovery 
if a death or within 15 days for other serious adverse events. 
If a participant experiences an adverse event after informed consent is completed but before the participant has 
started to receive the study intervention, the event will be reported as not related to the study intervention. 
 
5. Ethics and dissemination 
5a. Research ethics approval 
This protocol and all informed consent scripting and documentation (sample text included in Appendix A) will 
be reviewed and approved by the KPWRHI IRB with respect to compliance with applicable research and 
human subjects regulations. The KPWHRI IRB will also review participant recruitment, intervention and data 
collection materials and plans, any other requested documents and any subsequent modifications. No 
activities involving human subjects will take place unless they have been reviewed and approved. Subsequent 
to initial review and approval, the KPWHRI IRB will review a continuation and progress report at least 
annually. These reports will include the total number of participants enrolled, a report on study progress, 
summaries of adverse events and summaries DSMB meetings and recommendations. 
 
5b. Protocol amendments 
Any modifications to the protocol which may impact on the conduct of the study, potential benefit for the 
participant or may affect participant safety, including changes of study objectives, study design, participant 
population, sample sizes, study procedures, or significant administrative aspects will require a formal 
amendment to the protocol. Such amendments will be agreed upon by the study investigators and will be 
submitted for review and approval by the KPWHRI IRB prior to implementation. 
Administrative changes of the protocol are minor corrections and/or clarifications that have no effect on the way the 
study is to be conducted. These administrative changes will be agreed upon by the study investigators and will be 

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documented in a memorandum but do not require a formal protocol amendment. The KPWHRI IRB may be notified 
of administrative changes as appropriate for review and approval before implementation. 
 
5c. Consent 
We will request a waiver of consent to identify and approach potential participants. We will request a waiver of 
documentation of consent for collection of baseline survey data in advance of signed consent. 
The study programmer will identify potential study participants using the risk stratification tool and data from 
the EHR. Staff from the KPWHRI SRP will then mail an invitation letter and a hard copy of the Consent form to 
potential participants. The invitation letter will introduce the study, let potential participants know that research 
staff will be calling them to see if they are eligible and interested and will give a toll-free telephone number to 
call if the potential participant does not want to be contacted. The Study Consent form will contain a description 
of the study, study contact information and all required consent elements (Approved Consent Form in Appendix 
A). 
After mailing the invitation letter and Consent form, staff from the KPWHRI SRP will call potential participants to 
assess interest, complete telephone screening, and if the respondent is eligible and interested,collect verbal 
consent to collect baseline self-report data.  When the baseline survey is completed, the interviewer will collect 
the participant’s email address for e-Consent, and enter the participant into the study’s REDCap e-Consent 
database.  The study REDCap e-Consent database will send an email to the participant with link to the e-Consent 
form.  Both the email and e-Consent form will have a telephone number to call if the participant has questions 
or wants to discuss the consent before signing. The participant will review, sign and submit the e-Consent form.  
They will be able to print a copy for their own records or can request a copy from the study. The e-Consent 
instructions will clearly state this. If the participant does not return e-Consent, the study will send up to two 
email reminders and finally follow up by telephone, to answer any questions and, if the participant is willing, 
walk through consent and completion of the e-Consent by phone. 
If the participant does not want to use e-Consent, the study will mail two hard copies of the Consent form with a 
business reply envelope and instructions to sign and return one copy and keep the other for the participant’s 
records. If the paper consent is not received, the study will make up to two follow up reminder calls, and finally 
do a second mailing with business reply envelope. 
If after follow up, any participants do not return either e- or paper consent, the study will destroy their baseline 
survey data and will not contact them again. 
Consent for process measures and observations will be included in the signed written e- or paper consent.  For 
nurse and participant interview we will request a waiver of documentation of consent conduct informed verbal 
consent using scripts and materials that have been reviewed and approved prior to each activity and will 
document consent in study records. We will conduct no activities without prior review and approval by the 
KPWHRI Institutional Review Board. 
 
5d. Confidentiality 
All Kaiser Permanente staff must annually complete confidentiality training and sign a confidentiality agreement. 
All investigators, key personnel, and all those responsible for the design and conduct of research are required to 
receive training in the protection of human subjects. Access to areas where identifiable or protected health 
information is used is restricted and requires use of individualized key cards. Data handling procedures are 
clearly documented. All KPWHRI staff with access to identifiers or protected health information is required to 
review these procedures. New employees are trained regarding data handling procedures, confidentiality and 
security. 

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Access to all information stored on Kaiser Permanente computers is limited to staff who have been specifically 
granted rights by the Information Security Division. All Kaiser Permanente data are protected from unauthorized 
access by anyone outside the organization by firewall and virus-blocking software. Limiting access to only 
authorized individuals who are within the Kaiser Permanente firewall protects servers within KPWHRI. Servers 
are located in a locked room, accessible only to Kaiser Permanente computer support staff. Patient identifiers 
and demographic data are kept in separate files from protected health information. 
All research data collected from participants will be labeled with a unique study identification number and not 
the participant’s name or any other information that could identify the participant.  Only the code number will 
appear on data records and computer files. The participant’s contact information will be kept in restricted 
folders accessible only to relevant study staff. 
 
5e. Declaration of interests 
The independence of this study from any actual or perceived influence is critical. Therefore, any actual conflict 
of interest of persons who have a role in the design, conduct, analysis, or publication of this trial will be 
disclosed and managed. Further, persons who have a perceived conflict of interest will be required to have such 
conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. 
KPWHRI and its sub-contract, the Division of Research, Kaiser Foundation Hospitals have established policies and 
procedures for all study team members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 
 
5f. Access to data 
All study data will be collected and retained by KPWHRI.  No data with identifying information will be shared 
outside the institution.  Aggregate data and de-identified data sets may be shared as allowed by the Informed 
Consent and if approved by the Institutional Review Board. 
 
5g. Ancillary and post-trial care 
This study does not have provisions for ancillary or post-trial care. However, all participants enrolled in the study 
will be current members of Kaiser Foundation Health Plan of Washington and receiving care at KPWA. The 
proposed study interventions will be delivered by KPWA nurses and overseen by participants’ primary care 
health providers and their teams. Ancillary and post-trial care will thus be provided by the participants’ primary 
care provider and KPWA as covered by their own insurance.  The study will not provide compensation for those 
who may suffer harm from the trial. 
 
5h. Dissemination policy 
We will share study results with all participants in this study.  We will send a mailed study results letter or 
summary to all patient participants at the end of the study after analyses for our primary outcomes are 
complete. We will share results with nurses and providers in the KPWA healthcare delivery system by making 
presentations at staff meetings and sharing results at seminars and in internal newsletters. For patient 
participants we will also share their blinded baseline and 12-month CGM results with each participant after they 
have completed the protocol.  If a participant has an HbA1c test these results will also be shared. 
For the larger scientific and health care communities, we will disseminate results, methods and tools using 
presentations at scientific conferences, publications in peer-reviewed journals. We will post materials on 
publicly available websites as feasible and sharing tools and methods (e.g. manuals and guides, interview 
instruments, participant materials) as appropriate upon request. 
 
 
 

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