Closed Loop and Education for Hypoglycemia Awareness Restoration
- Conditions
- Diabetes Mellitus, Type 1
- Interventions
- Device: Omnipod 5 or Medtronic 780GBehavioral: My HypoCOMPaSS EducationBehavioral: HARPdoc Education
- Registration Number
- NCT06325202
- Lead Sponsor
- Milton S. Hershey Medical Center
- Brief Summary
The purpose of the CLEAR study is to determine the effect on counterregulatory responses (CRR) of intervening (by attempting to strictly avoid hypoglycemia) to improve awareness of hypoglycemic symptoms among adults with type 1 diabetes (T1D) who have impaired awareness of hypoglycemia (IAH). IAH affects 20-25% of adults with T1D, and rises with increasing duration of T1D.
- Detailed Description
Individuals with IAH exhibit blunted symptomatic and CR hormonal responses to hypoglycemia and, as such, have an impaired ability to respond to hypoglycemia. Thus, rates of severe hypoglycemia are up to 6-fold greater in those affected. Intensive management of T1D is necessary in preventing long-term complications, but can be complicated by recurrent episodes of hypoglycemia which lead to and sustain the CRR deficits of IAH. Technologies such as continuous glucose monitoring (CGM) and hybrid closed-loop (HCL) systems can reduce severe hypoglycemia (and also may reduce IAH) but the ability of technology to reverse impaired CRR (as assessed with experimental hypoglycemia clamp) remains unclear. Behavioral and psycho-educational interventions targeting knowledge/skills gaps, as well as particular cognitions and behaviors driving recurrent hypoglycemia, can also reduce severe hypoglycemia and improve awareness. No studies have compared technology with such behavioral interventions in terms of assessing their impact on IAH or the CRR (as a primary outcome). Unanswered questions include the degree of reduction in hypoglycemia required to restore awareness. Furthermore, participants may respond to different interventions according to their characteristics. For example, it remains unclear whether older individuals benefit from such interventions since they usually are excluded from studies. Therefore, there is an urgent need to determine effective interventions that can reverse IAH in a large representative population of adults with T1D and IAH. The investigators propose to study the effect of specific interventions aimed at restoring
* the CRR (tested via an experimental hypoglycemia clamp procedure)
* hypoglycemia awareness (self-reported via the Towler Questionnaire during the experimental hypoglycemia clamp procedure)
The study will use a Sequential Multiple Assignment Randomized Trial (SMART) design. At baseline, all participants who are HCL naïve will be randomized to HCL or Usual Care (UC) plus brief education (My HypoCOMPaSS) with a follow-up of two years. UC will consist of real-time continuous glucose monitoring (CGM) and insulin delivery via pump or multiple daily injections. Participants who fail to increase their CRR at 12 months will be randomized, or assigned, to a second intervention consisting of a small-group educational program focusing on motivations and unhelpful cognitions acting as barriers to hypoglycemia avoidance (HARPdoc). At baseline, all participants who are HCL non-naïve will be randomized to optimized HCL or HCL plus My HypoCOMPaSS; those with non-responsive CRR at 12 months will be randomized to either continue HCL (on the basis they need a longer period to reverse impaired CRR and total symptomatic responses) or to the HARPdoc intervention. Participants randomized to an HCL device are expected to wear the device continually, as well as a CGM. The My HypoCOMPaSS education requires 4-5 hours of training, whereas, the HARPdoc education requires four training sessions of seven hours each during weeks 1,2,3, and 6.
The specific aims and hypotheses are as follows:
Aim 1: To determine the effect on CRR (epinephrine increase ≥ 125 pg/ml over baseline) and total symptom responses (Towler Questionnaire increase ≥ 20% over baseline) during a hyperinsulinemic-hypoglycemic clamp procedure (glucose \< 50 mg/dl) after 12 months of HCL versus Usual Care plus My HypoCOMPaSS Educational Intervention among adults with T1D and IAH who have never used HCL therapy previously.
Hypothesis 1: At 12 months, those allocated to Usual Care plus My HypoCOMPaSS will be more likely to have improved CRR and total symptomatic responses than those allocated to HCL.
Aim 2: To determine the effect on CRR and total symptom responses at 12 months of HCL plus My HypoCOMPaSS versus HCL alone among adults with T1D and IAH who are currently using HCL therapy prior to entering the study.
Hypothesis 2: At 12 months, those allocated to HCL plus My HypoCOMPaSS will be more likely to have improved hypoglycemic awareness and improved CRR than those using HCL alone.
Aim 3: To determine the durability of effect over 24 months of the intervention that improves CRR at 12 months among adults with type 1 diabetes and IAH at baseline.
Hypothesis 3: At 24 months, CRR will improve further among those who had restored CRR at 12 months.
Aim 4. To determine the effect on hypoglycemic awareness (Towler Questionnaire increase ≥ 20% over baseline) and CRR (epinephrine increase ≥ 125 pg/ml over baseline) during a hyperinsulinemic hypoglycemic clamp procedure at 24 months of an in-depth educational program (HARPdoc), initiated throughout months 12-24, among adults with T1D and IAH at baseline, for whom the intervention allocated at baseline did not restore CRR at 12 months.
Hypothesis 4: At 24 months, those allocated to HARPdoc for months 12-24 months will be more likely to have improved hypoglycemic awareness and CRR than those who continue with the therapy allocated at baseline.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 324
- Clinical diagnosis of type 1 diabetes
- Gold Score or Clarke Score ≥ 4 (highly associated with IAH)
- Random non-fasting C-peptide < 200 pmol/L
- Diabetes duration ≥ 10 years
- HbA1c < 10.5%
- Total Daily Insulin Dose of < 1 unit/kg
- Ability to read and speak English (because validated non-English versions of the cognitive tests and the educational interventions are not available)
-
Medical conditions that limit participation in study activities, as determined by the PI (including but not limited to cognitive dysfunction, reduced hearing, reduced vision, cancer under active treatment, untreated angina, organ failure)
-
Active alcohol or drug abuse (as defined by DSM criteria of either 1) recurrent use of alcohol/drugs resulting in a failure to fulfill major role obligations at work, school, or home, 2) recurrent alcohol/drug use in situations in which it is physically hazardous, or 3) recurrent alcohol or drug-related legal problems)
-
Social determinants of health that limit participation in study activities, as determined by the PI (including but not limited to homelessness, food insecurity, inadequate social support)
-
Seizure disorder unrelated to hypoglycemia associated seizures, unless documented seizure-free for >12 months and on a stable regimen of anti-convulsant therapy
-
Skin conditions that would preclude the use of a CGM
-
Super-physiologic exposure to steroids within one month of enrollment
-
eGFR < 45 mL/min/1.73 m2
-
History of bariatric surgery that irreversibly alters gut innervation and structure
-
Hyper- or hypokalemia (serum potassium >5.5 or <3.5 mmol/L)*
-
Hemoglobin < 10 g/dL*
-
Medical condition that requires intermittent or continuous use of glucocorticoids at greater than physiological replacement doses
-
Pregnancy, plan for pregnancy, or breast feeding
-
Abnormal thyroid function tests of clinical significance, as determined by PI*
-
Liver transaminases > 3 times the upper limit of normal*
-
Hospitalization for mental illness in last year
-
History of adrenalectomy
- At discretion of the PI, laboratory tests may be repeated once. If the participant is not eligible after the second attempt, then the participant. The participant may be screened again.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description current HCL non-user: HCL x 12 months, then HCL x an additional 12 months Omnipod 5 or Medtronic 780G Hybrid closed loop device over a 12-month period for individuals currently not using a hybrid closed loop device, and then a hybrid closed loop device for an additional 12 months current HCL user: HCL x 12 months, then HCL x an additional 12 months Omnipod 5 or Medtronic 780G Hybrid closed loop device over a 12-month period for individuals currently using a hybrid closed loop device, and then a hybrid closed loop device for an additional 12 months current HCL non-user: HCL x 24 months Omnipod 5 or Medtronic 780G Hybrid closed loop device over a 24-month period for individuals currently not using a hybrid closed loop device current HCL user: HCL and My HypoCOMPaSS x 12 months, then HCL x 12 months Omnipod 5 or Medtronic 780G Hybrid closed loop device and My HypoCOMPaSS education over 12 months for individuals currently using a hybrid closed loop device, then hybrid closed loop device for 12 months current HCL user: HCL + My HypoCOMPaSS x 24 months My HypoCOMPaSS Education Hybrid closed loop device plus My HypoCOMPaSS education over a 24-month period for individuals currently using a hybrid closed loop device current HCL non-user: HCL x 12 months, then HCL + HARPdoc x 12 months Omnipod 5 or Medtronic 780G Hybrid closed loop device over a 12-month period for individuals currently not using a hybrid closed loop device, then a hybrid closed loop device plus HARPdoc education for an additional 12 months current HCL non-user: Usual Care and My HypoCOMPaSS x 12 months, then HCL x 12 months Omnipod 5 or Medtronic 780G Usual Care and My HypoCOMPaSS education over 12 months for individuals currently not using a hybrid closed loop device, then hybrid closed loop device for 12 months current HCL non-user: Usual Care and My HypoCOMPaSS x 12 months, then HCL x 12 months My HypoCOMPaSS Education Usual Care and My HypoCOMPaSS education over 12 months for individuals currently not using a hybrid closed loop device, then hybrid closed loop device for 12 months current HCL user: HCL x 12 months, then HCL + HARPdoc x 12 months HARPdoc Education Hybrid closed loop device over a 12-month period for individuals currently using a hybrid closed loop device, then a hybrid closed loop device plus HARPdoc education for an additional 12 months current HCL user: HCL and My HypoCOMPaSS x 12 months, then HCL x 12 months My HypoCOMPaSS Education Hybrid closed loop device and My HypoCOMPaSS education over 12 months for individuals currently using a hybrid closed loop device, then hybrid closed loop device for 12 months current HCL non-user: HCL x 12 months, then HCL + HARPdoc x 12 months HARPdoc Education Hybrid closed loop device over a 12-month period for individuals currently not using a hybrid closed loop device, then a hybrid closed loop device plus HARPdoc education for an additional 12 months current HCL non-user: Usual Care and My HypoCOMPaSS x 24 months My HypoCOMPaSS Education Usual Care and My HypoCOMPaSS education over 24 months for individuals currently not using a hybrid closed loop device current HCL user: HCL x 24 months Omnipod 5 or Medtronic 780G Hybrid closed loop device over a 24-month period for individuals currently using a hybrid closed loop device current HCL user: HCL x 12 months, then HCL + HARPdoc x 12 months Omnipod 5 or Medtronic 780G Hybrid closed loop device over a 12-month period for individuals currently using a hybrid closed loop device, then a hybrid closed loop device plus HARPdoc education for an additional 12 months current HCL user: HCL + My HypoCOMPaSS x 12 months, then HCL + My HypoCOMPaSS + HARPDOC x 12 months HARPdoc Education Hybrid closed loop device and My HypoCOMPaSS education over 12 months for individuals currently using a hybrid closed loop device, then hybrid closed loop device plus My HypoCOMPaSS eduction + HARPdoc education for 12 months current HCL user: HCL + My HypoCOMPaSS x 24 months Omnipod 5 or Medtronic 780G Hybrid closed loop device plus My HypoCOMPaSS education over a 24-month period for individuals currently using a hybrid closed loop device current HCL user: HCL + My HypoCOMPaSS x 12 months, then HCL + My HypoCOMPaSS + HARPDOC x 12 months Omnipod 5 or Medtronic 780G Hybrid closed loop device and My HypoCOMPaSS education over 12 months for individuals currently using a hybrid closed loop device, then hybrid closed loop device plus My HypoCOMPaSS eduction + HARPdoc education for 12 months current HCL user: HCL + My HypoCOMPaSS x 12 months, then HCL + My HypoCOMPaSS + HARPDOC x 12 months My HypoCOMPaSS Education Hybrid closed loop device and My HypoCOMPaSS education over 12 months for individuals currently using a hybrid closed loop device, then hybrid closed loop device plus My HypoCOMPaSS eduction + HARPdoc education for 12 months
- Primary Outcome Measures
Name Time Method Towler questionnaire measured during the clamp studies at 0 (baseline), 12, and 24 months the Towler questionnaire consists of 12 questions each on a 0-6 Likert scale; a change in the questionnaire that exceeds 20% between (1) 12 months and baseline, and (2) 24 months and baseline
epinephrine (pg/ml) measured during the clamp studies at 0 (baseline), 12, and 24 months a change in epinephrine (pg/ml) that exceeds 125 pg/ml between (1) 12 months and baseline, and (2) 24 months and baseline
- Secondary Outcome Measures
Name Time Method HbA1c measured during the clamp studies at 0 (baseline), 12, and 24 months glycated hemoglobin
sensor glucose coefficient of variation measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months sensor glucose coefficient of variation determined from the continuous glucose monitor (CGM) sensor
geometric mean of plasma glucagon measured during the clamp studies at 0 (baseline), 12, and 24 months geometric mean of plasma glucagon
geometric mean of plasma pancreatic polypeptide measured during the clamp studies at 0 (baseline), 12, and 24 months geometric mean of plasma pancreatic polypeptide
geometric mean of plasma free fatty acids measured during the clamp studies at 0 (baseline), 12, and 24 months geometric mean of plasma free fatty acids
% of time with sensor hypoglycemia <70 mg/dL measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months % of time with hypoglycemia \<70 mg/dL determined from the continuous glucose monitor (CGM) sensor
glucose infusion rate measured during the clamp studies at 0 (baseline), 12, and 24 months glucose infusion rate
resting heart rate measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months resting heart rate determined by an activity monitor smartwatch
Hypoglycemic Confidence Scale measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months Hypoglycemic Confidence Scale, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia, the range is 0 through 27 and higher scores correspond to higher confidence
Type 1 Diabetes Distress Scale measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months Type 1 Diabetes Distress Scale, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia
number of participants with emergency room (ER) visits throughout the duration of the 24 months of follow-up number of participants with emergency room (ER) visits
% time with sensor glucose in range measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months % time with glucose in range determined from the continuous glucose monitor (CGM) sensor
glycemia risk index measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months glycemia risk index determined from the continuous glucose monitor (CGM) sensor
heart rate during exercise measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months heart rate during exercise determined by an activity monitor smartwatch
% of time with sensor hypoglycemia <54 mg/dL measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months % of time with hypoglycemia \<54 mg/dL determined from the continuous glucose monitor (CGM) sensor
number of hypoglycemia events measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months number of hypoglycemia events determined from the continuous glucose monitor (CGM) sensor
sensor use as the average numbers of days per week measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months sensor use as the average number of days per week determined from the continuous glucose monitor (CGM) sensor
Diabetes Management Experiences Questionnaire measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months Diabetes Management Experiences Questionnaire, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia
EQ-5D-5L measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months EQ-5D-5L, a quality-of-life scale with 5 dimensions
device-related adverse events throughout the duration of the 24 months of follow-up device-related adverse events
all-cause mortality throughout the duration of the 24 months of follow-up all-cause mortality
Trail Making Test - Part B measured during the clamp studies at 0 (baseline), 12, and 24 months amount of time required to complete the Trail Making Test - Part B
24-hour step count measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months 24-hour step count determined by an activity monitor smartwatch
Diabetes Self-Management Questionnaire measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months Diabetes Self-Management Questionnaire, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia
severe hypoglycemic events, self-reported on a CLEAR data collection form throughout the duration of the 24 months of follow-up severe hypoglycemic events, self-reported on a CLEAR data collection form
major adverse cardiovascular events (MACE) throughout the duration of the 24 months of follow-up major adverse cardiovascular events (MACE)
Four Choice Reaction Time measured during the clamp studies at 0 (baseline), 12, and 24 months Four Choice Reaction Time, which measures reaction time and motor coordination
sleep duration measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months sleep duration determined from an activity monitor smartwatch
sleep quality measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months sleep quality determined by an activity monitor smartwatch
exercise bouts measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months exercise bouts determined by an activity monitor smartwatch
Hypo-METRICS questionnaire measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months Hypo-METRICS questionnaire, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia
Attitudes to Awareness of Hypoglycaemia measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months Attitudes to Awareness of Hypoglycaemia, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia
PROMIS Sleep Disturbance - Short Form 8a measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months PROMIS Sleep Disturbance - Short Form 8a
heart rate variability measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months heart rate variability determined by an activity monitor smartwatch
Hypoglycemia Fear Survey-II measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months Hypoglycemia Fear Survey-II, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia
Hospital Anxiety and Depression Scale measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months, the range is 0 through 42 and higher scores correspond to higher anxiety and depression Hospital Anxiety and Depression Scale
12-Item Hypoglycemia Impact Profile measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months 12-Item Hypoglycemia Impact Profile, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia
diabetic ketoacidosis (DKA) events throughout the duration of the 24 months of follow-up diabetic ketoacidosis (DKA) events
number of participants with hospitalizations throughout the duration of the 24 months of follow-up number of participants with hospitalizations
Trial Locations
- Locations (8)
University of California, San Diego
🇺🇸La Jolla, California, United States
AdventHealth
🇺🇸Orlando, Florida, United States
University of Kentucky
🇺🇸Lexington, Kentucky, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
University of Melbourne
🇦🇺Fitzroy, Victoria, Australia
University of Leicester
🇬🇧Leicester, United Kingdom
University of Sheffield
🇬🇧Sheffield, United Kingdom