Closed Loop and Education for Hypoglycemia Awareness Restoration

Diabetes Mellitus, Type 1 Clinical Trial

— CLEAR  

Official title:

Closed Loop and Education for Hypoglycemia Awareness Restoration (CLEAR), Conducted by the Impaired Awareness of Hypoglycemia Consortium (IAHC)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06325202
• Other study ID #: STUDY00020946
• Secondary ID: 1U01DK135126
• Status: Not yet recruiting
• Phase: N/A
• Start date: July 1, 2024
• Est. completion date: December 31, 2027

Study information

• Verified date: March 2024
• Source: Milton S. Hershey Medical Center
• Contact: Abid Kazi, PhD
• Phone: 717-531-0003
• Email: akazi[@]pennstatehealth.psu.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Not yet recruiting
• Enrollment: 324
• Est. completion date: December 31, 2027
• Est. primary completion date: June 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• 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)

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 1
• Hypoglycemia

Intervention

Device:
• Omnipod 5 or Medtronic 780G
Omnipod 5 and Medtronic 780G are hybrid closed loop devices that provide automated insulin delivery.

Behavioral:
• My HypoCOMPaSS Education
My HypoCOMPaSS is a brief, standardized psycho-educational program delivered in small groups. Facilitated discussions focus on advocating rigorous avoidance of hypoglycemia while maintaining time in target glycemic range.
• HARPdoc Education
The HARPdoc program targets cognitions around hypoglycemia that act as barriers to hypoglycemia avoidance and recovery of awareness using motivational and cognitive approaches, delivered by diabetes educators, trained and supported by a clinical psychologist, in small group format.

Locations

Country	Name	City	State
Australia	University of Melbourne	Fitzroy	Victoria
United Kingdom	University of Leicester	Leicester
United Kingdom	University of Sheffield	Sheffield
United States	University of California, San Diego	La Jolla	California
United States	University of Kentucky	Lexington	Kentucky
United States	University of Minnesota	Minneapolis	Minnesota
United States	AdventHealth	Orlando	Florida
United States	University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (11)

Lead Sponsor	Collaborator
Milton S. Hershey Medical Center	AdventHealth, Jaeb Center for Health Research, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), University of California, San Diego, University of Kentucky, University of Leicester, University of Melbourne, University of Minnesota, University of Pennsylvania, University of Sheffield

Countries where clinical trial is conducted

United States,  Australia,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	epinephrine (pg/ml)	a change in epinephrine (pg/ml) that exceeds 125 pg/ml between (1) 12 months and baseline, and (2) 24 months and baseline	measured during the clamp studies at 0 (baseline), 12, and 24 months
Primary	Towler questionnaire	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	measured during the clamp studies at 0 (baseline), 12, and 24 months
Secondary	geometric mean of plasma glucagon	geometric mean of plasma glucagon	measured during the clamp studies at 0 (baseline), 12, and 24 months
Secondary	geometric mean of plasma pancreatic polypeptide	geometric mean of plasma pancreatic polypeptide	measured during the clamp studies at 0 (baseline), 12, and 24 months
Secondary	geometric mean of plasma free fatty acids	geometric mean of plasma free fatty acids	measured during the clamp studies at 0 (baseline), 12, and 24 months
Secondary	glucose infusion rate	glucose infusion rate	measured during the clamp studies at 0 (baseline), 12, and 24 months
Secondary	HbA1c	glycated hemoglobin	measured during the clamp studies at 0 (baseline), 12, and 24 months
Secondary	% of time with sensor hypoglycemia <70 mg/dL	% of time with hypoglycemia <70 mg/dL determined from the continuous glucose monitor (CGM) sensor	measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	% of time with sensor hypoglycemia <54 mg/dL	% of time with hypoglycemia <54 mg/dL determined from the continuous glucose monitor (CGM) sensor	measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	number of hypoglycemia events	number of hypoglycemia events determined from the continuous glucose monitor (CGM) sensor	measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	% time with sensor glucose in range	% time with glucose in range determined from the continuous glucose monitor (CGM) sensor	measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	sensor glucose coefficient of variation	sensor glucose coefficient of variation determined from the continuous glucose monitor (CGM) sensor	measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	sensor use as the average numbers of days per week	sensor use as the average number of days per week determined from the continuous glucose monitor (CGM) sensor	measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	glycemia risk index	glycemia risk index determined from the continuous glucose monitor (CGM) sensor	measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	Trail Making Test - Part B	amount of time required to complete the Trail Making Test - Part B	measured during the clamp studies at 0 (baseline), 12, and 24 months
Secondary	Four Choice Reaction Time	Four Choice Reaction Time, which measures reaction time and motor coordination	measured during the clamp studies at 0 (baseline), 12, and 24 months
Secondary	sleep duration	sleep duration determined from an activity monitor smartwatch	measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	sleep quality	sleep quality determined by an activity monitor smartwatch	measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	24-hour step count	24-hour step count determined by an activity monitor smartwatch	measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	exercise bouts	exercise bouts determined by an activity monitor smartwatch	measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	resting heart rate	resting heart rate determined by an activity monitor smartwatch	measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	heart rate during exercise	heart rate during exercise determined by an activity monitor smartwatch	measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	heart rate variability	heart rate variability determined by an activity monitor smartwatch	measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	Hypo-METRICS questionnaire	Hypo-METRICS questionnaire, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia	measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	Hypoglycemic Confidence Scale	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	measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	Hypoglycemia Fear Survey-II	Hypoglycemia Fear Survey-II, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia	measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	Attitudes to Awareness of Hypoglycaemia	Attitudes to Awareness of Hypoglycaemia, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia	measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	Type 1 Diabetes Distress Scale	Type 1 Diabetes Distress Scale, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia	measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	Diabetes Self-Management Questionnaire	Diabetes Self-Management Questionnaire, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia	measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	Diabetes Management Experiences Questionnaire	Diabetes Management Experiences Questionnaire, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia	measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	PROMIS Sleep Disturbance - Short Form 8a	PROMIS Sleep Disturbance - Short Form 8a	measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	Hospital Anxiety and Depression Scale	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
Secondary	12-Item Hypoglycemia Impact Profile	12-Item Hypoglycemia Impact Profile, a Person-Reported Outcome Measure (PROM) specific to hypoglycemia	measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	EQ-5D-5L	EQ-5D-5L, a quality-of-life scale with 5 dimensions	measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
Secondary	device-related adverse events	device-related adverse events	throughout the duration of the 24 months of follow-up
Secondary	severe hypoglycemic events, self-reported on a CLEAR data collection form	severe hypoglycemic events, self-reported on a CLEAR data collection form	throughout the duration of the 24 months of follow-up
Secondary	diabetic ketoacidosis (DKA) events	diabetic ketoacidosis (DKA) events	throughout the duration of the 24 months of follow-up
Secondary	number of participants with hospitalizations	number of participants with hospitalizations	throughout the duration of the 24 months of follow-up
Secondary	number of participants with emergency room (ER) visits	number of participants with emergency room (ER) visits	throughout the duration of the 24 months of follow-up
Secondary	major adverse cardiovascular events (MACE)	major adverse cardiovascular events (MACE)	throughout the duration of the 24 months of follow-up
Secondary	all-cause mortality	all-cause mortality	throughout the duration of the 24 months of follow-up