Clinical trial NCT06325202: Closed Loop and Education for Hypoglycemia Awareness Restoration
Official title: Closed Loop and Education for Hypoglycemia Awareness Restoration (CLEAR), Conducted by the Impaired Awareness of Hypoglycemia Consortium (IAHC)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Diabetes Mellitus, Type 1
Keywords: impaired awareness of hypoglycemia
hybrid closed loop device
continuous glucose monitor
Lead sponsor: Milton S. Hershey Medical Center
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: University of Minnesota
name: University of Kentucky
name: University of Pennsylvania
name: AdventHealth
name: University of Leicester
name: University of Sheffield
name: University of Melbourne
name: Jaeb Center for Health Research
name: University of California, San Diego
First posted: 2024-03-22
Enrollment: 324
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Sequential Multiple Assignment Randomized Trial (SMART) design
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: epinephrine (pg/ml)
timeFrame: measured during the clamp studies at 0 (baseline), 12, and 24 months
measure: Towler questionnaire
timeFrame: measured during the clamp studies at 0 (baseline), 12, and 24 months
Secondary outcomes:
measure: geometric mean of plasma glucagon
timeFrame: measured during the clamp studies at 0 (baseline), 12, and 24 months
measure: geometric mean of plasma pancreatic polypeptide
timeFrame: measured during the clamp studies at 0 (baseline), 12, and 24 months
measure: geometric mean of plasma free fatty acids
timeFrame: measured during the clamp studies at 0 (baseline), 12, and 24 months
measure: glucose infusion rate
timeFrame: measured during the clamp studies at 0 (baseline), 12, and 24 months
measure: HbA1c
timeFrame: measured during the clamp studies at 0 (baseline), 12, and 24 months
measure: % of time with sensor hypoglycemia <70 mg/dL
timeFrame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: % of time with sensor hypoglycemia <54 mg/dL
timeFrame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: number of hypoglycemia events
timeFrame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: % time with sensor glucose in range
timeFrame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: sensor glucose coefficient of variation
timeFrame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: sensor use as the average numbers of days per week
timeFrame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: glycemia risk index
timeFrame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: Trail Making Test - Part B
timeFrame: measured during the clamp studies at 0 (baseline), 12, and 24 months
measure: Four Choice Reaction Time
timeFrame: measured during the clamp studies at 0 (baseline), 12, and 24 months
measure: sleep duration
timeFrame: measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: sleep quality
timeFrame: measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: 24-hour step count
timeFrame: measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: exercise bouts
timeFrame: measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: resting heart rate
timeFrame: measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: heart rate during exercise
timeFrame: measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: heart rate variability
timeFrame: measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: Hypo-METRICS questionnaire
timeFrame: measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: Hypoglycemic Confidence Scale
timeFrame: measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: Hypoglycemia Fear Survey-II
timeFrame: measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: Attitudes to Awareness of Hypoglycaemia
timeFrame: measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: Type 1 Diabetes Distress Scale
timeFrame: measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: Diabetes Self-Management Questionnaire
timeFrame: measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: Diabetes Management Experiences Questionnaire
timeFrame: measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: PROMIS Sleep Disturbance - Short Form 8a
timeFrame: measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: Hospital Anxiety and Depression Scale
timeFrame: 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
measure: 12-Item Hypoglycemia Impact Profile
timeFrame: measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: EQ-5D-5L
timeFrame: measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months
measure: device-related adverse events
timeFrame: throughout the duration of the 24 months of follow-up
measure: severe hypoglycemic events, self-reported on a CLEAR data collection form
timeFrame: throughout the duration of the 24 months of follow-up
measure: diabetic ketoacidosis (DKA) events
timeFrame: throughout the duration of the 24 months of follow-up
measure: number of participants with hospitalizations
timeFrame: throughout the duration of the 24 months of follow-up
measure: number of participants with emergency room (ER) visits
timeFrame: throughout the duration of the 24 months of follow-up
measure: major adverse cardiovascular events (MACE)
timeFrame: throughout the duration of the 24 months of follow-up
measure: all-cause mortality
timeFrame: throughout the duration of the 24 months of follow-up
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: Orlando
country: United States
facility: AdventHealth
state: Florida
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Fitzroy
country: Australia
facility: University of Melbourne
state: Victoria
city: Leicester
country: United Kingdom
facility: University of Leicester
city: Sheffield
country: United Kingdom
facility: University of Sheffield
Study officials:
affiliation: Penn State College of Medicine
name: Vernon M Chinchilli, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota
name: Elizabeth R Seaquist, MD
role: STUDY_CHAIR
affiliation: University of Sheffield
name: Simon Heller, MD
role: STUDY_CHAIR
References: