Closed Loop and Education for Hypoglycemia Awareness Restoration

NCT ID: NCT06325202

Last Updated: 2026-01-14

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

324 participants

Study Classification

INTERVENTIONAL

Study Start Date

2025-10-03

Study Completion Date

2029-07-31

Brief Summary

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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

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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.

Conditions

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Diabetes Mellitus, Type 1

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

SEQUENTIAL

Sequential Multiple Assignment Randomized Trial (SMART) design
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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current HCL non-user: HCL x 24 months

Hybrid closed loop device over a 24-month period for individuals currently not using a hybrid closed loop device

Group Type EXPERIMENTAL

Omnipod 5 or Medtronic 780G

Intervention Type DEVICE

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

current HCL non-user: HCL x 12 months, then HCL x an additional 12 months

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

Group Type EXPERIMENTAL

Omnipod 5 or Medtronic 780G

Intervention Type DEVICE

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

current HCL non-user: HCL x 12 months, then HCL + HARPdoc x 12 months

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

Group Type EXPERIMENTAL

Omnipod 5 or Medtronic 780G

Intervention Type DEVICE

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

HARPdoc Education

Intervention Type BEHAVIORAL

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.

current HCL non-user: Usual Care and My HypoCOMPaSS x 12 months, then HCL x 12 months

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

Group Type ACTIVE_COMPARATOR

Omnipod 5 or Medtronic 780G

Intervention Type DEVICE

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

My HypoCOMPaSS Education

Intervention Type BEHAVIORAL

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.

current HCL non-user: Usual Care and My HypoCOMPaSS x 24 months

Usual Care and My HypoCOMPaSS education over 24 months for individuals currently not using a hybrid closed loop device

Group Type ACTIVE_COMPARATOR

My HypoCOMPaSS Education

Intervention Type BEHAVIORAL

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.

current HCL user: HCL x 24 months

Hybrid closed loop device over a 24-month period for individuals currently using a hybrid closed loop device

Group Type EXPERIMENTAL

Omnipod 5 or Medtronic 780G

Intervention Type DEVICE

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

current HCL user: HCL x 12 months, then HCL x an additional 12 months

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

Group Type EXPERIMENTAL

Omnipod 5 or Medtronic 780G

Intervention Type DEVICE

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

current HCL user: HCL x 12 months, then HCL + HARPdoc x 12 months

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

Group Type EXPERIMENTAL

Omnipod 5 or Medtronic 780G

Intervention Type DEVICE

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

HARPdoc Education

Intervention Type BEHAVIORAL

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.

current HCL user: HCL and My HypoCOMPaSS x 12 months, then HCL x 12 months

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

Group Type ACTIVE_COMPARATOR

Omnipod 5 or Medtronic 780G

Intervention Type DEVICE

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

My HypoCOMPaSS Education

Intervention Type BEHAVIORAL

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.

current HCL user: HCL + My HypoCOMPaSS x 12 months, then HCL + My HypoCOMPaSS + HARPDOC x 12 months

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

Group Type ACTIVE_COMPARATOR

Omnipod 5 or Medtronic 780G

Intervention Type DEVICE

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

My HypoCOMPaSS Education

Intervention Type BEHAVIORAL

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

Intervention Type BEHAVIORAL

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.

current HCL user: HCL + My HypoCOMPaSS x 24 months

Hybrid closed loop device plus My HypoCOMPaSS education over a 24-month period for individuals currently using a hybrid closed loop device

Group Type EXPERIMENTAL

Omnipod 5 or Medtronic 780G

Intervention Type DEVICE

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

My HypoCOMPaSS Education

Intervention Type BEHAVIORAL

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.

Interventions

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Omnipod 5 or Medtronic 780G

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

Intervention Type DEVICE

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.

Intervention Type BEHAVIORAL

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.

Intervention Type BEHAVIORAL

Eligibility Criteria

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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.
Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role collaborator

University of Minnesota

OTHER

Sponsor Role collaborator

University of Kentucky

OTHER

Sponsor Role collaborator

University of Pennsylvania

OTHER

Sponsor Role collaborator

AdventHealth

OTHER

Sponsor Role collaborator

University of Leicester

OTHER

Sponsor Role collaborator

University of Sheffield

OTHER

Sponsor Role collaborator

University of Melbourne

OTHER

Sponsor Role collaborator

Jaeb Center for Health Research

OTHER

Sponsor Role collaborator

University of California, San Diego

OTHER

Sponsor Role collaborator

Milton S. Hershey Medical Center

OTHER

Sponsor Role lead

Responsible Party

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Vernon Michael Chinchilli

Distinguished Professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Vernon M Chinchilli, PhD

Role: PRINCIPAL_INVESTIGATOR

Penn State College of Medicine

Elizabeth R Seaquist, MD

Role: STUDY_CHAIR

University of Minnesota

Simon Heller, MD

Role: STUDY_CHAIR

University of Sheffield

Locations

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University of California, San Diego

La Jolla, California, United States

Site Status RECRUITING

AdventHealth

Orlando, Florida, United States

Site Status RECRUITING

University of Kentucky

Lexington, Kentucky, United States

Site Status RECRUITING

University of Minnesota

Minneapolis, Minnesota, United States

Site Status RECRUITING

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Site Status RECRUITING

University of Melbourne

Fitzroy, Victoria, Australia

Site Status RECRUITING

University of Leicester

Leicester, , United Kingdom

Site Status RECRUITING

University of Sheffield

Sheffield, , United Kingdom

Site Status RECRUITING

Countries

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United States Australia United Kingdom

Central Contacts

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Abid Kazi, PhD

Role: CONTACT

717-531-0003 ext. 320036

Venus Grella, MPH

Role: CONTACT

717-531-0003 ext. 343413

Facility Contacts

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Jeremy H Pettus, MD

Role: primary

858-246-2160

Keri Whitaker

Role: primary

407-303-2519

Simon Fisher, MD, PhD

Role: primary

859-562-0473

Sarah Chapeau

Role: primary

612-625-3654

Cornelia (Ginger) Dalton-Bakes

Role: primary

215-746-2085

Katrin Brown

Role: primary

61 3 9231 2574

Catriona Sims

Role: backup

61 3 9231 2574

Andrew Kingsnorth

Role: primary

44 116-258-4874

Simon Heller, MD

Role: primary

44 114-215-9009

Other Identifiers

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1U01DK135126

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY00020946

Identifier Type: -

Identifier Source: org_study_id

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