Closed Loop and Education for Hypoglycemia Awareness Restoration (CLEAR), Conducted by the Impaired Awareness of Hypoglycemia Consortium (IAHC)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 324
- 试验地点
- 8
- 主要终点
- Towler questionnaire
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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.
研究组 & 干预措施
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
干预措施: Omnipod 5 or Medtronic 780G (Device)
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
干预措施: Omnipod 5 or Medtronic 780G (Device)
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
干预措施: Omnipod 5 or Medtronic 780G (Device)
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
干预措施: HARPdoc Education (Behavioral)
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
干预措施: Omnipod 5 or Medtronic 780G (Device)
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
干预措施: My HypoCOMPaSS Education (Behavioral)
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
干预措施: My HypoCOMPaSS Education (Behavioral)
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
干预措施: Omnipod 5 or Medtronic 780G (Device)
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
干预措施: Omnipod 5 or Medtronic 780G (Device)
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
干预措施: Omnipod 5 or Medtronic 780G (Device)
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
干预措施: HARPdoc Education (Behavioral)
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
干预措施: Omnipod 5 or Medtronic 780G (Device)
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
干预措施: My HypoCOMPaSS Education (Behavioral)
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
干预措施: Omnipod 5 or Medtronic 780G (Device)
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
干预措施: My HypoCOMPaSS Education (Behavioral)
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
干预措施: HARPdoc Education (Behavioral)
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
干预措施: Omnipod 5 or Medtronic 780G (Device)
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
干预措施: My HypoCOMPaSS Education (Behavioral)
结局指标
主要结局
Towler questionnaire
时间窗: 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)
时间窗: 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
次要结局
- HbA1c(measured during the clamp studies at 0 (baseline), 12, and 24 months)
- sensor glucose coefficient of variation(measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- geometric mean of plasma glucagon(measured during the clamp studies at 0 (baseline), 12, and 24 months)
- geometric mean of plasma pancreatic polypeptide(measured during the clamp studies at 0 (baseline), 12, and 24 months)
- geometric mean of plasma free fatty acids(measured during the clamp studies at 0 (baseline), 12, and 24 months)
- % 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)
- glucose infusion rate(measured during the clamp studies at 0 (baseline), 12, and 24 months)
- resting heart rate(measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- Hypoglycemic Confidence Scale(measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- Type 1 Diabetes Distress Scale(measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- number of participants with emergency room (ER) visits(throughout the duration of the 24 months of follow-up)
- % time with sensor glucose in range(measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- glycemia risk index(measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- heart rate during exercise(measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- % 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)
- number of hypoglycemia events(measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- 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)
- Diabetes Management Experiences Questionnaire(measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- EQ-5D-5L(measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- device-related adverse events(throughout the duration of the 24 months of follow-up)
- all-cause mortality(throughout the duration of the 24 months of follow-up)
- exercise bouts(measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- Trail Making Test - Part B(measured during the clamp studies at 0 (baseline), 12, and 24 months)
- 24-hour step count(measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- Diabetes Self-Management Questionnaire(measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- severe hypoglycemic events, self-reported on a CLEAR data collection form(throughout the duration of the 24 months of follow-up)
- major adverse cardiovascular events (MACE)(throughout the duration of the 24 months of follow-up)
- Hypo-METRICS questionnaire(measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- Four Choice Reaction Time(measured during the clamp studies at 0 (baseline), 12, and 24 months)
- sleep duration(measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- sleep quality(measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- Attitudes to Awareness of Hypoglycaemia(measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- PROMIS Sleep Disturbance - Short Form 8a(measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- heart rate variability(measured during the two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- Hypoglycemia Fear Survey-II(measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- 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)
- 12-Item Hypoglycemia Impact Profile(measured two weeks prior to each clamp study at 0 (baseline), 12, and 24 months)
- diabetic ketoacidosis (DKA) events(throughout the duration of the 24 months of follow-up)
- number of participants with hospitalizations(throughout the duration of the 24 months of follow-up)
研究者
Vernon Michael Chinchilli
Distinguished Professor
Penn State Health Milton S Hershey Medical Center