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Trial registered on ANZCTR


Registration number
ACTRN12616000909426
Ethics application status
Approved
Date submitted
4/07/2016
Date registered
8/07/2016
Date last updated
6/02/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Use of the Hybrid Closed Loop therapy in hypoglycaemia awareness in people with Type 1 diabetes
Scientific title
Use of the Hybrid Closed Loop system in people with Type 1 diabetes and impaired awareness of hypoglycaemia
Secondary ID [1] 288765 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes Mellitus 298013 0
Condition category
Condition code
Metabolic and Endocrine 298174 298174 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will follow a randomised controlled parallel design. Potential participants will be identified using an in clinic screening tool for hypoglycaemic unawareness (Gold questionnaire) to assess if they are hypoglycaemia unaware. A Gold score greater than or equal to 4 implies impaired hypoglycaemia awareness.

Following a two weeks period of blinded continuous glucose monitoring (CGM) to assess baseline hypoglycaemia exposure, eligible participants will undergo a hyperinsulinaemic, hypoglycaemic clamp study at the beginning and at the end of a 6 weeks study period.
After the initial clamp study participants will be randomised to either hybrid closed-loop (intervention), or to continue on their conventional pump therapy (control). After 6 weeks, participants will undergo a second hypoglycaemic clamp, with analysis of their physiological and symptom response to hypoglycaemia compared to baseline. The hypoglycaemic clamp procedure and the hybrid closed loop system are detailed below.

Hyperinsulinemic hypoglycaemic clamp study:
The clamp studies will be performed before randomisation and 6 weeks post randomisation, irrespective of whether the participant is in the control or intervention group. The participant will present after an overnight fast for the clamp study in the morning. The clamp procedure will involve infusing insulin intravenously at a constant rate of 80mU/m2 per minute and plasma glucose targets will be achieved by adjusting the rate of infusion of a solution of 20% glucose in water. Prior to induction of hypoglycaemia, plasma glucose will be maintained in euglycaemia (5-6mmol/l) for 30 to 60 minutes followed by gradual reduction over 30 minutes to a nadir of 2.8mmol/l. This controlled decline will be guided by plasma blood glucose measurements taken at 5-minute intervals. The blood glucose concentration of 2.8mmol/l will be maintained for 40 minutes before euglycaemia will be restored. For the duration of the clamp procedure, blood glucose will be measured using glucose oxidase technique with a bedside YSI analyser. Venous blood will be sampled during the euglycaemic and hypoglycaemic phase to determine plasma insulin, glucagon, epinephrine, norepinephrine, cortisol, and growth hormone concentrations during both study days. Symptoms of hypoglycaemia will also be assessed with a questionnaire in which the participants will rate the symptoms on a scale of 1 (no symptoms) to 7 (extreme). The scores of the symptoms will be added up to give the total symptom score.

Hybrid Closed Loop System:
This system consists on an insulin pump (MiniMed (Trademark) Medtronic 670G, a continuous glucose monitoring system (3rd generation Enlite sensor), and an algorithm within the insulin pump that calculates background (basal) insulin delivery according to changes in the sensor glucose value. The insulin pump and continuous glucose monitor communicate wirelessly. The pump is small enough to fit in the palm of a hand, and is usually carried clipped to a belt. The pump is water resistant and is built to last 4 years. The hybrid closed-loop control algorithm is inbuilt into the insulin pump hardware.
The glucose sensor is the size of a 20 cent coin and clips on to the subcutaneously inserted glucose sensor. The sensor has an "inserter" and participants will be trained to insert the sensors themselves by a diabetes educator.
The insulin pump and glucose sensor transmitter communicate wirelessly, with a range of approximately 6 meters.

During the run-in phase all participants will receive individual education sessions on continuous glucose monitoring provided by a diabetes educator or a study doctor. Those randomised to the hybrid closed loop system will have additional training provided by a diabetes nurse educator before entering the 6 weeks study period. The following is an outline of the visit history during the run-in phase which also describes the duration and frequency of sessions, and also the post randomisation training required for those participants who go on to the intervention.

Visit 1: Screening and consent, blinded CGM and baseline glycaemic data collection (4 hours)
1. Confirm participant is able to take part in the study and sign a consent form.
2. Collect baseline data including height, weight and current diabetes treatment.
3. Ask the participant to complete some questionnaires about diabetes.
4. We will teach the participant how to insert a sensor and give them a Contour Next
glucometer (to use in addition to their usual glucometer) to record BGLs at least 4 times a day
5. We will also give a logbook and ask participants to record signs and treatment of hypoglycaemia
6. Start with blinded continuous glucose monitoring,

Visit 2: Sensor Download and Sensor Change (30 mins)
This visit will occur 7 days after visit 1 to:
1. Download the sensor and glucometer data
2. Change the sensor and transmitter
3. Check that the log book is up to date
Visit 2 may be able to happen at the participant location.

Visit 3: Sensor download, hyperinsulinaemic, hypoglycaemic clamp and randomisation (6 hours) This visit will occur 7 days after visit 2 to:
1. Download the sensor data and collect logbook data.
2. Particpants will then undergo a hyperinsulinaemic, hypoglyaceamic clamp as outlined above.
3. Participants will then be randomized to either stay on usual treatment (control), or to the hybrid closed loop system (intervention).

Visit 4: Entry into Study Arm (1 hour)
The schedule for this visit will depend on randomisation:
(i) Control Group
Those randomised to control will have visit 4 in combination with visit 3.
1. Participants will be issued with a new logbook.
2. Participants will be asked not to use other continuous glucose monitoring
systems for the duration of the study.
(ii) Intervention Group
We will ask the participant to come in to the clinic for the following visits to teach them how to operate the pump, insert sensors and use the closed loop function:
Participants will require general pump education, followed by CGM and HCL operation.
Visit 4A: (1 – 4 hours) This visit will occur within 7 days of visit 3 (clamp) but not on the clamp day. This session is to provide sensor and Minimed 670G pump training, including training on how to change a sensor and linking the sensor to the pump. We will provide them with a sensor user guide and enough sensors for the duration of the study.
Visit 4B: (1 – 2 hours) Once CGM data has been established for a minimum of 3 days, and maximum 7 days, participant returns for face to face instruction on HCL use and initiation.
During the intervention period the sensor needs to be changed every 7 days.

The overall intervention period is 8-10 weeks (two to three weeks run in, and 6 weeks post randomisation).

Adherence will be monitored by downloading the CGM data and examining the hybrid closed loop system pump download data - which includes an adherence report. All data is intention to treat analysis, so participants will be under no pressure to continue the intervention if they wish to withdraw.
Intervention code [1] 294205 0
Treatment: Devices
Comparator / control treatment
Standard insulin pump therapy (CSII), established for at least 3months
Control group
Active

Outcomes
Primary outcome [1] 297682 0
Adrenergic response to a hypoglycaemia.

This will be assessed measuring the epinephrine and norepinephrine response to hypoglycaemia during a hyperinsulinemic, hypoglycaemic clamp using high performance liquid chromatography.

A sub analysis of the adrenergic response to a hypoglycaemia who at baseline clamp have an epinephrine increase that is less than 2 fold is planned.
Timepoint [1] 297682 0
The hyperinsulinaemic, hypoglycaemic clamp will take place before and after the 6 weeks intervention/control period.
Secondary outcome [1] 325217 0
Glucagon response to hypoglycaemia.

This will be assessed measuring the glucagon response to hypoglycaemia during a hyperinsulinemic, hypoglycaemic clamp using a competitive radioimmunoassay.
Timepoint [1] 325217 0
The hyperinsulinaemic, hypoglycaemic clamp will take place before and after the 6 weeks intervention/control period.
Secondary outcome [2] 325218 0
Symptom score during during hypoglycaemia.

This will be assessed with the Cox symptom score during a hyperinsulinemic, hypoglycaemic clamp.
Timepoint [2] 325218 0
The hyperinsulinaemic, hypoglycaemic clamp will take place before and after the 6 weeks intervention/control period.
Secondary outcome [3] 325219 0
Hypoglycaemia awareness.

This will be assessed using the Gold and Clarke questionnaire.
Timepoint [3] 325219 0
At baseline and after the 6 weeks intervention/control period.
Secondary outcome [4] 325220 0
Fear of Hypoglycaemia

This will be assessed using the Hypoglycaemia Fear Survey (University of Virginia)
Timepoint [4] 325220 0
At baseline and after the 6 weeks intervention/control period.
Secondary outcome [5] 325221 0
The % time sensor glucose is in target range (3.9–10 mmol/L) during HCL insulin delivery vs standard pump therapy

This will be measured with a continuous glucose monitor that is uploaded onto Medtronic software.
Timepoint [5] 325221 0
Measured for 2 weeks; 4-6 weeks post-randomisation.
Secondary outcome [6] 325222 0
Average glycaemic control.

This will be measured by HbA1c.
Timepoint [6] 325222 0
At baseline and after the 6 weeks intervention/control period.
Secondary outcome [7] 325223 0
Average Fasting blood glucose (mmol/L)
Timepoint [7] 325223 0
As measured during the two CGM time blocks during run-in, and 4-6 weeks post randomisation. Defined as fasting capillary blood glucose level on waking (between 5am and 9am), at least 6 hrs after an insulin bolus for carbohydrate.
Secondary outcome [8] 325230 0
Episodes of severe hypoglycaemia
Timepoint [8] 325230 0
Assessed continuously over the whole study period ( coma +/- convulsions and may require parenteral therapy (glucagon or i.v.glucose). This will be assessed by patient report in an issued logbook.
Secondary outcome [9] 325387 0
Hospitalisation rate for diabetic ketoacidosis
Timepoint [9] 325387 0
Assessed continuously over the overall study period by patient report in an issued logbook.

Secondary outcome [10] 325388 0
Health status

This will be assessed using the EQ-5D questionnaire.
Timepoint [10] 325388 0
At baseline and after the 6 weeks intervention/control period.
Secondary outcome [11] 325389 0
Treatment satisfaction

This will be assessed using the Diabetes treatment satisfaction questionnaire DTSQ status and change.
Timepoint [11] 325389 0
This will be assessed at baseline (status) and after the 6 weeks intervention/control period (change).
Secondary outcome [12] 325448 0
Insulin response to hypoglycaemia.

This will be assessed measuring the insulin response to hypoglycaemia during a hyperinsulinemic, hypoglycaemic clamp using a using a non-competitive chemiluminescent immunoassay.
Timepoint [12] 325448 0
The hyperinsulinaemic, hypoglycaemic clamp will take place before and after the 6 weeks intervention/control period.
Secondary outcome [13] 325450 0
Growth hormone response to hypoglycaemia.

This will be assessed measuring the growth hormone response to hypoglycaemia during a hyperinsulinemic, hypoglycaemic clamp using a using a non-competitive enzyme immunoassay with a chemiluminescent substrate.
Timepoint [13] 325450 0
The hyperinsulinaemic, hypoglycaemic clamp will take place before and after the 6 weeks intervention/control period.
Secondary outcome [14] 325451 0
Cortisol response to hypoglycaemia.

This will be assessed measuring the cortisol response to hypoglycaemia during a hyperinsulinemic, hypoglycaemic clamp using a using a non-competitive chemiluminescent immunoassay.
Timepoint [14] 325451 0
The hyperinsulinaemic, hypoglycaemic clamp will take place before and after the 6 weeks intervention/control period.
Secondary outcome [15] 325452 0
Copeptin response to hypoglycaemia.

This will be assessed measuring the copeptin response to hypoglycaemia during a hyperinsulinemic, hypoglycaemic clamp using a sandwich immunoluminometric assay.
Timepoint [15] 325452 0
The hyperinsulinaemic, hypoglycaemic clamp will take place before and after the 6 weeks intervention/control period.

Eligibility
Key inclusion criteria
1. Aged 12 to 55 years
2. Diagnosed with type 1 diabetes
3. C-peptide negative (less than 0.05 nmol/L)
4. On CSII for greater than or equal to 3 months
5. Impaired awareness of hypoglycaemia: greater than or equal to a score of 4 on Gold’s questionnaire
6. Understands study protocol requirements and agrees to comply with them
Minimum age
12 Years
Maximum age
55 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Has adrenal insufficiency
2. Has growth hormone insufficiency
3. Has multiple pituitary hormone deficiency
4. Is pregnant
5. Chronic kidney disease (eGFR<45mL/min.1.73m2)
6. Any non-insulin glucose lowering agent, for example metformin SGLT2 inhibitor or GLP-1 analogues within the last 3 months
7. Oral steroid use within the last 3 months
8. Cardiovascular disease:
a. Uncontrolled hypertension (diastolic blood pressure >100mmHg and/or sustained systolic level (3 successive readings) > 160mmHg). Subjects taking antihypertensive medication will NOT be excluded provided they are maintained at a stable dose for 3 months prior to screening
b. Has a history of acute myocardial infarction, heart failure, angina, transient ischemic attack (TIA), cerebrovascular accident (CVA), or thromboembolic disease.
9. Has serious or unstable medical or psychological conditions which, in the opinion of the investigator, would compromise the ability to meet protocol requirements.
10. Poor visual acuity that precludes patients from using the pump technology
11. Any additional condition(s) that in the investigator’s opinion would warrant exclusion from the study or prevent the subject from completing the study

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is concealed through randomisation using a computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be allocated to the intervention or the control group using adaptive randomisation (specifically, minimisation). The following stratifying factors will be used in the minimisation: age group and duration of diabetes. The program ‘MinimPy’ will be used to allocate participants: http://sourceforge.net/projects/minimpy.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 6046 0
Princess Margaret Hospital - Subiaco
Recruitment hospital [2] 6047 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [3] 6048 0
Royal Perth Hospital - Perth
Recruitment hospital [4] 6049 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [5] 6050 0
Rockingham General Hospital - Cooloongup

Funding & Sponsors
Funding source category [1] 293958 0
Government body
Name [1] 293958 0
National Health and Medical Research Council
Address [1] 293958 0
GHD Building Level 1
16 Marcus Clarke St
Canberra ACT 2601
Country [1] 293958 0
Australia
Funding source category [2] 293959 0
Charities/Societies/Foundations
Name [2] 293959 0
Juvenile Diabetes Research Foundation
Address [2] 293959 0
Level 4, 80-84 Chandos St
St Leonards NSW 2065
Country [2] 293959 0
Australia
Funding source category [3] 293960 0
Commercial sector/Industry
Name [3] 293960 0
Medtronic
Address [3] 293960 0
18000 Devonshire St
Northridge, CA 91325
United States
Country [3] 293960 0
United States of America
Primary sponsor type
Hospital
Name
Princess Margaret Hospital
Address
Roberts Road
Subiaco WA 6008
Country
Australia
Secondary sponsor category [1] 292776 0
None
Name [1] 292776 0
Address [1] 292776 0
Country [1] 292776 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295378 0
Princess Margaret Hospital Ethics Committee
Ethics committee address [1] 295378 0
Roberts Road
Subiaco WA 6008
Ethics committee country [1] 295378 0
Australia
Date submitted for ethics approval [1] 295378 0
08/03/2016
Approval date [1] 295378 0
21/07/2016
Ethics approval number [1] 295378 0
2016051EP

Summary
Brief summary
BACKGROUND: Approximately one third of patients with Type 1 diabetes (T1D) have impaired awareness of hypoglycaemia and these have an associated threefold increase in the likelihood of a severe hypoglycaemic event. For the patient and the family, impaired hypoglycaemia awareness has profound consequences for their ability to function in society and for quality of life. The limitations associated with this morbidity place a significant burden and result in anxiety and other mental health problems. Impaired hypoglycaemia awareness (IAH) and counter-regulatory failure develop as a result of recurrent hypoglycaemia and avoidance of hypoglycaemia has been shown to correct defective responses. The clinical problem has been the difficulty of avoiding hypoglycaemic exposure. Hybrid closed loop system which is based on automated insulin delivery dependent on real time continuous glucose monitoring and minimal patient interaction is a tool which could potentially avoid hypoglycaemia and improve hypoglycaemia awareness in this subgroup of patients with IAH. It is hypothesised that the use of hybrid closed loop therapy can lead to recovery of the counter-regulatory hormones and restore awareness of hypoglycaemia in this patient cohort.
AIM: This study will assess as to whether a hybrid closed loop system can improve hypoglycaemic awareness as assessed by epinephrine response in hyperinsulinemic hypoglycaemic clamp studies.
METHOD: 38 participants (aged from 12 to 55 years old) with T1D and impaired hypoglycaemia awareness will undergo a parallel randomised controlled trial. After 2 weeks of baseline blinded CGM period, the subjects will undergo a hypoglycaemic clamp study to measure hormonal and symptomatic responses to a standardised hypoglycaemic stimulus in a hyperinsulinemic, hypoglycaemic clamp. They will then be randomised to either hybrid closed loop or standard CSII therapy for six weeks. After the six weeks study period, participants will undergo a second hyperinsulinemic hypoglycaemic clamp to determine the change in hormonal and symptomatic responses to hypoglycaemia.
OUTCOMES: The primary outcome is the increase in epinephrine response to hypoglycaemia in the hypoglycaemic clamp study. Secondary outcomes include other counterregulatory hormonal responses to hypoglycaemia in the hypoglycaemic clamp study, glycaemic outcomes (CGM data, HbA1c) and psychosocial outcomes (including recovery of hypoglycaemia awareness score, fear of hypoglycaemia, treatment satisfaction).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64402 0
Prof Timothy Jones
Address 64402 0
Department of Endocrinology & Diabetes
Princess Margaret Hospital for Children
Roberts Road
Subiaco WA 6008
Country 64402 0
Australia
Phone 64402 0
+61 8 93408090
Fax 64402 0
Email 64402 0
Tim.Jones@health.wa.gov.au
Contact person for public queries
Name 64403 0
Prof Timothy Jones
Address 64403 0
Department of Endocrinology & Diabetes
Princess Margaret Hospital for Children
Roberts Road
Subiaco WA 6008
Country 64403 0
Australia
Phone 64403 0
+61 8 93408090
Fax 64403 0
Email 64403 0
Tim.Jones@health.wa.gov.au
Contact person for scientific queries
Name 64404 0
Prof Timothy Jones
Address 64404 0
Department of Endocrinology & Diabetes
Princess Margaret Hospital for Children
Roberts Road
Subiaco WA 6008
Country 64404 0
Australia
Phone 64404 0
+61 8 93408090
Fax 64404 0
Email 64404 0
Tim.Jones@health.wa.gov.au

No information has been provided regarding IPD availability
Summary results
No Results