Efficacy of Closed-loop Insulin Therapy in Adults Prone to Hypoglycemia

Study Overview
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Brief Summary
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This study is a RCT of 3 month at home comparing closed-loop control (CLC) system vs sensor and pump therapy (S&P), with a 3-month extension phase, in Type 1 diabetic patient prone to hypoglycemia. After a 2-week run-in phase with blinded CGM, patients who spent 5% or more time below 70mg/dL will be eligible to continue. They will will be randomly assigned 2:1 to the use of closed-loop control (CLC) using Tandem Control-IQ vs S&P for 3 months, which is the timing of the primary outcome for the RCT. After 3 months, the S&P group will use CLC for up to 3 months and the CLC group will continue using CLC for up to 3 additional months.

Detailed Description
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This study is randomized controlled trial of 3 month at home closed-loop control (CLC) system vs sensor and pump therapy (S&P), with a 3-month extension phase. The objective is to assess the efficacy and safety of home use of a Control-to-Range (CTR) closed-loop (CL) system in patients with type 1 diabetes prone to hypoglycemia. The CLC system will consist of Tandem Control-IQ Automated Insulin Delivery System (AIDS), including Tandem X2 insulin pump with embedded Control-IQ algorithm and Dexcom G6 CGM After consent is signed, eligibility will be assessed. All participants will initiate a run-in phase of 2 weeks of blinded Dexcom G6 CGM wear and personal insulin pump. Prior to overall initiation of the RCT, the time spent with CGM below 70 mg/dl during the run-in phase will be assessed. Only patients showing % time with CGM <70 mg/dl of 5% or above can be randomized. Included patients who cannot be randomized will be replaced. Subsequent participants who show randomization criteria during the run-in phase will be randomly assigned 2:1 to the use of closed-loop control (CLC) using Tandem Control-IQ vs S&P for 3 months, which is the timing of the primary outcome for the RCT. After 3 months, the S&P group will use CLC for up to 3 months and the CLC group will continue using CLC for up to 3 additional months.

Official Title
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A Randomized Clinical Trial to Assess the Efficacy of Adjunctive Closed Loop Control Versus Sensor and Pump Therapy in the Management of Type 1 Diabetes Prone to Hypoglycemia

Conditions
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Type 1 Diabetes Mellitus With Hypoglycemia

Intervention / Treatment
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* Device: Closed-loop insulin infusion driven by continuous glucose monitoring through an algorithm, in free-life conditions
* Device: Continuous Subcutaneous Insulin Infusion and Continuous Glucose Monitoring


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one year and using insulin for at least 1 year Use of an insulin pump for at least 6 months Age ≥18 .0 years old HbA1c level <10.5% at screening Clarke score >3 and/or experience of severe hypoglycemia during the previous 6 months For females, not currently known to be pregnant If female and sexually active, must agree to use a form of contraception to prevent pregnancy while a participant in the study. A negative serum or urine pregnancy test will be required for all premenopausal women who are not surgically sterile. Participants who become pregnant will be discontinued from the study. Also, participants who during the study develop and express the intention to become pregnant within the timespan of the study will be discontinued. Willingness not to use glucose-lowering agents (such as Pramlintide, Metformin, GLP-1 analogs, SGLT2 inhibitors) during the study. This does not concern treatment with Metformin active and stable for more than 3 months prior the inclusion. Moreover, the use of SGLT2 inhibitors is not allowed in the 3 months prior to enrollment. Willingness to suspend use of any personal CGM for the duration of the clinical trial Willingness to establish network connectivity on at least a weekly basis Currently using no insulins other than one of the following rapid-acting insulins at the time of enrollment: insulin lispro (Humalog), insulin aspart (Novolog). Patients using glulisine (Apidra) may switch to lispro or aspart at least one month prior to enrollment. Investigator has confidence that the participant can successfully operate all study devices and is capable of adhering to the protocol Subject is covered by social health or similar insurance Informed consent form signed Exclusion Criteria: Use of SGLT2 inhibitors in the 3 months prior to enrollment Hemophilia or any other bleeding disorder A condition, which in the opinion of the investigator or designee, would put the participant or study at risk Participation in another pharmaceutical or device trial at the time of enrollment or during the study Employed by, or having immediate family members employed by Tandem or Dexcom Persons deprived of freedom, protected by law or vulnerable persons Any associated chronic disease or therapy (except insulin) affecting glucose metabolism Impaired renal function (Creatinine Clearance < 30 ml/min) Patient who had pancreas transplantation or pancreatic islet transplantation Patient having severe problems of uncorrected hearing and/or visual acuity Subjects with known allergy to CGM adhesives Patients that have frequent exposure to magnetic resonance imaging (MRI), computed tomography (CT) scan, or high-frequency electrical heat (diathermy) treatment Patient without any social or familial support able to intervene in case of severe hypoglycemic episode

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Closed-Loop Control (CLC)<br>Closed-loop subcutaneous insulin infusion driven by continuous glucose monitoring through an algorithm | Device: Closed-loop insulin infusion driven by continuous glucose monitoring through an algorithm, in free-life conditions<br>* Continuous subcutaneous insulin infusion according to an automated algorithm from continuous glucose monitoring data<br>* Other names: Artificial Pancreas;|
| Active Comparator: Sensor Augmented Pump (SAP)<br>Closed-loop subcutaneous insulin infusion and continuous glucose monitoring manage by patient | Device: Continuous Subcutaneous Insulin Infusion and Continuous Glucose Monitoring<br>* Insulin delivered subcutaneously by a pump and manage by the patient with the help of a CGM sensor<br>* Other names: CSII and CGM;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in percent of time spent with blood glucose level below 70 mg/dL | Baseline-treatment difference in % of time spent with blood glucose level below 70 mg/dL over the 3 months follow-up | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of time within target range 70-180 mg/dL |  | 3 months | 
| Percent of time spent with blood glucose level above 180 mg/dL |  | 3 months | 
| Mean blood glucose level |  | 3 months | 
| Percent of time spent with blood glucose level below 54 mg/dL |  | 3 months | 
| Percent of time spent with blood glucose in range 70-140 mg/dL |  | 3 months | 
| Glucose variability measured with the coefficient of variation (CV) |  | 3 months | 
| Glucose variability measured with the standard deviation (SD) |  | 3 months | 
| Percent of time spent with blood glucose level below 60 mg/dL |  | 3 months | 
| Low blood glucose index (LBGI) | <2.5 low risk , [2.5-5] medium risk, >5 high risk | 3 months | 
| Hypoglycemia events (defined as at least 15 consecutive minutes <70 mg/dL) |  | 3 months | 
| Percent of time spent with blood glucose level above 250 mg/dL |  | 3 months | 
| Percent of time spent with blood glucose level above 300 mg/dL |  | 3 months | 
| High blood glucose index (HBGI) | <2.5 low risk , [2.5-5] medium risk, >5 high risk | 3 months | 
| HbA1c at 3 months |  | at 3 months | 
| HbA1c change from baseline to 3 months |  | 3 months | 
| Fear of Hypoglycemia Survey | Total score from 0 (no fear) to 132 (important fear) | 3 months | 
| Hyperglycemia Avoidance Scale | Total score from 0 (do not avoid) to 40 (always avoid) | 3 months | 
| Diabetes Distress Scale | Total score range from 28 (low stress) to 168 (high stress) | 3 months | 
| Hypoglycemia Confidence Scale | Total score from 0 (no confidence) to 36 (very confident) | 3 months | 
| Clarke Hypoglycemia Awareness | Score range from 0 to 7. If more than 4 : reduced perception, if less : normal perception. | 3 months | 
| INSPIRE survey | Total score from 0 (high acceptance) to 110 (low acceptance) | 3 months | 
| System Usability Scale (SUS) | Total score from 0 (low acceptance) to 100 (high acceptance) | 3 months | 
| Insulin | Total daily insulin (units/kg), Basal: bolus insulin ratio | 3 months | 
| Weight and Body Mass Index (BMI) |  | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 diabetes, Hypoglycemia, Closed-loop insulin infusion