Artificial Pancreas With Carbohydrate Suggestion for Patients With Type 1 Diabetes Prone to Hypoglycemia

A Pilot Study Evaluating the Safety and Performance of an Artificial Pancreas With Carbohydrate Suggestion for Patients With Type 1 Diabetes Prone to Hypoglycemia

Achieving near-normoglycemia has been established as the main objective for most patients with Type 1 Diabetes (T1D). Automated insulin delivery (AID) systems, the so-called artificial pancreas (AP) or closed-loop systems, may represent the ideal solution, especially for patients not reaching the therapeutic goals with multiples doses of insulin or open-loop delivery systems. Despite the advances in recent years that have proven the efficacy and safety of these devices in clinical trials and clinical practice settings, such evidence cannot be extrapolated to highly unstable patients, as problematic hypoglycemia remains an exclusion criterion in most of the trials.

The SAFE-AP system is a single-hormone hybrid closed-loop controller based on a proportional derivative with an insulin feedback controller that integrates a safety layer with insulin-on-board constraints and sliding mode reference conditioning. The hybrid closed-loop system includes a second safety feedback loop with a controller that triggers carbohydrate recommendations to the patient. Both control loops are coordinated to ensure that the counter-regulatory effect of rescue carbohydrates is not counteracted with insulin. Such system has been previously proven effective in unannounced exercise, one of the main challenges in AID systems development. Additionally, the algorithm has been recently tailored to achieve a better control in the subgroup of T1D patients prone to hypoglycemia.

In this project, a rigorous clinical testing of the SAFE-AP system will be carried out in 12 patients with T1D and problematic hypoglycemia, despite treatment with continuous subcutaneous insulin infusion. The safety and performance of the system will be evaluated in a 32-hour pilot study, including 4 meals, one overnight period and 2 unannounced aerobic exercise sessions. The study will be performed in a hospital setting with the on-site supervision of a specialized nurse and a diabetologist, as well as an engineer in remote control.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus Prone to Hypoglycemia
• Intervention / Treatment: Device: Automated Insulin Delivery System (SAFE-AP)

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects aged 18 or more with Type 1 Diabetes for at least 5 years.
• Treated with continuous subcutaneous insulin infusion (CSII) for at least six months.
• Trained to carbohydrate counting.

• Subjects prone to hypoglycemia, despite optimal diabetes management and hypoglycemia-specific education programs, as defined by >4 hypoglycemic episodes per week and at least one of the following:

  1. Occurrence of at least 2 severe hypoglycemic episodes during the last 2 years (need for third party).
  2. Occurrence of at least 1 severe hypoglycemic episode during the last 2 years and high glycemic variability (coefficient of variation >36%).
  3. Impaired awareness of hypoglycemia (Clarke test ≥4).
• Physical examination, laboratory data and EKG without alterations. Abnormalities considered clinically irrelevant by the investigator will not be exclusion criteria.
• Negative SARS-CoV-2 PCR test performed at arrival.
• Subject willing to wear the SAFE-AP system continuously throughout the study.

Exclusion Criteria:

• Pregnancy and breastfeeding.
• History of drug or alcohol abuse.
• Progressive fatal disease.
• Clinically relevant microvascular complications (macroalbuminuria, pre-proliferative and proliferative retinopathy), cardiovascular, hepatic, neurological, endocrine or other systematic, apart from T1D, which may hamper the implementation of the clinical study protocol or interpretation of results study.
• Scheduled surgery during the study period.
• Mental conditions that prevent the subject to understand the nature, purpose and possible consequences of the study.
• Subjects who are unlikely to meet the clinical study protocol, eg. uncooperative attitude, inability to return for follow-up visits, or poor probability of completing the study.
• Using an experimental drug or device during the past 30 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Automated Insulin Delivery System (SAFE-AP); Sliding Mode Reference Conditioning (SMRC) Closed-loop insulin administration. Automated insulin infusion based on subcutaneous continuous glucose monitoring (CGM). Commercially available insulin infusion systems and CGM devices will be used. However, insulin infusion will be driven by the software under investigation (SAFE-AP) based on blood glucose estimations from CGM.

Device: Automated Insulin Delivery System (SAFE-AP); Each subject will undergo a 32-hour in-hospital study, including 4 meals (60 grams of carbohydrates each, except 50 grams for breakfast), one overnight period and 2 unannounced aerobic exercise sessions. Each exercise session consists of three 15-minute sets on a cycle ergometer at 70% of maximum heart rate with 5 minutes of rest between sets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of CGM time in glucose range 70-180 mg/dl during the study.	From 12 AM of the first day of study until 4 PM of the second day of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of CGM time in glucose range 70-180 mg/dl during nighttime		From 22 PM of the first day of study until 7 AM of the second day of study
Percentage of CGM time in glucose range 70-180 mg/dl during exercise and recovery		Defined as 3 hours after exercise initiation
Percentage of CGM time in glucose range 70-180 mg/dl during postprandial period		Defined as 4 hours since mealtime
Percentage of CGM time in hypoglycemia (<70 mg/dL and <54 mg/dL) during the study		From 22 PM of the first day of study until 7 AM of the second day of study
Percentage of CGM time in hypoglycemia (<70 mg/dL and <54 mg/dL) during nighttime		From 22 PM of the first day of study until 7 AM of the second day of study
Percentage of CGM time in hypoglycemia (<70 mg/dL and <54 mg/dL) during exercise and recovery		Defined as 3 hours after exercise initiation
Percentage of CGM time in hypoglycemia (<70 mg/dL and <54 mg/dL) during postprandial period		Defined as 4 hours since mealtime
Percentage of CGM time in hyperglycemia (>180 mg/dL and >250 mg/dL) during the study		From 22 PM of the first day of study until 7 AM of the second day of study
Percentage of CGM time in hyperglycemia (>180 mg/dL and >250 mg/dL) during nighttime		From 22 PM of the first day of study until 7 AM of the second day of study
Percentage of CGM time in hyperglycemia (>180 mg/dL and >250 mg/dL) during exercise and recovery		Defined as 3 hours after exercise initiation
Percentage of CGM time in hyperglycemia (>180 mg/dL and >250 mg/dL) during postprandial period		Defined as 4 hours since mealtime
Glucose coefficient of variation during the study		From 22 PM of the first day of study until 7 AM of the second day of study
Number of hypoglycemic events	Defined as sensor glucose <70 mg/dL during 15 minutes or symptomatic hypoglycemia confirmed with plasma glucose	From 22 PM of the first day of study until 7 AM of the second day of study
Number of carbohydrate rescue events during the study		From 22 PM of the first day of study until 7 AM of the second day of study
Number of acute metabolic events during the study	Defined as severe hypoglycemia and diabetic ketoacidosis	From 22 PM of the first day of study until 7 AM of the second day of study

Collaborators and Investigators

• Sponsor: Hospital Clinic of Barcelona
• Collaborators: Universitat de Girona; Universitat Politècnica de València
• Investigators: Study Director: Ignacio Conget, MD PhD, Hospital Clinic of Barcelona; Study Chair: Marga Giménez, MD PhD, Hospital Clinic of Barcelona

Publications and helpful links

General Publications

• Vinals C, Beneyto A, Martin-SanJose JF, Furio-Novejarque C, Bertachi A, Bondia J, Vehi J, Conget I, Gimenez M. Artificial Pancreas With Carbohydrate Suggestion Performance for Unannounced and Announced Exercise in Type 1 Diabetes. J Clin Endocrinol Metab. 2021 Jan 1;106(1):55-63. doi: 10.1210/clinem/dgaa562.
• Rossetti P, Quiros C, Moscardo V, Comas A, Gimenez M, Ampudia-Blasco FJ, Leon F, Montaser E, Conget I, Bondia J, Vehi J. Closed-Loop Control of Postprandial Glycemia Using an Insulin-on-Board Limitation Through Continuous Action on Glucose Target. Diabetes Technol Ther. 2017 Jun;19(6):355-362. doi: 10.1089/dia.2016.0443. Epub 2017 May 1.
• Quiros C, Bertachi A, Gimenez M, Biagi L, Viaplana J, Vinals C, Vehi J, Conget I, Bondia J. Blood glucose monitoring during aerobic and anaerobic physical exercise using a new artificial pancreas system. Endocrinol Diabetes Nutr (Engl Ed). 2018 Jun-Jul;65(6):342-347. doi: 10.1016/j.endinu.2017.12.012. Epub 2018 Feb 23. English, Spanish.

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2021
• Primary Completion (Actual): April 6, 2022
• Study Completion (Actual): April 6, 2022

Study Registration Dates

• First Submitted: November 7, 2022
• First Submitted That Met QC Criteria: November 16, 2022
• First Posted (Actual): November 29, 2022

Study Record Updates

• Last Update Posted (Actual): November 29, 2022
• Last Update Submitted That Met QC Criteria: November 16, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Hypoglycemia; Type 1 Diabetes; Artificial Pancreas; Closed-loop; Automated insulin delivery
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin
• Other Study ID Numbers: HEAP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No