The present clinical trial aims to examine alternative strategies for preventing/mitigating
      hypoglycemic events among adults with type 1 diabetes utilizing a highly personalized control
      system. This system offers two configurable options: a single-hormone configuration with
      automatic rescue carbohydrate recommendations (sHC) and a dual-hormone configuration with
      subcutaneously administered glucagon boluses (dHmG). The main question addressed in this
      study focuses on determining whether the dHmG outperforms the sHC in terms of minimizing the
      time spent below the target range and number of hypoglycemic events.

      Each participant will undergo two 12-hour controlled inpatient studies, including each an
      unannounced 30-min aerobic exercise session and a meal challenge. The order of these studies,
      comparing the dHmG to the sHC, will be randomized.

Dual-hormone Artificial Pancreas Versus Single-hormone Under Exercise and a Meal Challenge

Type 1 Diabetes

RATIONALE OF THE STUDY

      Automated insulin delivery (AID), commonly referred to as artificial pancreas, represents the
      most advanced treatment for individuals with type 1 diabetes (T1D). AID is recognized for its
      ability to optimize insulin treatment, thereby maximizing the time spent within the target
      range (TIR) while minimizing instances of blood glucose levels falling below or exceeding the
      target range. At present, several hybrid AID systems are commercially available, primarily in
      the EU and US, providing this population with the benefits of this advanced therapy. Despite
      the benefits offered by current AID systems and diabetes technology in general for the
      treatment of T1D, only approximately 20% of individuals achieve the recommended glycemic
      target. The existing systems heavily rely on timely and accurate information from the user
      regarding two significant glycemic disturbances: meals and physical activity. Overestimation
      of carbohydrate intake and physical activity are the primary drivers contributing to
      postprandial and episodic hypoglycemia, respectively, with potential consequences during the
      overnight period.

      The current investigation aims to examine alternative strategies for preventing/mitigating
      hypoglycemic events utilizing a highly personalized control system. This system offers two
      configurable options: a single-hormone configuration with automatic rescue carbohydrate
      recommendations and a dual-hormone configuration with subcutaneously administered glucagon
      boluses. The research question addressed in this study focuses on determining whether the
      dual-hormone configuration outperforms the single-hormone with rescue carbohydrate
      recommendations configuration in terms of minimizing the time spent below the target range.

      HYPOTHESIS

      Our hypothesis suggests that the utilization of the dual-hormone configuration will result in
      a decrease in the amount of time spent below the target range (70-180 mg/dL) and a reduction
      in the number of hypoglycemic events in comparison to the single- hormone configuration with
      automatic rescue carbohydrate recommendations.

      MAIN OBJECTIVES

      Primary objectives of this study are: (1) to evaluate the duration of time spent below the
      target range (70-180 mg/dL) and (2) to assess the occurrence of Level 1 (<70 mg/dL) and Level
      2 (<54 mg/dL) hypoglycemic events. These objectives will be examined within the context of a
      12-hour, highly supervised, controlled, randomized clinical trial that incorporates real-life
      challenges. These challenges will involve an unannounced 30-min aerobic exercise session, as
      well as the consumption of a meal that will be announced.

      INVESTIGATIONAL PLAN

      Study design:

      This study follows a longitudinal, prospective, randomized crossover interventional design.
      Each participant will undergo two inpatient studies, including an unannounced exercise
      session and a meal challenge. The order of these studies, comparing the dual-hormone
      configuration (dHmG) to the single-hormone configuration with rescue carbohydrate
      recommendations (sHC), will be randomized. The study will comprise five visits:

      Visit 1: Screening visit. This visit will take place one week prior to Visit 2. During the
      screening visit, patients will provide informed consent, undergo examinations, and undergo
      tests to ensure their safety in participating in the study. Each subject will also be
      instructed to wear a continuous glucose monitoring (CGM) device.

      Visit 2: Randomization visit an Incremental Exercise test. This visit will take place 2 weeks
      before Visit 3. Patients will be assigned to one of two randomization schedules and will
      receive further instructions regarding their participation in the study. All necessary
      materials for conducting CGM will be provided during this visit. Additionally, an incremental
      exercise test will be conducted during this visit to determine the optimal intensity for the
      aerobic exercise sessions.

      Visits 3 and 4: Experimental study days. Each subject will undergo two interventions,
      consisting of an unannounced 30-min aerobic exercise test and a 60 g carbohydrate meal
      challenge. These interventions will occur at 2-3 week intervals (wash-out period), allowing
      for the completion of the two experiments within approximately 3 weeks.

      Visit 5: Final visit (follow-up visit). This visit will take place 1 week after the
      conclusion of Visit 4. Subjects will undergo a physical examination, and safety variables
      will be determined in the laboratory, following the same procedures outlined in Visit 1.

      Study population:

      Fifteen adults, ranging in age from 18 to 65 years, who have been diagnosed with T1D for more
      than 1 year and do not have advanced chronic micro- and macroangiopathic diabetic
      complications, will be recruited from individuals attending the Diabetes Unit at the Hospital
      Clínico Universitario de Valencia. These individuals must be on intensive insulin treatment
      with continuous subcutaneous insulin infusion (CSII) and have fair metabolic control (HbA1c
      <9.0%) while not experiencing hypoglycemia unawareness. Out of the recruited participants,
      five individuals will undergo an initial feasibility test for the dual-hormone (dHmG)
      configuration, while, subsequently, ten individuals will be randomly assigned to the dHmG vs.
      sHC study.

      Sample size:

      Five adults with T1D will initially participate in a preliminary feasibility study testing
      the dHmG. Subsequently, an additional ten adults with T1D will be enrolled in the
      interventional study comparing dHmG versus sHC. As the present study is exploratory in
      nature, a formal determination of the sample size was not calculated.

      Study procedure and schedule:

      The study will commence with a preliminary stage focused on evaluating the safety and
      feasibility of the coordinated dHmG (consisting of AID with manual glucagon administration)
      in five adults diagnosed with T1D. Following confirmation of safety data by the data and
      safety monitoring board, ten adult participants will be randomly assigned to the order in
      which the modalities (dHmG and sHC) will be tested, following a brief algorithm refinement
      procedure.

      Description of study days:

      Visit 1 (screening visit): After patients have provided informed consent, a series of
      examinations and tests will be conducted a week prior to Visit 2, including: Medical History,
      Physical examination, Standard 12-lead ECG, Clinical Laboratory Tests, detection of
      asymptomatic hypoglycemia using a validated Spanish version of the Clarke Test questionnaire,
      short version of the International Physical Activity Questionnaire to all participants and
      METS (metabolic equivalents) calculation.

      Visit 2 (randomization visit and incremental exercise test): If the outcome of the first
      visit is favorable, patients will be eligible for enrollment in the study and undergo
      randomization. They will be provided with instructions on the use of CGM for two weeks of
      monitoring prior to the commencement of the experimental study visits, which includes system
      calibration and preparation. Additionally, an incremental exercise test will be conducted
      during this visit to determine the optimal intensity for the aerobic exercise sessions.

      Visits 3 and 4 (intervention days): Each subject will undergo two study sessions, each of
      which will include an unannounced aerobic exercise test and a 60 g carbohydrate meal
      challenge that will be announced. The algorithm will utilize the individual's
      insulin/carbohydrate ratio to calculate the meal insulin bolus without any reduction. These
      sessions will be scheduled at intervals of 2-3 weeks and assigned randomly. In one session,
      the dHmG configuration for glucose control will be employed, while the sHC will be used in
      the other session. Participants will wear a CSII system with the CGM device.

      Visit 5 (follow-up visit): Subjects will be required to attend a follow-up visit after
      completing the two study days. During this visit, a physical examination and laboratory
      safety variables, as described in Visit 1, will be repeated.

      Study duration:

      The anticipated duration of this study will be four months, with subject recruitment
      scheduled to commence in December 2023 and the completion of experiments projected for March
      2024.

      ETHICAL AND LEGAL ASPECTS

      The procedures set out in this study protocol, pertaining to the conduct, evaluation, and
      documentation of this study, are designed to ensure that the sponsor and investigator (in
      this case the same person) comply with the principle of the good clinical practice guidelines
      and the Declaration of Helsinki in the conduct, evaluation and documentation of this study.
      The study will also be carried out in keeping with local legal requirements.

      This study involves the collection and use of biological samples for research purposes, in
      accordance with the provisions of Law 14/2007 on biomedical research and Royal Decree
      1716/2011 on Biobanks.

      An informed consent document that includes both information about the study and the consent
      form will be prepared and given to the subjects. The documents will be in a language
      understandable to the subject and will specify who will inform the subject.

      The study database will not contain any information that could allow the individual
      identification of the study participants. The data obtained will be used exclusively for the
      purposes described in this research project. The information will be treated as confidential
      and will be stored and processed in accordance with the provisions of EU Regulation 2016/679
      of the European Parliament and the Council of 27 April 2016 on the protection of personal
      data and the free movement of such data, as well as Organic Law 3/2018 of December.

Automated insulin delivery system algorithm with a dual-hormone configuration (insulin and glucagon) for glucose control

Automated insulin delivery system with a single-hormone configuration (insulin) with rescue carbohydrate recommendations for glucose control

Evaluation of Dual-hormone Artificial Pancreas With Closed-loop Glucose Control Versus Single-hormone With Carbohydrate Recommendations Under Unannounced Exercise and Meal Challenge in Adults With Type 1 Diabetes.

Percentage of time spent below the target range

Occurrence of hypoglycemic events during at least 15 min

Percentage of time spent within target range (70-180 mg/dL)

Percentage of time spent within target range (70-140 mg/dL)

Percentage of time spent with glucose levels < 3.0 mmol/l (54 mg/dl)

Standard deviation of sensor glucose levels

Total insulin administered during the inpatient study

Total glucagon administered during the inpatient study

Number of rescue carbohydrate recommendations applied during the inpatient study

Number of glucagon boluses administered during the inpatient study

Total number of carbohydrates ingested (g) during the inpatient study

12-hour inpatient study that will include an unannounced 30-min aerobic exercise session and a meal challenge. Automated insulin and glucagon delivery will be performed using a dual-hormone configuration system for glucose control .

12-hour inpatient study that will include an unannounced 30-min aerobic exercise session and a meal challenge. Automated insulin delivery will be performed using a single-hormone configuration system with carbohydrate recommendations if needed for glucose control .

Dual-hormone Artificial Pancreas Versus Single-hormone Under Exercise and a Meal Challenge

About this trial

Study ID

Status

Type

Phase

Placebo

Accepting

Not accepting

Trial Timing

What is this trial about?

What are the participation requirements?

Locations

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Status