The Insulin-Only Bionic Pancreas Pivotal Trial

This multi-center randomized control trial (RCT) will compare efficacy and safety endpoints using the insulin-only configuration of the iLet Bionic Pancreas (BP) System versus Usual Care (UC) during a 13-week study period. Participants may be enrolled initially into a screening protocol and then transfer into the RCT protocol, or they may enter directly into the RCT protocol. The RCT will be followed by an Extension Phase in which the RCT Usual Care (UC) Group will use the insulin-only configuration of the iLet Bionic Pancreas (BP) System for 3 months. At the completion of use of the BP system in the RCT only, participants will enter a 2-4 day Transition Phase and be randomly assigned to either transition back to their usual mode of therapy (MDI or pump therapy) based on therapeutic guidance from the iLet BP System or transition back to their usual mode of therapy based on what their own insulin regimens were prior to enrolling in the RCT.

There is an optional ancillary study to assess the safety of utilizing self-monitored blood glucose (SMBG) measurements instead of continuous glucose monitor (CGM) measurements as input into the iLet for \~48-60 hours. The Study is intended to mirror a real-world situation where CGM may not be available for an extended period of time (eg, user runs out of sensors and is awaiting new shipment).

Primary Objective

• To compare the efficacy and safety of the insulin-only configuration of the iLet BP System (using insulin lispro, insulin aspart) the BP System using Fiasp (BPFiasp) \[adults only\]) in maintaining near-normal glycemia relative to usual care in a home-use study in adults and children with T1D.

Secondary Objectives • To assess the impact of the insulin-only configuration of the iLet BP System on quality of life and treatment satisfaction.

The study has four major parts: (1) the Test-Run Phase, (2) the RCT Period, (3) the Extension Phase for the UC Arm, and (4) the Transition Phase. These four parts are described below, and detailed in the main part of the protocol.

A Test-Run Phase will be conducted to (1) test the functionality of all aspects of the iLet BP System, (2) train the clinical staff on the execution of the clinical protocol, and (3) provide hands-on training with the device prior to initiating the RCT Period. The initial test run will be conducted at one site (MGH) with \~5 participants using the iLet BP system for 4-7 days. If there are no safety or consequential device issues, a test run will be conducted at each of the other 15 sites, with \~2 participants per site using the iLet BP system for 4-7 days. The iLet BP system will use insulin lispro or insulin aspart. Results of this Test-Run Phase will be evaluated for safety prior to beginning the RCT Period as described in section 3.3.

The 13-week, parallel-group, multi-center RCT Period is designed to compare the insulin-only iLet BP Group using insulin lispro, insulin aspart, or Fiasp (adults only); and a control group following usual care (UC Group). Upon completion of the RCT Period, the BP Group will enter the 2-4 day Transition Phase and the UC Group will enter the Extension Phase.

The UC Group Extension Phase will immediately follow the RCT Period. Participants from the UC Group who complete the primary outcome visit, miss no more than 3 of the maximum possible number of the weekly questionnaires, attend all clinic visits, and follow study procedures for collecting CGM data during the RCT Period, will be given the option to use the iLet BP system for 13 weeks. The visit schedule and procedures for the Extension Phase will be similar to that of the BP Group in the RCT Period.

A 2-4 day Transition Phase will be conducted for all participants who complete BP use at the end of the RCT Period (BP Group). Participants will be randomly assigned (1:1) to either transition back to their usual mode of therapy (MDI or pump therapy) based on therapeutic guidance from the iLet BP system or transition back to their usual mode of therapy based on what their own insulin regimens were prior to enrolling in the RCT Period. For those randomized to using their pre-study regimens, the dosing can be adjusted by the investigator to mitigate safety issues but should follow pre-study regimen as closely as possible.

An optional ancillary study will be offered to participants who are using the iLet at the time of the 13-week randomized trial visit. This will will assess the safety of utilizing blood glucose measurements instead of CGM measurements as input into the iLet for \~48-60 hours. It will be completed at the end of the RCT for those in the BP Group prior to the Transition Phase.

Test-Run Visit and Phone Contact Schedule

* Screening Visit - Eligibility assessed, informed consent, point-of-care/local HbA1c, testing and procedures similar to the RCT Screening Visit including psychosocial questionnaires; if eligible, BP system started.

  o For participants who completed the separate screening protocol, eligibility will be reassessed. Point-of-care/local HbA1c will be obtained if more than 28 days have elapsed. Participants will not need to repeat the psychosocial questionnaires.
* Phone contact after 1-2 days
* Shut-down visit at the end of the study period 4-7 days

RCT Period Visit and Phone Contact Schedule

* Screening Visit (which may be completed as part of a separate screening protocol)

  * Eligibility assessed, informed consent signed, point-of-care/local HbA1c, psychosocial questionnaires completed, blinded Dexcom G6 CGM sensor placed for non Dexcom G6 users.

    * For baseline data collection, participants using a personal Dexcom G6 who have at least 85% of possible glucose data in last 14 days can skip the blinded CGM wear
    * Participants using a personal Dexcom G6 with \<85% of data will use their personal Dexcom G6.
    * For participants who completed the separate screening protocol, eligibility will be reassessed. Point-of-care/local HbA1c will be obtained if more than 28 days have elapsed. Participants will not need to repeat the psychosocial questionnaires or blinded CGM wear.
* If the separate screening protocol or Test Run Phase of this protocol was completed or blinded CGM wear is not needed, randomization can proceed immediately. If blinded CGM wear was performed as part of this protocol, randomization visit will occur14-21 days after screening.
* Prior to randomization, eligibility will be reassessed and blood drawn for central lab HbA1c
* BP study start/UC study start on day of Randomization Visit
* Phone contacts after 1-2 days and 7 (±2) days
* Visits at 2 weeks (±4 days), 6 weeks (±4 days), 10 weeks (±4 days), and \~13 weeks (91-98 days from randomization):

  * Participants in the UC Group will wear a blinded Dexcom G6 sensor throughout the entire study unless they are current users of the Dexcom G6 CGM, in which case they will continue to use their own Dexcom G6 CGM.
  * At the 6-week and 13-week visits, central lab HbA1c determination and psychosocial questionnaires

UC Group Extension Phase Visit and Phone Contact Schedule

* BP initiation at 13-week visit
* Phone contacts after 13 weeks plus 1-2 days and 14 weeks (±2 days)
* Visits at 15 weeks (± 4 days), 19 (±4 days), 23 (±4 days), and \~26 weeks (182-189 days):

  * At the 19-week and 26-week visits, central lab HbA1c determination and psychosocial questionnaires

Transition Phase Visit Schedule

* Randomization and transition to UC regimen at 13-week visit for RCT BP Group for a period of 2-4 days in duration.
* Visit ≤4 days later for end of study

Ancillary Study Day 1 (13-week visit of the RCT) - stop CGM, start blinded CGM, start SMBG at least every 2 hours during waking hours and at least once during each overnight for the next 48-60hrs.

Day 2: Phone call for safety

Day 3: stop iLet, stop blinded CGM, restart unblinded CGM, enter Transition Phase.

Eligibility Criteria:
Inclusion Criteria:

* 1. Clinical diagnosis of T1D for at least one year and using insulin for at least 1 year 2. Diabetes managed using the same regimen (either pump or MDI, with or without CGM) for ≥ 3 months

  3. Age ≥ 6 years old
  * Exception: the initial 5-participant test run will be limited to \>18 years old

    4. Current use of a CGM, or if not a CGM user, at least 3 blood glucose meter tests daily on average over the last 4 weeks (according to judgment of investigator if meter is not available).

    5. Willingness not to start any new non-insulin glucose-lowering agent during the course of the trial

    6. For participants \<18 years old, living with one or more parent/legal guardian knowledgeable about emergency procedures for severe hypoglycemia.

    7. For participants \>18 years old who live alone, participant has a relative or acquaintance who lives within 30 minutes of participant and is willing to be contacted to check on participant if study staff feel that participant may be experiencing a medical emergency and can't be reached.

    8. Investigator believes that the participant can safely use the iLet and will follow the protocol
  * The investigator will take into account the participant's HbA1c level, compliance with current diabetes management, and prior acute diabetic complications. For this reason, there is no upper limit on HbA1c specified for eligibility.

    9. If a GLP-1 agonist or pramlintide is being used, participant must be willing to discontinue use while the iLet BP system is being used, including the randomized trial and extension study.

Exclusion Criteria:

* Eligibility may be assessed initially in a separate screening protocol or at a screening visit in the RCT protocol. To be eligible for all phases of the study, a participant must meet all of the following inclusion criteria and none of the exclusion criteria:

Exclusion

1. Unable to provide informed consent (e.g. impaired cognition or judgment)
2. Unable to safely comply with study procedures and reporting requirements (e.g. impairment of vision or dexterity that prevents safe operation of the bionic pancreas, impaired memory)
3. Unable to speak and read English

   • For pediatric participants, both caregivers and participants must be able to speak and read English
4. Plan to change usual diabetes regimen in the next 3 months

   * This would include changing from MDI to pump. pump to MDI, change in insulin automation delivery system, starting a CGM if not previously used, changes in drug therapy specifically for glucose control except for changes in one insulin analog to another.
   * Changes in insulin dose, carb ratio, sensitivity factor and basal rate profile are allowed.
5. Current use of non-FDA approved closed-loop or hybrid closed-loop insulin delivery system
6. Use of Apidra as the pre-study rapid-acting insulin analog and unwilling to switch to lispro or aspart for the duration of the study
7. Known hemoglobinopathy (sickle cell trait is not an exclusion)
8. Current participation in another diabetes-related clinical trial
9. History of cystic fibrosis, pancreatitis, or other pancreatic disease, including pancreatic tumor or insulinoma, or history of complete pancreatectomy
10. Electrically powered implants (e.g. cochlear implants, neurostimulators) that might be susceptible to RF interference
11. Established history of allergy or severe reaction to adhesive or tape that must be used in the study
12. Current use of SGLT2 inhibitors or a sulfonylurea drug (use more than 3 months prior to enrollment is acceptable)

    • If using GLP1 agonist, pramlintide, or metformin drugs must be on a stable dose for 3 months prior to enrollment (and as per inclusion criterion #8, must be willing to discontinue use of GLP-1 agonist or pramlintide while using the iLet BP system during the RCT and the extension phase).
13. Pregnant (positive urine hCG), breast feeding, plan to become pregnant in the next 3 months, or sexually active without use of contraception
14. For adults \>18 years old, most recent (must be within the last 2 years) eGFR \<30 ml/min OR currently in renal failure on dialysis

    • If no eGFR is available for an adult participant during the last 2 years, one must be obtained to confirm eligibility
15. Presence of a medical condition or use of a medication that, in the judgment of the investigator, clinical protocol chair, or medical monitor, could compromise the results of the study or the safety of the participant. Conditions to be considered by the investigator may include the following:

    * Alcohol or drug abuse
    * Use of prescription drugs that may dull the sensorium, reduce sensitivity to symptoms of hypoglycemia, or hinder decision making during the period of participation in the study
    * Coronary artery disease that is not stable with medical management, including unstable angina, angina that prevents moderate exercise (e.g. climbing a flight of stairs) despite medical management, or within the last 12 months before screening a history of myocardial infarction, percutaneous coronary intervention, enzymatic lysis of a presumed coronary occlusion, or coronary artery bypass grafting
    * Congestive heart failure with New York Heart Association (NYHA) Functional Classification III or IV
    * History of TIA or stroke in the last 12 months
    * Untreated or inadequately treated mental illness
    * History of eating disorder within the last 2 years, such as anorexia, bulimia, or diabulemia or omission of insulin to manipulate weight
    * History of intentional, inappropriate administration of insulin leading to severe hypoglycemia requiring treatment
16. Employed by, or having immediate family members employed by Beta Bionics, or being directly involved in conducting the clinical trial, or having a direct supervisor at place of employment who is also directly involved in conducting the clinical trial (as a study investigator, coordinator, etc.); or having a first-degree relative who is directly involved in conducting the clinical trial