Institutional Review Board Intervention/Interaction Detailed Protocol Principal Investigator: Melissa Putman MD Project Title: Clinical study of the iLet bionic pancreas in a pregnancy configuration Version Date: 23 Jan 2026 Version Name/Number: Version Abbreviations ACOG American College of Obstetrics and Gynecology ADA American Diabetes Association AID Automated Insulin Delivery BG Blood Glucose BMI Body Mass Index BP Bionic Pancreas CGM Continuous Glucose Monitor CHF Congestive Heart Failure DPP-4 Dipeptidyl peptidase-4 FDA Food and Drug Administration FEV1 Forced Expiratory Volume in 1 second GLP-1 Glucagon-like peptide-1 GUI Graphical User Interface HCG Human Chorionic Gonadotropin IOBP Insulin-only Bionic Pancreas IRB Institutional Review Board ISO International Organization for Standardization IUD Intrauterine device IV Intravenous MDI Multiple Daily Injections OCP Oral Contraceptives PK Pharmacokinetics RDA Recommended Dietary Allowances SC Subcutaneous SGLT-2 Sodium-glucose co-transporter-2 T1D Type 1 Diabetes T2D Type 2 Diabetes TIA Transient Ischemic Attack UC Usual Care UI User Interface • Background and Significance Rates of pre-existing diabetes in pregnancy are rising rapidly. United States national data demonstrate that the number of pregnancies affected by pre-existing diabetes (including type 1 diabetes [T1D] and type 2 diabetes [T2D]) increased by almost 30% over a 5-year period from 2016 to 2021. 1 Maternal pre- existing diabetes now affects almost 40,000 US pregnancies per year. 1 Intrauterine exposure to hyperglycemia has been linked to an increased risk of future diabetes in exposed offspring, even when compared to their own siblings.2,3 thus, the rising rates of pre-existing diabetes in pregnancy set up a vicious intergenerational cycle of diabetes. These rising rates are principally driven by T2D, the prevalence of which has tripled over the past two decades in the obstetric population.4 T2D now accounts for 60% of cases of pre-existing diabetes in pregnancy.4 Even though T1D and T2D are managed similarly in pregnancy and convey a similarly increased risk of adverse outcomes,5, 6, 7, 8 most clinical trials studying interventions in pre-existing diabetes in pregnancy have only included people with T1D.9-13 T1D and T2D in pregnancy result in substantial maternal and neonatal morbidity. Diabetes carries a high risk of maternal and fetal morbidity that is directly related to hyperglycemia.9,14,15 In early pregnancy, hyperglycemia can lead to miscarriage and congenital malformation.16 Later in pregnancy, hyperglycemia is associated with hypertensive disorders of pregnancy, preterm birth, and stillbirth.7-9,17-22 At delivery, fetal overgrowth increases the risk of shoulder dystocia, birth trauma (leading to nerve palsy or clavicular fracture), higher-order perineal lacerations, and cesarean delivery.23-26 After delivery, infants exposed to diabetes in-utero commonly develop neonatal hypoglycemia which can require intravenous dextrose administration, leading to parent-baby separation and disruption of breastfeeding.26 Other neonatal complications include respiratory distress syndrome, hyperbilirubinemia, and even cardiomyopathy or death.7,9,27 Most individuals with diabetes do not meet recommended pregnancy glycemic targets and will experience at least one diabetes- related complication; the risk of each of these complications is directly related to the severity of hyperglycemia.4,6,9,28,29 Importantly, seemingly small reductions in the amount of hyperglycemia (e.g. 5% increase in time in target range) result in clinically meaningful reduction in the risk of perinatal complications.9,30 Table 1. Glycemic Targets in Pregnant and Non-Pregnant People with Diabetes 7, 8, 20, 21 Glycemia metric Pregnant Non-Pregnant Target range (CGM)+ 63-140 mg/dl 70-180 mg/dl Fasting glucose 70-95 mg/dl 80-130 mg/dl 1-hour postprandial glucose* 110-140 mg/dl <180 mg/dl 2-hour postprandial glucose* 100-120 mg/dl <180 mg/dl Hemoglobin A1c† <6% <7% *Outside of pregnancy, postprandial glucose is not commonly checked; in pregnancy, postprandial glucose is a major therapeutic target. †A1c is a primary clinical metric outside of pregnancy and a secondary clinical metric in pregnancy. +Non-pregnant and T1D-affected pregnancy goal is > 70% time in range. Table 1. Glycemic Targets in Pregnant and Non-Pregnant People with Diabetes 7, 8, 20, 21 Glycemia metric Pregnant Non-Pregnant Target range (CGM)+ 63-140 mg/dl 70-180 mg/dl Fasting glucose 70-95 mg/dl 80-130 mg/dl 1-hour postprandial glucose* 110-140 mg/dl <180 mg/dl 2-hour postprandial glucose* 100-120 mg/dl <180 mg/dl Hemoglobin A1c† <6% <7% *Outside of pregnancy, postprandial glucose is not commonly checked; in pregnancy, postprandial glucose is a major therapeutic target. †A1c is a primary clinical metric outside of pregnancy and a secondary clinical metric in pregnancy. +Non-pregnant and T1D-affected pregnancy goal is > 70% time in range. • Risk of hypoglycemia: Hypoglycemia is the primary therapy-limiting complication in T1D and insulin-requiring T2D. The risk of hypoglycemia is substantial during pregnancy when aiming for tight glycemic control. In T1D, the incidence of severe hypoglycemia (an event requiring another person to administer treatment) is 5- fold greater in the 1st trimester (when insulin sensitivity is greatest) than prior to pregnancy and remains more than 2-fold higher in the 2nd trimester compared to prior to pregnancy.33 • Burden of self-management: Self-management of intensive insulin therapy requires extreme vigilance and a high degree of health literacy and numeracy that creates a barrier to optimal outcomes in many patients with T1D and T2D. Furthermore, T2D outside of pregnancy is usually managed with non-insulin agents without intensive glucose monitoring; thus, newly pregnant individuals with T2D often need to rapidly learn to monitor glucose, safely administer insulin, and adjust insulin doses based on carbohydrate intake, physical activity, and blood glucose trends, while at the same time navigating other pregnancy-related medical issues. • Dynamic changes in insulin requirements: Insulin requirements double over the course of gestation, with relatively stable insulin total daily dose during the initial 20 weeks, followed by a gradual rise in insulin resistance over the second half of pregnancy (Figure 1).34 In T1D, the vast majority of the increase in requirement is dosed prandially (4-fold intensification of carbohydrate ratios compared to pre-pregnancy).35 The substantial late-pregnancy insulin resistance is a universal phenomenon that can lead to requirements of >2 units per kg body weight of insulin per day in 45% of those with T2D,36 with attendant risk of hypoglycemia that accompanies the use of high-dose insulin. • Dynamic changes in food intake and absorption: There are pregnancy-related gastrointestinal symptoms and physiologic changes in appetite and gut motility that fluctuate over gestation. For example, nausea and vomiting is extremely common in early pregnancy; inability to plan food intake-appropriate insulin dosing puts pregnant individuals with nausea and vomiting at risk of postprandial hyper- and hypo-glycemia. Figure 1. Total daily insulin requirement in optimally managed people with T1D by gestational week.34 These challenges result in substantial psychosocial distress for pregnant patients with diabetes, characterized by anxiety, guilt, “constant pressure”, and, in some cases, difficult relationships with health care professionals.44 Notably, most people with T1D or T2D in pregnancy do not achieve recommended glycemic targets.30,37 1.a Current diabetes technologies fail to produce the level of glycemic control necessary to address excess morbidity in pregnancy complicated by diabetes. The CONCEPTT trial,9 published in 2017, demonstrated that use of adjunctive CGM in T1D-affected pregnancy (as compared to fingerprick glucometer monitoring alone) improved glycemic control (8% increase pregnancy-specific time in range [63-140 mg/dL]) and dramatically reduced the risk of neonatal complications including large for gestational age birthweight (69% to 53%), neonatal hypoglycemia (28% to 15%), and neonatal intensive care unit admission (43% to 27%). Still, even in this modern-era clinical trial population, the rates of complications remained high (e.g., large for gestational age birthweight >5-fold higher than expected in the general population), indicating that much more progress is needed to improve morbidity in diabetes-affected pregnancy. Available data in T2D-affected pregnancy suggest that glycemic and pregnancy outcomes are just as poor or worse.4,7,8,37,38 While automated insulin delivery (AID) technology has improved glycemic control and the burden associated with self-management of T1D in non-pregnant individuals,39 all systems available in the US target a glycemic range higher than that recommended during pregnancy. There is a dearth of research on the use of AID in pregnant individuals with only a few published trials,10,40-42 resulting in limited obstetric clinical implementation in the US; furthermore, we are unaware of any AID studies that have included pregnant individuals with T2D. The PICLS trial 43 randomized 24 pregnant women at 14-18 weeks’ gestation to the Medtronic 670g in hybrid closed loop mode (automated basal insulin delivery, with a requirement for carbohydrate counting) or sensor augmented (suspend on low) mode. Completers randomized to AID had higher average sensor glucose in the 2nd and 3rd trimester (137 and 132 mg/dl vs 126 and 120 mg dl, p<0.05) and a higher hemoglobin A1c (A1c) in the 3rd trimester (6.6% vs 6.2%, p<0.05) compared to those randomized to sensor augmented mode, indicating that an AID system designed for non-pregnancy targets may not be aggressive enough to outperform manual insulin delivery in achieving pregnancy glycemic goals. The AiDAPT trial (published October 2023)10 randomized 124 participants to an AID system that is available in the United Kingdom and requires carbohydrate counting. The system allows the target glucose to be set as low as 81-90 mg/dl, which is lower than all available FDA-cleared systems. The trial demonstrated an increase of 10.5% in pregnancy-specific time in range (63-140 mg/dL) with the AID system compared to usual care; 47% of those in the AID group attained the T1D target of >70% pregnancy-specific time in range (compared to 11% in the usual care group). This study demonstrates that when targets are set appropriately, AID technology is a promising advance for T1D in pregnancy. The CRISTAL trial (published June 2024) randomized 95 participants to standard care vs the Medtronic 780g hybrid closed loop system, which is FDA-cleared and allows the target glucose to be set as low as 100 mg/dl. This device requires carbohydrate counting. Participants using the hybrid closed loop system were advised to enter unconsumed carbohydrates to increase insulin delivery, which is not recommended by the manufacturer. The trial found similar pregnancy-specific time in range in the two groups (66.5% in the Medtronic 780g group, 63.2% in the standard care group, p=0.17), with lower time below 63 mg/dl in the Medtronic 780g group. Participants assigned to the Medtronic 780g reported higher treatment satisfaction. In combination with the studies described above, this study suggests that AID in pregnancy is safe, however most participants still did not achieve the time in pregnancy-specific range goal of > 70% with this device that was not designed to meet pregnancy goals. There is one ongoing trial of an additional AID system available in the US (CIRCUIT: NCT04902378) in T1D-affected pregnancy. This device does not use an algorithm that specifically targets pregnancy glycemic goals and requires carbohydrate counting.44 Results are expected in summer, 2025. Thus, there is a significant need for development of AID systems that have pregnancy-appropriate algorithms in order to improve maternal and neonatal health outcomes in people with diabetes. In addition, to our knowledge, no study of AID in pregnancy has previously included participants with T2D, which is a significant unmet need. The iLet Bionic Pancreas (iLet) Figure 2. iLet bionic pancreas Figure 2. iLet bionic pancreas The iLet is an AID device whose distinguishing features include (a) initiation with only the patient’s body weight (rather than a complex set of insulin delivery settings), (b) continuous, rapid adaptation to changing user needs, and (c) the elimination of carbohydrate counting and user-initiated correction boluses. These features have the potential to markedly reduce the burden associated with insulin self-management, increase the accessibility of AID therapy, and improve outcomes of patients with limited health literacy or subspecialist access. The iLet is an insulin pump with embedded algorithms that automatically adjust insulin dosing based on glucose readings received via Bluetooth from a Dexcom CGM (Figure 1). The iLet software includes three separate control algorithms that independently, autonomously, rapidly, and continually adapt to changes in insulin requirement for the individual user over time, including with substantial abrupt changes in insulin resistance.45 The algorithms include (1) a basal controller, which provides for the basal requirements of the user, (2) a correction controller, which determines correction dosing needed for hyperglycemia, and (3) a meal controller, which learns what qualitative meal announcements mean for the user’s meal type (“breakfast”, “lunch”, “dinner,”) and the relative amount of carbohydrate content for that meal type (“usual for me”, “more”, “less”). The meal dosing algorithm autonomously adapts to deliver ~75% of the learned insulin requirement for that meal type and size based on past usage. The control algorithms used by the iLet require initiation with only the user’s body weight, which can be up to 255 kg (561 lbs). No information about the patient’s insulin dosing, carbohydrate-to-insulin ratios, or insulin correction factors is entered, and carbohydrate counting is not required. Different targets can be set by the user during the day and overnight. On the FDA-cleared device, these targets include 110 mg/dL (lower target), 120 mg/dL (usual target), or 130 mg/dL (higher target). This is the only setting that can be adjusted after the device is initialized. Figure 2 shows the commercially available iLet device and components. Change to figure 3 Figure 2. Mean glucose levels according to time of day in the Insulin-only Bionic Pancreas Pivotal Trial in children and adults with T1D. The figure represents an envelope plot of CGM glucose levels over the 13-week trial period from midnight to midnight. Solid circles represent hourly median values of participants’ mean glucose levels. The interquartile range is represented by shaded areas and the 10th and 90th percentiles by the dashed lines. Figure 2. Mean glucose levels according to time of day in the Insulin-only Bionic Pancreas Pivotal Trial in children and adults with T1D. The figure represents an envelope plot of CGM glucose levels over the 13-week trial period from midnight to midnight. Solid circles represent hourly median values of participants’ mean glucose levels. The interquartile range is represented by shaded areas and the 10th and 90th percentiles by the dashed lines. Figure 4. Change in percent time in target range between the iLet and standard of care over 13 weeks in the Insulin-Only Bionic Pancreas Pivotal Trial49 The iLet algorithm was developed with the goal of achieving glycemic targets for non-pregnant people with T1D, aiming for 70% time in range (70-180) mg/dL and A1c <7%.39,51 Although the iLet allows users to effectively reach these targets, it is not currently configured to achieve the more stringent targets for pregnancy (i.e., target range of 63-140 mg/dL, Table 1). In addition, the pregnancy fasting glucose target (< 95 mg/dL), is 15 mg/dL lower than the lowest target option available on the iLet, which will make it challenging for users to meet this goal with the device. Our preliminary data below show that without adjustments to the iLet’s configuration, it is unlikely that the iLet will allow users to successfully reach pregnancy glycemic goals. Therefore, we now propose make changes to the iLet to allow for its successful use during pregnancy by: (1) adding two lower glucose targets (90 and 100 mg/dL) (2) modifying the meal controller algorithm such that a larger triggered meal bolus is delivered (90% vs 75% of learned insulin requirement for meal type). We also propose to utilize extra-rapid acting insulin, faster-acting insulin aspart (Fiasp, faster aspart), that was shown to provide 2% greater time in range (70-180 mg/dl), with a non-significant reduction in hypoglycemia (-0.04%, p=0.11) compared to using the iLet with conventional aspart or lispro.52 Faster aspart recently demonstrated to be safe and associated with a lower risk of severe hypoglycemia and lower mean 2nd trimester glucose compared to conventional aspart in a randomized trial in T1D- and T2D-affected pregnancy.53 If successful, these changes could be easily implemented in clinical practice via a software upgrade to the device. 1.b. Preliminary Data. Participants in the T1D iLet pivotal trial did not achieve the pregnancy-specific glycemic targets using the FDA-cleared configuration. We conducted a new analysis of data from the iLet pivotal trial,49 calculating the pregnancy-specific time in range (63-140 mg/dl) for the non-pregnant participants in the study. We found that the mean (SD) pregnancy-specific time in range in iLet users (N=206) was 39.9% (7.4%). The mean (SD) pregnancy-specific time in range in female participants aged 18-50 was nominally higher at 43.6% (6.2%). Notably, no participants achieved the pregnancy goal of >70% pregnancy-specific time in range (63-140 mg/dl); the highest pregnancy-specific time in range observed was 69%. These data illustrate that the iLet in its current configuration is suboptimal for achieving glycemic goals in pregnancy. Table 2. Effect of iLet Target on Pregnancy-Specific Time in Range in the iLet Pivotal Trial iLet Target Person-days with this target (%) β [95% CI] percent in time in pregnancy- specific range* 100 mg/dl 561 (3%) +7.9% [7.6%, 8.3%] 110 mg/dl 3,909 (20%) +5.2% [5.0%, 5.3%] 120 mg/dl 11,402 (60%) Reference 130 mg/dl 3,161 (17%) -4.0% [-4.1%, -3.8%] 140 mg/dl 72 (0%) -8.4% [-9.8%, -7.0%] Table 2. Effect of iLet Target on Pregnancy-Specific Time in Range in the iLet Pivotal Trial iLet Target Person-days with this target (%) β [95% CI] percent in time in pregnancy- specific range* 100 mg/dl 561 (3%) +7.9% [7.6%, 8.3%] 110 mg/dl 3,909 (20%) +5.2% [5.0%, 5.3%] 120 mg/dl 11,402 (60%) Reference 130 mg/dl 3,161 (17%) -4.0% [-4.1%, -3.8%] 140 mg/dl 72 (0%) -8.4% [-9.8%, -7.0%] Figure 3. Results of the MGH Bionic Pancreas T2D Pilot Study Figure 3. Results of the MGH Bionic Pancreas T2D Pilot Study Promising pilot data support use of the iLet in T2D. In an unpublished outpatient pilot study (Figure 5), five participants with T2D on multiple daily injections at baseline participated in a random-order crossover trial, using usual care versus iLet, each for a 7-day period. During the iLet treatment, the device’s target was set at 100 mg/dL. Excluding the initial 48 hours for device adaptation (as pre-specified), use of the iLet resulted in improved mean CGM glucose and reduced hypoglycemia as compared to usual care. During iLet use, all participants met ADA-recommended average glucose targets for non-pregnant individuals (versus 60% during usual care).51 These data suggest that use of the iLet with a lower glucose target can safely improve glycemic control in people with T2D. The iLet can rapidly adapt to acute changes in insulin resistance with glucocorticoid treatment. Data collected from the Insulin-only Bionic Pancreas Pivotal Trial49 included five participants treated with acute glucocorticoids while using the iLet as well as 5 participants in the standard care group. As shown in Table 3, CGM metrics including mean glucose and TIR did not change substantially before and during glucocorticoid treatment, illustrating the ability of the iLet to adapt to rapid changes in insulin resistance and insulin needs. Table 3. Treatment with Glucocorticoids during the Insulin-only Bionic Pancreas Pivotal Trial Metric Bionic Pancreas Standard Care Before Glucocorticoids During Glucocorticoids Before Glucocorticoids During Glucocorticoids N 5 5 4 5 Mean Glucose (mg/dL) mean ± SD 161 ± 10 165 ± 10 175 ± 15 185 ± 27 % Time in Range 70-180 mg/dL mean ± SD 65% ± 8% 64% ± 8% 59% ± 9% 54% ± 18% % Time <70 mg/dL median (quartiles) 2.3% (2.3%, 2.7%) 1.6% (0.8%, 2.0%) 1.1% (0.7%, 2.0%) 0.0% (0.0%, 0.2%) % Time <54 mg/dL median (quartiles) 0.57% (0.25%, 0.70%) 0.21% (0.15%, 0.24%) 0.05% (0.03%, 0.34%) 0.00% (0.00%, 0.00%) % Time >180 mg/dL median (quartiles) 30% (26%, 40%) 38% (30%, 40%) 39% (33%, 47%) 48% (31%, 52%) • Specific Aim and Objective Aim: Optimize the iLet to meet pregnancy-specific glycemic targets in non-pregnant individuals with T1D and T2D. We will optimize the iLet algorithm to reach pregnancy glycemic goals by (a) adding two lower glucose targets (90 and 100 mg/dL) to the current options (110, 120, and 130 mg/dL); and (b) increasing the triggered meal bolus insulin delivery from 75% of the learned insulin requirement (current configuration) to 90% of the learned insulin requirement (pregnancy configuration). In this three-phase crossover trial, each non-pregnant female participant (age 18-49) with T1D (N=10) or T2D (N=10) will first use the iLet with usual settings for 16 days (phase 1), then crossover to pregnancy-specific settings for the next 16 days (phase 2), and then will factory-reset the device and use pregnancy-specific settings for the final 16 days (phase 3), with close follow up to ensure safety and adjust targets for each participant. We will compare glycemic, safety, and psychosocial outcomes during treatment with the pregnancy- specific configuration to those during treatment with the usual iLet configuration (phase 1 vs phase 2), and will assess the safety of using the pregnancy-specific configuration in the absence of a preceding adaptation period with the usual configuration. We hypothesize that lowering the iLet glucose target and increasing the triggered meal bolus insulin delivery (phase 2) will improve pregnancy-specific time in range (63-140 mg/dL) compared to the usual iLet algorithm (phase 1), without increasing time below 54 mg/dL. • General Description of Study Design The study schema is presented in Figure 6. This is a single-arm crossover trial comparing the iLet with its currently FDA-approved configuration to a new pregnancy-specific configuration with lower target options and increased meal bolus insulin. We will investigate how the pregnancy-specific configuration performs both after an initial period of adaptation with the usual configuration as well as immediate initiation with the pregnancy-specific configuration without any prior adaptation. This will provide critical information about the safety and efficacy of lower targets and increased triggered meal bolus insulin prior to introducing the device to pregnant individuals. Non-pregnant female individuals aged 18-49 with T1D or T2D will be enrolled. Participants will first use the iLet with faster aspart in the current FDA-approved configuration. Subsequently, participants will crossover to the pregnancy-specific configuration with and without a prior adaptation period. We will not include a comparison with participants’ usual diabetes care because the efficacy of the iLet compared to usual care in non-pregnant adults with T1D has already been established,49 and the goal of this Aim is to identify how adjustments to the iLet can be used to meet the more stringent glycemic targets required during pregnancy. In the usual configuration and both pregnancy configuration iLet treatment periods, we will work with participants to maximize pregnancy-specific time in range (63-140 mg/dl). We will conduct close follow up for the initial 6 days in each pregnancy configuration phase to ensure participant safety and make target adjustments as needed to reach glycemic goals. Figure 6. Study Schema. • Subject Selection 4.a Eligibility criteria. The study population will be representative of those expected to benefit from use of the iLet with a pregnancy-specific algorithm, namely people aged 18-49 who were assigned female sex at birth. Up to 60 individuals with diabetes are expected to be recruited and screened for participation in this proposal, and 20 (10 with T1D and 10 with T2D) will meet eligibility criteria and will be enrolled. Inclusion • Age 18-49 years old at time of signing informed consent • Female sex assigned at birth • Able to provide informed consent • Clinical diagnosis of type 1 diabetes (T1D) or type 2 diabetes (T2D) for at least 1 year • Using insulin with a stable regimen for ≥ 3 months prior to screening and collection of baseline CGM data: either multiple daily injections of insulin (MDI), basal-only without bolus insulin, an insulin pump without automation, or an automated insulin delivery (AID) system • People using of the commercially available iLet with its FDA approved settings will be allowed to enroll since this trial is specifically testing new settings • Willing to stop all non-insulin diabetes medications except for a stable dose of metformin during the trial period and no use of glucagon-like-peptide-1 receptor agonist in the four weeks prior to enrollment • Documented retinal exam for diabetic retinopathy screening within the last 12 months • Able to speak and read English sufficiently to understand the pump user interface and provide written materials for safe operation of the iLet • Willing to share CGM data and hypoglycemia alarms during participation with a partner or close acquaintance • For participants 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. • Willing and able to switch to faster-acting insulin aspart (Fiasp) when using the iLet • Willing to attempt to maximize time with glucose in the pregnancy range of 63-140 mg/dl.  • Participant has commercial glucagon available for treatment of severe hypoglycemia or will obtain it prior to randomization • Willing to authorize the study team to contact the participant’s primary physician to inform them about the participation in this study. • No plans for trips outside the United States during the period of study participation • 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 (there is no upper limit for eligibility), compliance with current diabetes management, prior acute diabetic complications, cognitive ability, and general medical condition. For this reason, there is no upper limit on HbA1c specified for eligibility. Exclusion • Current use of an AID system not FDA approved for T1D • Current participation in another diabetes-related interventional trial • Established history of allergic or severe reaction to adhesive or tape, that cannot be premedicated. Must be able to tolerate adhesive used to place CGM. • History of severe hypoglycemic episode in the preceding 12 months or hypoglycemic seizure in the preceding 5 years • Hypoglycemia unawareness, as determined by score of ≥ 4 on Clarke Hypoglycemia Awareness survey • Pregnant (positive urine hCG), plan to become pregnant in the next 3 months, recently postpartum (within 3 months), or sexually active without use of contraception • Previous history of bariatric surgery • Proliferative retinopathy • Current use of hydroxyurea or unable to avoid hydroxyurea use during the study (interferes with accuracy of Dexcom sensor) • 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 substance use disorder • 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, such has opioids or short-acting benzodiazepines • 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 • Severe liver disease such as end-stage cirrhosis • Renal failure requiring dialysis or known eGFR <60 • Untreated or inadequately treated mental illness • History of untreated or inadequately treated eating disorder within the last 2 years, such as anorexia, bulimia, or diabulimia or omission of insulin to manipulate weight • History of intentional, inappropriate administration of insulin leading to severe hypoglycemia requiring treatment • 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. 4.b. Local Recruitment Procedures Participants will be recruited from the patient population seen at Mass General Brigham (MGB) for diabetes clinical care and from the local community. We will use queries of the electronic medical record (including schedules of Diabetes providers across the MGB system as well as the MGB Research Patient Data Registry [RPDR]) to identify potential participants. An initial query of RPDR identified N=6970 patients cared for within MGB who are female, age 18-49, have T1D or T2D, and can be contacted for research studies. We will leverage the electronic medical record infrastructure to approach potential participants virtually using research invitations or targeted research announcements, consistent with MGB research policies. Other recruitment methods will include in-person recruitment during clinical appointments, paper and digital advertisements (including on MGB Rally), MGB approved research registries (including IRB-approved screening registries), and physician referrals. We will follow MGB policies for approaching potential participants for research. Study recruitment methods may consist of the following: • IRB approved paper and digital advertisements, brochures, postcards, flyers and/or newsprint advertisements • Culling of pre-existing databases held by the investigators of patients who have expressed interest in the bionic pancreas. • Those identified will be sent one of the aforementioned IRB approved materials via US mail or e-mail, or contacted via phone, and will be provided information about how to complete the consent process. • Research Invitations: Patient Gateway Personalized Letters • Study staff will review medical records to identify potential participants that meet inclusion and exclusion criteria. Research invitations will be sent electronically using the EPIC Patient Gateway system or via US mail to participants who have not opted out of receiving invitations and meet basic inclusion criteria based on medical record review. These letters will include an opt out period, after which the study team may call participants to gauge their interest in participating if they have not previously indicated they did not wish to be contacted. All recruitment materials will be approved by the IRB prior to their implementation. • Subject Enrollment 5.a. Pre-Screening Procedures: Prospective participants will be briefed by a study staff member regarding the study procedures and the inclusion and exclusion criteria. Potential participants will have the option of being prescreened over the phone to assess initial eligibility prior to inviting them for a full screening visit. Informed consent will not be obtained at this time. 5.b. Consent Procedures Potential participants will be provided with a paper or electronic copy of the IRB-approved consent form to read and review at least 24 hours prior to a planned consent and screening visit. Once potential participants have had time to review the consent document, they will meet with a study provider (MD, PA, or NP) that will explain the study, answer any questions, and administer informed consent. All participants will receive a verbal explanation in terms suited to their comprehension of the purposes, procedures and potential risks of the study and of their rights as research participants. The participants will be encouraged to discuss participation with their family and medical providers. A copy of the signed consent form will be provided to the participant. If an NP or PA is administering the consent, participants and/or their parents/guardians will be offered the chance to speak with a study MD if they wish. A licensed physician investigator will be available to speak with the participants during the consent process. Every attempt will be made to arrange for informed consent to be obtained by a team member that is not directly involved in the participant’s clinical care. If the physician who first discussed the study with the potential participant is their own physician, that physician will be instructed to give the participant the consent form to take home and review and to tell the participant to call back if they wish to participate. Additionally, a different member of the research team that is not involved in the participant’s care will contact the potential participant after the investigator has presented the study to them. • STUDY PROCEDURES 6.a. Study visits: Candidate participants will be required to attend a screening visit during which eligibility will be assessed as an outpatient. Eligible participants will participate in a training visit to learn how to use the iLet and will be trained on study procedures. Study visits may be virtual or in-person depending on preferences of the participant and the study team. The trial will consist of three study phases: (1) first, 16 days using the iLet with its usual, currently FDA approved algorithm and settings, followed by (2) 16 days using the iLet with pregnancy-specific adjustments, followed by (3) factory reset of the iLet with initiation using the pregnancy-specific configuration for the final 16 days. The hierarchical co-primary outcomes will be 1) the percentage of time with glucose in the pregnancy-specific target range 63-140 mg/dl and 2) the percentage of time with glucose less than 54 mg/dl (non-inferiority). The co-primary outcomes will be assessed in the last 14 days of the relevant study phase. Screening Visit (visit 1): • Participants will have a screening visit to confirm eligibility once informed consent is obtained. • Documentation of inclusion/exclusion criteria. The participant will be interviewed, and the case report form will be completed by study staff to establish whether the participant is eligible to continue with the screening. • A medical history will be elicited from the participant and extracted from available medical records with respect to the participant’s diabetes history, current diabetes management, other past and current medical problems, past and current medications, and any known allergies. • A urine pregnancy test will be performed. If the test is positive, the volunteer will be informed of the result and the visit will be ended. • If the visit is being conducted virtually, a pregnancy test will be provided to the participant and verbal report of the result will be acceptable. • Height and weight will be measured. • If the visit is being conducted virtually, a verbal report of the participant’s weight and height will be acceptable. A scale will be provided for participants who do not already have a scale at home. • Participants who have been screened and are eligible can participate without having to be re-screened for a period of six months. The study staff should verbally confirm that there have been no health events that would make them ineligible if the interval between screening and participation is longer than 2 months. • Baseline CGM data will be collected during 14-day run-in period. Participants using a Dexcom G7 CGM system with at least 85% of sensor values in the prior 14 days weeks can skip the baseline CGM data collection. Other participants will be provided blinded Dexcom G7 sensors to wear for 14 days. The run-in CGM data collected will be used for computing the baseline CGM metrics. Study start, Phase 1. iLet initiation with standard configuration (visit 2): • Participants will be trained on the use of the iLet, setting up and using the Dexcom G7 CGM, changing faster aspart pre-filled cartridges, and placing infusion sets. Participants will receive one-on-one training on the operation of all study devices. All training on the use of study devices, recognition of failed infusion sets, and the ketone action plan will only be performed by study personnel with the appropriate training (CDE, PA, RN, NP, or MD). Both the participant and the study staff must be satisfied that the participant is comfortable with the operation of all study devices before she begins the study. Additional training sessions may be arranged as needed. Study staff may follow up with participants that need additional support before the end of their first day to confirm everything is working and the participant is comfortable. • The body weight of the participant will be documented for entry into the iLet at initiation. • A urine pregnancy test will be performed. If the test is positive, the volunteer will be informed of the result and the visit will be ended. The date of the last menstrual period will also be documented, along with usual cycle length. • The participants will place a Dexcom G7 CGM sensor if not already using one, and study staff will confirm they are doing it properly. • Study staff will supervise the setup of the insulin cartridge and infusion set. • The participant will be asked to demonstrate their competency by placing at least one practice infusion set and one site in themselves, and “teach back” to confirm they adequately understand when to replace an infusion set. Study staff will be trained that participants who have not previously used an insulin pump or this type of infusion set may need additional training. • The control algorithm will be initialized only with the participant’s weight. • If applicable, the participant’s own insulin infusion pump will be stopped and disconnected, and its infusion set will be removed. For participants using long-acting insulin prior to initiating the bionic pancreas, an MD, PA, or NP will review their medication regimen and advise them to stop taking any insulin outside of the iLet once it is started. • The target will be set at 120 mg/dL over the day and night; however, the target may be set at 130 mg/dL, at investigator discretion if the participant is using long-acting insulin or stopping oral diabetes medications to account for washout. • Study staff will verify that data streaming is working prior to the participant leaving the Diabetes Research Center. • The participants will complete study questionnaires regarding device satisfaction, diabetes distress, and quality of life. Study staff will provide supplies and review the study procedures. Check In Visits via telehealth during standard (typical) settings phase (Visits 3 & 4): Study staff will call participants at 2 days (±1 day) and 6 days (±1 day) from the start of the study phase. Phone/zoom contacts will be made according to the contact window, regardless of the day of the week. Study staff will: • Review any adverse events or device issues experienced • Answer any questions the participant may have • Review glucose control • Review study policies and procedures related to glucose management and inquire about any hypoglycemic or hyperglycemic events • Review any need for a change in the glucose target setting to maximize time in the pregnancy-specific target range (63-140 mg/dl). • Assess the participant’s ability to follow the protocol and use the device Crossover- Phase 2. iLet initiation- change to pregnancy configuration (Visit 5): • At the end of the 16-day study period, participants will return to the clinic and answer the post questionnaires for the study phase. • Study staff will review any changes in the participant’s medical history or medications to ensure continued eligibility and will document any adverse events that may have occurred since their last study visit. • Study staff will specifically ask participants if they had any infusion site or CGM sensor site reactions or other skin irritation in the past 14 days and will document any reactions. • Any changes to medications or medical history and any adverse events that may have occurred since their last study visit will be documented. • The body weight of the participants will be documented • The iLet, Dexcom CGM data, and glucose meters will be downloaded. • A urine pregnancy test will be performed. If the test is positive, the volunteer will be informed of the result and the visit will be ended. • Pregnancy-specific configuration will be enabled:The meal bolus algorithm will be adjusted to deliver 90% of the predicted meal bolus. • The initial target will be set at 110 mg/dl. Targets of 100 mg/dl and 90 mg/dl targets will also be available in the pregnancy configuration. • • • The investigator may make adjustments to maximize time in pregnancy-specific target range (63-140 mg/dl) or for safety as needed at his/her discretion. Study staff will review iLet use and procedures as detailed below. Check In Visits via telehealth during pregnancy setting phase (Visits 6, 7, 8, and 9): Study staff will call or have a video visit with participants at 2 days (±1 day), 4 days (±1 day), 6 days (±1 day), and 14 days (±2 days) from the start of the study phase. Phone/video contacts will be made according to the contact window, regardless of the day of the week. Study staff will: • Review any adverse events or device issues experienced • Answer any questions the participant may have • Review CGM data and glucose control • Review study policies and procedures related to glucose management and inquire about any hypoglycemic or hyperglycemic events • Review any need for a change in the glucose target setting or triggered meal bolus amount. • Assess the participant’s ability to follow the protocol and use the device Factory Reset- Phase 3. iLet initiation directly to pregnancy configuration (Visit 10): • At the end of the phase 2 study period, participants will return to the clinic and answer the post questionnaires for the study phase. • Study staff will review any changes in the participant’s medical history or medications to ensure continued eligibility and will document any adverse events that may have occurred since their last study visit. • Study staff will specifically ask participants if they had any infusion site or CGM sensor site reactions or other skin irritation in the past 14 days and will document any reactions. • Any changes to medications or medical history and any adverse events that may have occurred since their last study visit will be documented. • The body weight of the participants will be documented • The iLet, Dexcom CGM data, and glucose meters will be downloaded. • A urine pregnancy test will be performed. If the test is positive, the volunteer will be informed of the result and the visit will be ended. • The iLet will be factory-reset, and the control algorithm will be initialized only with the participant’s weight using the pregnancy-specific configuration. • • Pregnancy-specific configuration will be enabled: • The meal bolus algorithm will be adjusted to deliver 90% of the predicted meal bolus. • The initial target will be set at 110 mg/dl. Targets of 100 mg/dl and 90 mg/dl targets will also be available in the pregnancy configuration. • The investigator may make adjustments to maximize time in pregnancy-specific target range (63-140 mg/dl) as needed at his/her discretion. Study staff will review iLet use and procedures as detailed below. Check In Visits via telehealth during pregnancy setting phase (Visits 11, 12, 13, and 14): Study staff will call participants at 2 days (±1 day), 4 days (±1 day), 6 days (±1 day), and 14 days (±2 days) from the start of the study phase. Phone/video contacts will be made according to the contact window, regardless of the day of the week. Study staff will: • Review any adverse events or device issues experienced • Answer any questions the participant may have • Review CGM data and glucose control • Review study policies and procedures related to glucose management and inquire about any hypoglycemic or hyperglycemic events • Review any need for a change in the glucose target setting or triggered meal bolus amount. • Assess the participant’s ability to follow the protocol and use the device Final Visit (Visit 15): • At the end of the 16-day (+2 day) phase 3 period, participants will return to the research center and answer the post questionnaires for the study phase. • Study staff will review any changes in the participant’s medical history or medications to ensure continued eligibility and will document any adverse events that may have occurred since their last study visit. • Study staff will specifically ask participants if they had any infusion site or CGM sensor site reactions or other skin irritation in the past 28 days and will document any reactions. • Any changes to medications or medical history and any adverse events that may have occurred since their last study visit will be documented. • The body weight of the participants will be documented • The iLet, glucose meters, and Dexcom CGM data will be downloaded. • The Dexcom CGM sensor and all iLet infusion sites will be removed. • A provider (MD, PA, or NP) will review the last several hours of insulin dosing and assist the participant in resuming their usual care. TABLE OF PROCEDURES Visit Procedures Screening (Visit 1) Study Start (Visit 2) Check In Call (Visit 3) Check In Call 2 (Visit 4) Crossover (Visit 5) Check In Call 3 (Visit 6) Check In Call 4 (Visit 7) Check In Call 5 (Visit 8) Factory Reset (Visit 9) Check In Call 7 (Visit 10) Check In Call 8 (Visit 11) Check In Call 9 (Visit 12) Final (Visit 13) Days from start visit (window): 0 2 (±1) 6 (±1) 16* (+2) 18# (±1) 20# (±1) 22# (±1) 32* (+2) 34# (±1) 36# (±1) 38# (±1) 48# (+2) Informed Consent X Eligibility Assessment (includes medical history) X Height X Weight X X X X X Urine pregnancy test X X3 X1 X1 Adverse Event querying (includes glucose control) X X X X X X X X X X X X Psychosocial questionnaires5 X X X X Blinded CGM sensor placement2 X X4 iLet initiation, standard configuration X iLet initiation, pregnancy configuration X X Data download X X X iLet removal, transition to usual care X * visit may be split into separate shutdown and start up visit; start up visit must occur within 14 days of shutdown visit # may differ based on length of window between study phases 1 if separate startup visit occurs 14 days after shutdown visit 2 Run-inCGM for 14 days will be collected in those not using a Dexcom G7 CGM and who do not have 85% of CGM data available over the preceding 14 days 3 Includes documentation of last menstrual cycle 4 participants will place a Dexcom G7 CGM sensor if not already using one, and study staff will confirm they are doing it properly. 5 patient reported outcome questionnaires include: Diabetes Distress Scale (DDS), Hypoglycemia Fear Survey (HFS), Hypoglycemia Confidence Scale (HCS), INSPIRE Survey, Perceived Benefits and Burdens of AID, and Hyperglycemia Avoidance Scale 6.b. iLet use and procedures wear period: Glucose evaluation and management • Study participants will keep their study issued Contour Next One glucometer easily accessible at all times in case a calibration is needed, and they will do all calibrations with this meter. They will keep a glucometer, fast-acting carbohydrates, and a glucagon emergency kit easily accessible. • Participants are encouraged to check their BG as often as they wish to confirm the accuracy of the Dexcom CGM and for safety. However, they should use the study provided glucose meter for all checks. Restrictions • Participants may not take hydroxyurea during the study due to potential interference with CGM sensing. Hydroxyurea is known to interfere with the accuracy of the Dexcom CGM. • Participants are not allowed to exceed the maximum daily doses of acetaminophen from all sources during the study due to potential interference with the Dexcom CGM. • Adult: 1 g every 6 hours, up to 4 g every 24 hours • The iLet must be kept dry during exercise. • Participants will be asked to refrain from alcohol consumption during the entire study • Participants will be instructed not tamper with the iLet device in any way, including changing any settings. Any settings change will occur under the guidance of the study team. Patient Care • Any medical advice needed by the participants during their participation, which is not directly related to BG control during the experiment, should be obtained by them in the usual manner with their personal health care provider. • If a participant develops an illness during the experiment, they can seek medical care as usual. As long as the participant is not hospitalized, the study can be continued. If the participant is unable to eat for a period exceeding one day, they must notify study staff so that the medical staff can assess the safety of continuing in the study. • If a participant requires hospitalization during the experiment, they will discontinue the experiment and their participation in that study phase will end. The data collected up to their admission will not be used for the primary glycemic analysis but will be used in safety analyses. The participant can repeat the study phase 2 weeks after discharge. iLet Specific Instruction • During the study, the iLet will be worn by the participant at all times to ensure good radio-frequency signal reception. • The iLet is not water resistant and therefore must be removed for showering. Participants are urged to take appropriate precautions when they are disconnected from the iLet, including frequent BG checks and having carbohydrate readily available. • The Dexcom CGM transmitter is water resistant and can be left on for bathing and swimming. • Participants may not remove the iLet for more than 1 hour at a time (e.g. for bathing) and may not remove it for more than 2 hours total in any 24 hour period. • Participants will keep their study issued Precision Xtra ketone meter, extra infusion sets and insulin cartridges easily accessible at all time. • Participants will be required to check their ketone levels whenever their CGM has been above 300 mg/dl for 90 minutes or if glucose is above 400mg once and to notify study staff if the result is ≥ 0.6 mmol/l. • Participants will keep their iLet charged, which will require charging at least once per day. • Participants will be asked to change their insulin infusion set and reservoir at least every 3 days during every arm in the study. • Participants will be taught to replace their infusion set if there is any doubt that it may not be working. They will be taught how to recognize potential infusion set failures. • Participants will be taught to replace their infusion set if their ketones are ≥ 0.6 mmol/l. • Participants will be asked to announce the three major meals of the day, but not small or low carb snacks, to the iLet. The meal announcement will consist of choosing the type of meal (breakfast, lunch, dinner) and the size of the meal relative to typical meals for that participant (Usual for me, more than or less than usual). If participants eat snacks of similar size as a small meal, they will be instructed to announce the snack as a meal according to the closest meal-type. • The iLet will generate the following CGM glucose related alarms to the participant: • Urgent Low Glucose: ≤55 mg/dl • Low Glucose: ≤70 mg/dl • Fall Rate Alert: CGM glucose <100 mg/dl and CGM trend is dropping more than 2 mg/dl/min • High Glucose: ≥300 mg/dl for 90 minutes • Participants will be trained in recognizing and responding to all of these alarms. • Low Glucose Alarm: Participants will be trained on troubleshooting for various scenarios that could lead to a low glucose alarm. For instance, a threshold alarm could be due to true hypoglycemia, poor Dexcom CGM calibration, or a compression artifact at the site of the sensor. • The first step for all low glucose-related alarms will be to perform a fingerstick BG measurement. • If the BG measurement is not consistent with the fact that a threshold alarm has occurred: the participant will assess the possibility of a compression artifact (they will be trained in the causes and recognition of these events). If a compression artifact is suspected, they will take steps to relieve the pressure on the transmitter. If compression is not suspected, they will calibrate the Dexcom CGM as long as there has been no food or carbohydrate intake in the last 30 minutes. If a calibration is delayed for this reason, it will be performed at the next opportunity if it is still necessary. • If the BG measurement is consistent with a low threshold alarm: the participant will treat hypoglycemia with carbohydrate ingestion according to their usual practice. Participants will be instructed to consider using less carbohydrate to treat or prevent hypoglycemia, since due to insulin suspension 5-10 grams is often sufficient and is less likely to lead to hyperglycemia. • Hyperglycemia Alarm: Participants will be trained on troubleshooting for various scenarios that could lead to hyperglycemia. For instance, hyperglycemia could be due to true hyperglycemia or poor Dexcom CGM calibration. • The first step in responding to hyperglycemia according to the CGM will be to perform fingerstick BG and ketone measurements. • If the BG measurement is not consistent with the CGM glucose: the participant will calibrate the Dexcom CGM as long as there has been no carbohydrate intake in the last 30 minutes and there is no steep rise or fall in glucose (>2 mg/dl/min). If a calibration is delayed for this reason, it will be performed at the next opportunity if it is still necessary. The participant will be taught to continue to monitor CGM and BG measurements to confirm accuracy and normoglycemia. • If the BG measurement is consistent with the CGM glucose: • The participant will be asked to investigate their insulin infusion site and consider replacing it, check for any occlusions along the fluid path, and check to make sure that the cartridge is not empty. • Study staff will recommend the participant continue to monitor their BG until it returns to normoglycemia, and to contact study staff with any questions or concerns. • If ketones ≥ 0.6 mmol/l are present: • Participants will be advised to change their insulin infusion set and will be reminded that the BP should dose insulin accordingly. • Study staff will recommend the participant continue to monitor their ketone levels and BG every 60-90 minutes until ketones return to < 0.6 mmol/l and BG is < 180 mg/dl, and to contact study staff with any questions or concerns. • If participants experience persistent hyperglycemia lasting more than 2 hours, they will be instructed to contact study staff for consideration of infusion set replacement and/or correction insulin according to the above protocol. • If total insulin dosing exceeds 160 units/day (the capacity of the insulin cartridge) such that the participant is having to change the cartridge and infusion set more frequently than once a day and/or if the participant is having persistent hyperglycemia above target lasting more than 48 hours, a protocol for administering supplemental basal insulin with subcutaneous long-acting insulin will be considered as follows: • First, confirm the following: • the participant is consistently announcing meals, and the majority of the meals are being announced as “Usual for me”. • the meal doses for all meal types (e.g., “Breakfast”, “Lunch”, and “Dinner”) has successfully adapted. • the glucose target has been progressively reduced to “Lower” (110 mg/dL in the usual settings arm, 90 mg/dL in the pregnancy settings arm). • The goal for the recommended approach to long-acting insulin dose adjustment is to provide only a fraction of the basal insulin need. If too much long-acting insulin is added, suspension of insulin delivery by the iLet control algorithm may not be effective in preventing hypoglycemia. • An appropriate range for the long-acting insulin dose may be chosen by determining the Total Daily Basal administered by the iLet (available in the History menu under “Insulin History” on the iLet, and also in the Bionic Report on the web portal) and selecting a starting dose of long-acting insulin that is one-half of the “Total Daily Basal” administered by the iLet. The ratio of basal to bolus insulin may be modified per investigator discretion. • To adjust the dose of long-acting insulin after initiation, it is recommended that half of the updated “Total Daily Basal” administered by the iLet be added to the amount of long-acting insulin given daily, modified as needed based on the investigator’s discretion. • Dexcom CGM Bluetooth connection interruption: Participants will receive alerts if Dexcom CGM Bluetooth connection is interrupted for more than 2 hours. • If the Dexcom sensor has been lost, it will be replaced. • If a Dexcom CGM sensor fails during the course of an experiment the system will provide basal insulin based on past requirements and will allow announcement of meals and entry of fingerstick BG measurements, which will be treated as Dexcom CGM data and may result in administration of insulin. The Dexcom CGM sensor will be replaced as soon as possible and normal iLet control will resume when the new sensor is online • If there is a complete failure of iLet operation and it is anticipated that restarting it will take more than an hour, participants may take over their own BG control using their pre-study mode of diabetes management or with insulin injections until the iLet can be brought back online. • If necessary, a staff member will meet the participant to assist with troubleshooting. This meeting may be delayed until morning if the problem occurs overnight - in this case, the participant will use their own pump or injections until a meeting is possible. • If necessary, the iLet device may be replaced. If the failure occurs at night, every effort should be made to correct the problem as soon as possible, which should almost always be possible within 12 hours. General instruction • Participants may participate in any activities that they wish, as long as they abide by the policies above. • There are no restrictions of any kind on diet or exercise, although participants should attempt to maintain similar dietary habits and exercise habits during the study. The iLet must be kept dry during exercise. • Participants may choose to withdraw from the study at any time. If they withdraw from the study, they should contact a provider immediately. If they are wearing the iLet, a provider will help them transition to their own diabetes regimen safely. • Participants will be asked to report symptomatic hypoglycemia, carbohydrate interventions, any other adverse events, time spent exercising, any unscheduled infusion set changes at each study visit. • Participants will be instructed not tamper with the iLet device in any way, including changing any settings. Any settings change will occur under the guidance of the study team. • Response to Hypoglycemia • Participants in all study arms are encouraged to check their BG for any symptoms of hypoglycemia and in response to any CGM alarms. • While using the iLet bionic pancreas, participants will be instructed to consider using less carbohydrate to treat or prevent hypoglycemia, since due to insulin suspension 5-10 grams is often sufficient and is less likely to lead to hyperglycemia. • If a participant experiences a seizure or unconsciousness associated with hypoglycemia the PI will make a determination regarding whether it will be safe to allow them to continue in the study. A participant using the iLet bionic pancreas when they experienced severe hypoglycemia will suspend use of the device until a determination is made about the safety of having them continue. • If the PI concludes that the event is explainable and unlikely to recur, the participant will be allowed to continue to use the system. Further study participation of an individual participant will be discontinued if they experience more than one episode of DKA requiring hospitalization, more than one episode of seizure or unconsciousness associated with hypoglycemia, or one of each. • Response to Hyperglycemia • Participants will be asked to check ketones whenever CGM glucose is > 300 mg/dl for 90 minutes, > 400 mg/dl once, or with symptoms of diabetic ketoacidosis. • Participants will be instructed to check their insulin infusion site and their pump or bionic pancreas for normal operation any time they experience hyperglycemia. If there is any suspicion of insulin infusion set malfunction, the site should be replaced. Participants will be taught how to recognize if an infusion set might be failing and need replacement, including recognizing that the sensor glucose is rising or not falling despite sufficient insulin being pumped by the iLet, that the sensor glucose is >300 mg/dl for more than 90 minutes, or that the sensor glucose is >400 mg/dl. • It will be emphasized in participant training to have a low threshold of suspicion to changing out the infusion set, “when in doubt, change it out.” Participants will be told that sufficient supplies are available so that they should not hesitate to change out the infusion set if they have any doubt that it is working well. • Participants may contact a study provider (MD, PA, or NP) for advice at any time, and may contact the troubleshooting support team, as they wish. They will be assisted in checking the bionic pancreas for any malfunction and correcting and problems that are found. • If no correctable fault is found, but there is doubt regarding the correct function of the bionic pancreas system, an entirely new backup bionic pancreas system may be brought to the participant’s location by study staff. • If a participant experiences DKA or HHS requiring hospitalization, the PI will make a determination regarding whether it will be safe to allow them to continue in the study. A participant using the bionic pancreas when they experienced DKA or HHS will suspend use of the device until a determination is made about the safety of having them continue. • If the PI concludes that the event is explainable and unlikely to recur, the participant will be allowed to continue to use the system. Further study participation of an individual participant will be discontinued if they experience more than one episode of DKA or HHS requiring hospitalization, more than one episode of seizure or unconsciousness associated with hypoglycemia, or one of each. Response to Other Medical Needs If the participant experiences any non-emergent medical concerns outside the scope of diabetes care, he or she will see their personal physician. If the participant experiences urgent or emergent medical concerns outside the scope of diabetes care and their primary care physicians, they should visit a walk-in clinic or emergency room, or if necessary, call 911. Monitoring of Bionic Pancreas Performance Beta Bionics customer support will be readily available by phone for consultation at all times during the course of the study. Supervision by Study Staff A study provider (MD, PA, or NP) will be on call at all times during the course of each study phase. All device training will be performed by study personnel with the appropriate training and experience, such as a Certified Diabetes Educator, Physician’s Assistant, Registered Nurse, Nurse Practitioner, or Physician. Study staff will emphasize to participants that they must carefully follow study policies, including the ketone action plan, for their safety. They will be instructed to call study staff whenever indicated or needed, regardless of the hour. Study staff will be trained that if a participant calls and is found to be in Zone 2 of the Ketone Action Plan or has a plasma glucose <54 mg/dl, they must speak directly to a Certified Diabetes Educator, Physician’s Assistant, Registered Nurse, Nurse Practitioner, or Physician. If a participant calls and is in Zone 3 of the Ketone Action Plan or has had a severe hypoglycemic event requiring assistance from another person, either the participant or someone with them and assisting them must speak directly to a Physician’s Assistant, Registered Nurse, Nurse Practitioner, or Physician. Whenever a participant contacts with hyperglycemia and is in Zone 2 or Zone 3 of the ketone action plan or has a glucose <54 mg/dl, study staff with the appropriate training and experience (Certified Diabetes Educator, Physician’s Assistant, Registered Nurse, Nurse Practitioner, or Physician) must attempt to ascertain whether the participant has the capacity to care adequately for themselves with guidance. If based on their experience and judgement they believe the participant may not be adequately able to care for themselves without assistance, then they must either directly communicate with someone on the scene who they judge to have that capacity, or call 911, or both. If based on their experience and judgment study staff believes that the participant needs emergency care, they should recommend to the participant that they go to an emergency department. Study staff should determine which emergency department the participant will be taken to and follow up within 15 minutes of the expected arrival time to make sure they have arrived. If the study staff calls 911 they should remain on the telephone with the participant until the ambulance arrives and speak to the Emergency Medical Technicians to provide history and determine where the participant will be taken. Whenever a participant is sent to the emergency department, study staff must confirm that the participant has arrived at ED within an hour, and study staff member should speak with a member of the medical staff at the emergency department to confirm arrival and provide information about the reason for referral to the ED. If a participant cannot be reached and there is concern for their wellbeing (e.g. if their Clarity data shows hypoglycemia or severe hyperglycemia) then study staff should attempt to reach close contacts. If no contacts are available or their contacts do not succeed in reaching them quickly, then 911 should be called and a well-being check should be requested. Study staff must follow up on and document the results of the well-being check. 6.c. Study Materials: Study Drug: The study involves subcutaneous administration of faster-acting insulin aspart (Fiasp, Novo Nordisk) supplied in a pre-filled cartridge for use with the iLet. These cartridges are commercially available by prescription and are indicated for adult and pediatric patients with diabetes. Study devices: Continuous glucose monitor: The Dexcom G7 will be used with the iLet in each study phase. One transcutaneous glucose sensor for the Dexcom CGM will be inserted in the subcutaneous tissue. The Dexcom CGM will provide input to the iLet and be used to collect data on the primary outcome. The sensor is powered by the battery within the transmitter that clips to the sensor. The whole assembly is held to the skin with an adhesive patch and communicates wirelessly via Bluetooth Low Energy with iLet. If the sensor fails for any reason during the experiment, it will be replaced promptly. A blinded version of the device in which glucose values are masked, will be used during the run-in for participants who do not typically wear a Dexcom CGM. iLet Bionic Pancreas: The iLet system receives the same CGM glucose values from the Dexcom transmitter worn on the body. The iLet has an integrated graphical user interface (GUI) and touchscreen display that displays the current CGM glucose, a graphical history of the CGM glucose, and doses of insulin delivered by the control algorithm. The GUI can also be used to input optional meal announcements, designating the type of meal as Breakfast, Lunch, or Dinner, and the size of the meal as Usual for Me, More, or Less. This will trigger a partial meal-priming bolus, the size of which will adapt throughout the course of the trial to meet a target of 75% of the insulin needs for that size and mealtime in its typical settings. With study-specific pregnancy settings, the meal-priming bolus amount will be adjusted to meet a target of 90% of the insulin needs for a meal type and size. The factory-set Usual glucose target level for the iLet in its typical settings is 120 mg/dl. In the iLet’s typical settings, the glucose target can be changed by the user to be Lower (110 mg/dl) or Higher (130 mg/dl) target. During the pregnancy settings phase, two additional targets will be available: 100 mg/dl and 90 mg/dl. The target adjustment can be done on a permanent basis, or for a recurring overnight period. Participants will be trained not to change the study specific programmed target without consulting with the study team. At the initiation of the pregnancy setting phases, the targets will be set at 110 mg/dl. During allphases, a change in the study specific programmed target will be made based on the judgement of the investigator based on prespecified parameters. For example, the permanent target may be lowered after 48 hours if the percent time above 140 mg/dl is >25% and there is minimal hypoglycemia (% time <54 mg/dl is <1% and there is minimal need for carbohydrate treatment for hypoglycemia). Similarly, the permanent target may be raised in an individual participant if there is excessive hypoglycemia (% time <54 mg/dl is >1% or there is frequent need for carbohydrate treatment for hypoglycemia). In addition, during the pregnancy settings phase, the meal bolus may be changed back to 75% of the triggered bolus amount if post-prandial hypoglycemia is noted. This is consistent with the intended clinical use of the iLet, in which a health care provider will consult with the user on the appropriate target. The iLet will be configured to use the default tmax setting, 65 minutes, for all participants regardless of the type of insulin used and will not be adjusted during the study. During periods when the Dexcom CGM is offline, such as the period after a sensor is replaced and before the new sensor has been calibrated, the GUI can be used to manage meal boluses as usual and will administer correction boluses in response to entered BG values, During these times the control algorithm will determine and direct the administration of insulin basal rates either based on the participant's weight early in the course of the experiment, or on the average of adaptively determined basal rates for that time of day once sufficient experience has been accumulated (i.e. 24 hours or more) by the control algorithm. The controller will also administer insulin in response to any entered BG values just as if they were Dexcom CGM values. The device also displays visual alarms, sounds audible alarms, and generates vibration alarms for problems with the functioning of the iLet. iLet Infusion Set: While using the iLet, participants will be provided with iLet infusion sets for the system. Study staff will work with the participants to ensure they are properly inserting the infusion set and will help them troubleshoot if problems related to the infusion set arise. Participants will be instructed to replace their infusion set as needed when it fails (or is suspected of failing) or falls out, or at least every 3 days. Participants may need to replace the infusion set sooner depending on their insulin needs, as an infusion set change is required when starting a new insulin cartridge. Ascensia Diabetes Care Contour Next One Glucose Meter: The Contour Next One glucometer is FDA approved and commercially available. Blood glucose measurements for Dexcom CGM calibrations and other required BG measurements will be obtained via finger stick with the Contour Next One in both study arms. Abbott Precision Xtra Ketone Meter: The Precision Xtra is FDA approved and commercially available. Blood ketone measurements for hyperglycemia management will be obtained via finger stick with the Precision Xtra ketone meter in the iLet arm. Resources for participants: • A study staff member will be on-call at all times to answer any questions relating to study protocol and assist with troubleshooting any issues they may arise. • Participants will be referred to their own medical providers for issues not directly related to the study and to local Emergency Medical Services for medical emergencies.If there is a technical problem with the iLet that cannot be resolved over the phone, the participant may be asked to come to the local study site or the study staff may meet them at another location. If this is not possible or would be too disruptive (i.e. in the middle of the night) the participant will be asked to take over his/her own glycemic control using his/her insulin pump (if on CSII), by giving subcutaneous insulin injections (if on MDI), or reverting to pre-study diabetes management until such time as a meeting can be arranged for in-person inspection of the device. This should occur within 12 hours. Sources of materials Data and material collected at baseline: • Age • Sex • Race and ethnicity • Socioeconomic status indicators • Date of last menstrual period • Date of diabetes diagnosis • Medical, surgical, and social history, allergies, and review of systems relevant to inclusion and exclusion criteria • Medications (prescription and non-prescription) • Diabetes medication regimen (including type of insulin and/or pump used and duration of injections or pump use) and other non-insulin diabetes medications • Average total daily dose of insulin in the last 30 days–for comparison with insulin dosing during both arms of the study • Usage of CGM, if any (type of CGM, days per month worn, usage of data, whether insulin is dosed based on CGM alone, alarm settings) • Height and weight • Urine HCG Data and material collected while on the iLet study device (both phases): • CGM glucose every five minutes • All fingerstick BG measurements taken by the participant (meter download) • Information collected from email surveys on hypoglycemia, carbohydrate interventions, local skin reactions at infusion site, any unscheduled infusion set changes or CGM sensor changes, any other adverse events. • Insulin total daily dose (from the iLet) • Timing of meal announcements and size of meals announced • Body weight at the beginning and end of each phase • Time participants were not under iLet control during each phase • Time without CGM monitoring data during each phase • List of technical faults associated with the iLet including cause and resolution • Log of all scheduled and non-scheduled contacts with participants • Date of last menstrual period at the beginning and end of each phase • Data from questionnaires about treatment satisfaction, diabetes-related distress, fear of hypoglycemia, impact of diabetes-related demands, and attitudes and expectations regarding the iLet at the beginning of the study and at the end of each phase Brief description of questionnaires: 1. Diabetes Distress Scale (DDS): The DDS is a 28-item survey that assesses seven sources of diabetes distress for adults with T1D. It captures feelings of powerlessness; management distress; hypoglycemia distress; negative social perceptions by others; eating distress; physician (health care) distress; and friend/family distress. Items are scored on a 6-point scale from not a problem to a very serious problem. It is administered before, during, and at the end of the intervention. The scale is valid and reliable and has been shown to be sensitive to change over time. Administration time is 5 minutes. 2. Hypoglycemia Fear Survey (HFS): HFS measures several dimensions of fear of hypoglycemia among adults with type 1 diabetes. It consists of 23 items and produces two sub-scale scores; a Behavior sub-scale that measures behaviors involved in avoidance and/or over-treatment of hypoglycemia and a Worry sub-scale that measures anxiety and fear surrounding hypoglycemia. The HFS-Y consists of 25 items and the HFS-P consists of 26 items; both produce sub-scale scores similar to the Adult HFS. It is administered before, during, and at the end of the intervention. All versions of the HFS are valid and reliable. Administration time is 5-10 minutes. 3. Hypoglycemia Confidence Scale (HCS): The HCS (20) is a 9-item self-report scale that examines the degree to which people with diabetes feel able, secure, and comfortable regarding their ability to stay safe from hypoglycemic-related problems. It has been validated for use in adults with type 1 diabetes and insulin-using type 2 diabetes. Administration time is approximately 5 minutes. • 4. Hyperglycemia Avoidance Scale54: This is a 22-item instrument that assesses anxiety related to high blood sugars and avoidance behaviors. The tool is divided into 4 subscales (immediate action, worry, low blood glucose preference, and avoid extremes). Certain subscales are predictive of severe hypoglycemia, driving mishaps, and higher hemoglobin A1c levels. Administration time is 5-10 minutes. 5. INSPIRE Survey: There are five versions of the INSPIRE. We will administer the Adult version. The INSPIRE (Insulin Delivery Systems: Perceptions, Ideas, Reflections and Expectations) survey was developed to assess various aspects of a user’s experience regarding automated insulin delivery for both patients and family members. The surveys include various topics important to patients with type 1 diabetes and their family members based upon >200 hours of qualitative interviews and focus groups. The adult survey includes 31 items. Response options include a 5-point Likert scale from strongly agree to strongly disagree, along with an N/A option. Administration time is approximately 5 minutes. 6. Perceived Benefits and Burdens of AID: This is a 38-item measure that assesses both the benefits from, and difficulties with, use of the BPA total score is generated. Administration time is 10 minutes. 6.c. Remuneration Financial compensation will be provided to all participants who complete the screening visit. Participants will be paid $25 for completing the screening visit whether or not they are eligible to participate in the study. Study participants will be compensated $75 for completing each of the 4 study visits (study start, crossover, factory reset, and final; $300 total) and $30 each for completing the 10 check-in calls ($300 total). Participants will also be compensated $25 for completing the questionnaires after the study start visit and both crossover visits, as well as $50 for completion of the questionnaires at the final study visit ($125 total). The total compensation for a participant who completes the entire study, and all procedures would be $725. Compensation will be paid to participants for all procedures completed; any procedures not completed will not be compensated, including for early study discontinuation. • Risks and Discomforts Risks are detailed below. Loss of confidentiality is a potential risk; however, data are handled to minimize this risk. Hypoglycemia, hyperglycemia and ketone formation are always a risk in participants with diabetes using insulin, and participants will be monitored for this. Potential Risks of the BP Even though the BP has been extensively tested prior to this study, there is still a risk that parts of the system may not function properly. The following are possible reasons the system may deliver too much insulin or incorrectly stop insulin delivery: • CGM sensor reads higher or lower than the actual glucose level which increases risk for hypoglycemia and hyperglycemia with automated insulin delivery system; • Device malfunctions that could produce a suspension of insulin delivery or over delivery of insulin. Risk of Hypoglycemia. As with any person having diabetes and using insulin, there is always a risk of hypoglycemia. All of the previous studies in adults with type 1 and type 2 diabetes have shown that hypoglycemia is similar in the typical insulin-only configuration of the bionic pancreas when compared with usual care. However, the risk of hypoglycemia may be greater during the pregnancy-specific configuration arm due to the lower targets and greater triggered meal bolus delivered in order to maximize percent time spent in pregnancy-specific target 63-140 mg/dL. Participants will be counseled about that the risk of hypoglycemia may be greater during the study due to changing the target glucose range to 63-140 mg/dl and the corresponding changes to the iLet configuration used to attain these targets. Symptoms of hypoglycemia can include sweating, jitteriness, and not feeling well. There is the possibility of fainting or seizures (convulsions) and that for a few days the participant may not be as aware of symptoms of hypoglycemia. A CGM functioning poorly and significantly over-reading glucose values could lead to inappropriate insulin delivery. Risk of Hyperglycemia Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an extended period or if the pump or infusion set is not working properly. If there is a prolonged period of time without insulin, it is possible that diabetic ketoacidosis (DKA) could occur in susceptible patients. Extreme levels of hyperglycemia and dehydration can lead to hyperosmolar hyperglycemic syndrome (HHS). A CGM functioning poorly and significantly under-reading glucose values could lead to inappropriate suspension of insulin delivery. Participants using the BP will be issued a ketone meter and ketone test strips to use to carefully monitor for ketosis and be given instructions on how to mitigate hyperglycemia and ketosis should it occur. Fingerstick Risks About 1 drop of blood will be removed by fingerstick for measuring blood glucose and ketones. This is a standard method used to obtain blood for routine laboratory tests. Pain is common at the time of lancing. In about 1 in 10 cases, a small amount of bleeding under the skin will produce a bruise. A small scar may persist for several weeks. The risk of local infection is less than 1 in 1000. This should not be a significant contributor to risks in this study as fingersticks are part of the usual care for people with diabetes. Questionnaires As part of the study, participants will complete questionnaires which include questions about their private attitudes, feelings and behavior related to use of the BP as well as managing diabetes It is possible that some people may find these questionnaires to be mildly upsetting. Similar questionnaires have been used in previous research and these types of reactions have been uncommon. Other Risks Some participants may develop skin irritation or allergic reactions to the adhesives used to secure the CGM, or from tape to secure the insulin infusion sets for the continuous subcutaneous insulin infusion. If these reactions occur, different adhesives or “under-taping” (such as with IV 3000, Tegaderm, etc.) will be tried, sites will be rotated frequently, and a mild topical steroid cream or other medication may be required. Data downloaded from the CGM, pump, and the home glucose and ketone meter will be collected for the study as measures of diabetes self-management behaviors. Downloaded data from the participant’s personal CGM or pump (if any) will include data from prior to the date of the screening visit. Some participants may be uncomfortable with the researchers’ having such detailed information about their daily diabetes habits. • Benefits During both study phases, participants may potentially benefit from better glycemic control. In addition, participants enrolled in this study may benefit from this technology if they become pregnant in the future. It is possible that an individual participant may not benefit from study participation. It is expected that this protocol will yield increased knowledge about using an automated closed-loop to control the glucose levels during pregnancy. This research is a critical step on the path towards development of an automated insulin delivery device that can be used in pregnant individuals with T1D and T2D. Risk Assessment Based on the facts that (1) adults with diabetes experience mild hypoglycemia and hyperglycemia frequently as a consequence of the disease and its management, (2) the study intervention involves periodic automated insulin dosing that may increase the likelihood of hypoglycemia, and periodic automated attenuation of insulin delivery that may increase the likelihood of hyperglycemia, (3) mitigations are in place, and have been tested in prior studies using the investigational device system in the home setting, that limit the likelihood of excessive insulin dosing or prolonged withdrawal of insulin, and (4) rapid reversal of hypoglycemia and hyperglycemia can be achieved, it is the assessment of the investigators that this protocol falls under 21 CFR 50.52 which is a clinical investigation that involves greater than minimal risk but presents the prospect of direct benefit to individual subjects. The protocol is considered a significant risk device study, due to the fact that the BP is not approved for use with the specific pregnancy configuration that is being studied and is also not approved for use in people with T2D. Therefore, an IDE approval from the FDA is required to conduct the study. • Statistical Analysis Outcomes: Co-primary outcomes55: Pregnancy-specific time in range (63-140 mg/dL) (%, superiority) and time below < 54 mg/dL (%, non-inferiority), ascertained during days 3-16 of the usual configuration period and days 14-28 of the phase 2 pregnancy configuration period. Glycemic secondary outcomes55: >70% pregnancy-specific time in range (63-140) mg/dl (binary), <1% time below 54 mg/dL (binary), <4% time below 63 mg/dL (binary), >25% above 140 mg/dL (binary); time below 63 mg/dL (%), time above 140 mg/dL (%), time above 180 mg/dL (%), time above 250 mg/dL (%); standard deviation (SD, mg/dL); coefficient of variation (CV, %); symptomatic hypoglycemia (binary), hypoglycemia requiring carbohydrate treatment (binary). Mean fasting blood glucose (mg/dL), mean 1-hour postprandial blood glucose (mg/dL), mean 2-hour postprandial blood glucose (mg/dL), as assessed using CGM data and iLet meal announcement timing. Glycemic outcome data will be ascertained on days 3-16 of the usual configuration treatment period and days 3-16 of the pregnancy configuration treatment period using CGM (except for symptomatic hypoglycemia and hypoglycemia requiring carbohydrate treatment, which will be assessed via participant survey). Secondary outcomes will also include all of the above co-primary and secondary glycemic metrics in phase 3. Device-related secondary outcomes: Daytime target at the end of each pregnancy-specific configuration period (90, 100, 110, 120, or 130 mg/dL), overnight target at the end of each pregnancy-specific configuration period, use of the 90% predicted meal bolus at the end of each pregnancy-specific configuration period (binary). Insulin total daily dose (units and units/kg), daily basal dose (units, units/kg body weight, % of total), daily bolus dose (units, units/kg body weight, and % of total), number of meal announcements per day in each treatment period. Outcomes will be reported separately for T1D and T2D. Patient reported outcomes: Satisfaction with insulin delivery (Insulin Device Satisfaction Survey56), diabetes distress (Diabetes Distress Scale57), fear of hypoglycemia (Hypoglycemia Fear Survey-II58, Hypoglycemia Confidence Scale59), hyperglycemia avoidance (Hyperglycemia Avoidance Scale)54, attitude toward AID therapy (Insulin Delivery Systems: Perceptions, Ideas, Reflections and Expectations [INSPIRE]60), subjective well-being (World Health Organization Well-Being Index61) at the end of each treatment period. Acceptability of the iLet (Bionic Pancreas User Opinion Survey62) at the final study visit. Safety Outcomes: Severe hypoglycemia (defined as hypoglycemia that required assistance of another person due to altered consciousness and required the other person to actively administer carbohydrate, glucagon, or other resuscitative actions), diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), sustained hyperglycemia (defined as average glucose ≥ 160 mg/dl measured over a 7-day period without an improving trajectory). Safety outcomes will be ascertained over entire treatment period. Statistical Analysis Glycemic data from days 3-16 in the usual iLet configuration treatment period (phase 1) and days 3-16 in the phase 2 pregnancy-specific iLet configuration treatment period will be included in the primary analyses. Participants with T1D and T2D will be analyzed together and descriptive exploratory analyses will be conducted in each type separately. The paired t-test will be used to assess whether outcomes differ by configuration. A gating procedure for hypothesis testing of hierarchical co-primary outcomes will be used. For the co-primary outcome of pregnancy-specific time in range (63-140 mg/dl), a significance threshold of 0.05 will be used for superiority testing. If there is a significant difference in pregnancy-specific time in range (63-140 mg/dl) between treatment groups, we will evaluate the co-primary outcome of time below 54 mg/dL using one- sided non-inferiority testing at a significance level of 0.05. If no significant difference in pregnancy-specific time in range (63-140 mg/dl) is detected, time below 54 mg/dl will be treated as a secondary outcome. Differences between the comparison groups in continuous secondary outcomes, as well as co-primary and secondary glycemic metrics in phase 3 compared to phase 1 will be reported with point effect estimates and 95% confidence intervals. The confidence intervals between phase 3 and phase 2 will also be compared. Binary secondary outcomes, including safety outcomes, will be compared between each study treatment using the exact McNemar test. Multinomial Generalized Estimating Equation (GEE) models will be used in the analysis of categorical secondary outcomes with more than 2 categories.63 Power and sample size We will enroll 20 participants (N=10 with T1D and N=10 with T2D) and analyze diabetes types together for the co-primary outcomes. With at least 80% of participants having outcome data (N=16), we will have 80% power to detect a difference of 10% in pregnancy-specific time in range (63-140 mg/dL) between two iLet phases (Phase 1 and Phase 2), assuming the standard deviation of this outcome is 13%.9,10 Power calculations for noninferiority testing for the co-primary outcome were performed using a simulation-based approach. For each participant, 4,032 data points were generated for each phase/arm of the study, which corresponds to 1 measurement every 5 minutes for 14 days. Hypoglycemic events were simulated where each measurement had a 1% probability of time below 54 mg/dL, as supported by previous published and preliminary data with the iLet device. For each iteration, the proportion of measurements that are below 54 mg/dL under control was subtracted from the proportion under treatment, and a 90% confidence interval was calculated for this difference. (Note that a 90% interval, not a 95% interval, was generated due to the one-sided nature of noninferiority testing.)64 If the upper limit of this confidence interval is below the noninferiority margin, then we reject the null hypothesis that the rate of hypoglycemia is higher under treatment. We repeat this procedure for 10,000 iterations. Conditional on rejecting the null hypothesis of no treatment effect for the pregnancy-specific time in range outcome, we will have >99% power to conclude one-sided noninferiority of the phase 2 pregnancy-specific iLet configuration compared to the usual iLet configuration (phase 1) for time below 54 mg/dL, with a noninferiority margin of 0.5%. This margin is based on a published clinical consensus of <1% as the goal in T1D. A narrower margin was selected for this trial (50% of the consensus goal).55 Missing data: It is anticipated that 80% of participants enrolled in the study will have sufficiently complete outcome data. For time in range, this is defined by the International Consensus on Use of CGM as having 70% of possible CGM readings for at least 70% of monitoring days.55 Currently, there are no universally accepted approaches for handling of missing CGM data in clinical trials,65 but the following approaches will be used. We will first examine participant user experience surveys to understand whether periods of missing data are likely to be missing completely at random (data loss due to device malfunction or data transfer error), missing at random (data loss is more common among certain participant demographics that are fully observed), or missing not at random (data loss during times of better or worse glycemic control, such as during hospitalization or extreme hypo/hyperglycemic events). If data appear to be plausibly missing completely at random or missing at random, then primary reporting of results will be among participants who have sufficiently complete outcome data. As a sensitivity analysis, we will use a linear interpolation procedure to address any apparent “gaps” in CGM data among all participants.66 • Monitoring and Quality Assurance 10.a Monitoring of Source Data Data will be captured on case report forms, and any original source documentation will be maintained in the participant’s study chart or medical record. During the study, Dexcom CGM data will be collected in various ways. Dexcom CGM data will be automatically stored in the bionic pancreas device (from which it will be downloaded at intervals). If the participant uses the Dexcom CLARITY app the CGM data will be wirelessly streamed for storage in the cloud, which will provide redundancy in data capture and mitigate the risk of data loss. All of the data will be combined in a single database in the MGB Institutional Lab Archives and will be compared against the primary data files for integrity. A numeric code will be substituted for the participants personal identifying information in the study database, which will be password protected. The key linking the medical record number of the participant with the numeric code, along with case report forms, and all information that is personally identifiable, will be kept in in a password protected computer database. All paper forms will be kept in a locked filing cabinet in the Diabetes Research Center, which has controlled access. All printed computer data will be disposed of confidentially when no longer needed. Only the study staff will have access to the study database. Participants may not withdraw from the de-identified database, but they may elect to have the key linking their medical record to the de-identified database destroyed. An audit of procedures, regulatory documentation, and a sample of participant files will be performed by a member of the Diabetes Research Center at least biannually. The audit will be conducted by a staff member who is not directly involved in the conduct of the study. This audit will include a review of regulatory documentation, such as IRB and FDA correspondence, and a review of participant files, including a review of consents, case report forms, and other data from study visits. The study data may be shared with collaborators at Beta Bionics, but only in a form in which all personally identifiable information has been removed. Shared data will be in the form of a database in which only a number identifies participants. Participants may not withdraw their data, as it will be stored in non-personally identifiable form. 10.b Safety Monitoring and Reporting An external Data and Safety Monitoring Board will oversee the conduct of the study and review its results on a regular basis. The DSMB will be informed if there are any changes to the study protocol that could significantly impact the safety or scientific validity of the study. Additionally, the DSMB will be informed of any severe or unexpected adverse events, including but not limited to any severe hypoglycemia or DKA, within 72 hours. A final DSMB meeting will convene after the completion of the study. Stopping Rules The participation of individual participants may be discontinued if they experience the following while utilizing the iLet bionic pancreas (study device): • Diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar state (HHS) requiring hospitalization • Seizure or unconsciousness associated with hypoglycemia In the case that a participant experiences one of the above events, the PI will make a determination regarding whether it will be safe to allow them to continue in the study. A participant using the iLet when they experienced the event will suspend use of the device until a determination is made about the safety of having them continue. If the PI concludes that the event is explainable and unlikely to recur, the participant will be allowed to continue to use the system. Further study participation of an individual participant will be discontinued if they experience more than one episode of DKA or HHS requiring hospitalization, more than one episode of seizure or unconsciousness associated with hypoglycemia, or one of each. If more than 2 participants must be withdrawn from the study for these reasons, the study will stop and a vote of the DSMB will be required to restart it. Note that participants may discontinue participation at any time and participants may be removed from the trial for other reasons, for instance failure to comply with study procedures or intercurrent illness that is unrelated to the iLet but that precludes safe participation. Discontinuation of participation for these reasons will not contribute to a decision to discontinue the trial. Adverse Events Reportable Adverse Events For this protocol, a reportable adverse event includes any untoward medical occurrence that meets one or more of the following criteria: • A serious adverse event • An Adverse Device Effect as defined below • An Adverse Event occurring in association with a study procedure • Hypoglycemia meeting the definition of severe hypoglycemia as defined below • Diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS) as defined below Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse events unless associated with an Adverse Device Effect. Skin reactions from sensor placement are only reportable if severe and/or required treatment. Pregnancy occurring during the study will be recorded. Definitions Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the relationship between the adverse event and the device(s) under investigation. Serious Adverse Event (SAE): Any untoward medical occurrence that: • Results in death. • Is life-threatening; (a non-life-threatening event which, had it been more severe, might have become life-threatening, is not necessarily considered a serious adverse event). • Requires inpatient hospitalization or prolongation of existing hospitalization. • Results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions (sight threatening). • Is a congenital anomaly or birth defect. • Is considered a significant medical event by the investigator based on medical judgment (e.g., may jeopardize the participant or may require medical/surgical intervention to prevent one of the outcomes listed above). Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of participants (21 CFR 812.3(s)). Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which the device may have caused or to which the device may have contributed (Note that an Adverse Event Form is to be completed in addition to a Device Deficiency or Issue Form). Device Complaints: A device complication or complaint is something that happens to a device or related to device performance, whereas an adverse event happens to a participant. A device complaint may occur independently from an AE, or along with an AE. An AE may occur without a device complaint or there may be an AE related to a device complaint. Device Malfunction: Any failure of a device to meet its performance specifications or otherwise perform as intended. Performance specifications include all claims made in the labeling for the device. The intended performance of a device refers to the intended use for which the device is labeled or marketed. (21 CFR 803.3) Hypoglycemic Events Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse event when the following definition for severe hypoglycemia is met: the event required assistance of another person due to altered consciousness, and required another person to actively administer carbohydrate, glucagon, or other resuscitative actions. This means that the participant was impaired cognitively to the point that he/she was unable to treat himself/herself, was unable to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or experienced seizure or coma. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. If plasma glucose measurements are not available during such an event, neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Hyperglycemic Events/Diabetic Ketoacidosis Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse event when one of the following criteria is met: (1) the event involved DKA, as defined by the Diabetes Control and Complications Trial (DCCT) and described below, or (2) in the absence of DKA if evaluation or treatment was obtained at a health care provider facility for an acute event involving hyperglycemia or ketosis. Hyperglycemic events are classified as DKA if the following are present: • Symptoms such as polyuria, polydipsia, nausea, or vomiting; • Serum ketones >1.5 mmol/L or large/moderate urine ketones; • Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and • Treatment provided in a health care facility Hyperglycemic events are classified as HHS if the following are present: • Symptoms such as polyuria, polydipsia, nausea, or vomiting; • Plasma glucose levels are very elevated (typically > 600 mg/dL); • Plasma effective osmolarity is >320 mOsm/L; • Absence of significant ketones; and • Treatment provided in a health care facility All reportable Adverse Events—whether volunteered by the participant, discovered by study personnel during questioning, or detected through physical examination, laboratory test, or other means—will be reported on an adverse event form online. Each adverse event form is reviewed by the Medical Monitor to verify the coding and the reporting that is required. Relationship of Adverse Event to Study Device The study investigator will assess the relationship of any adverse event to be related or unrelated by determining if there is a reasonable possibility that the adverse event may have been caused by the study device. To ensure consistency of adverse event causality assessments, investigators should apply the following general guideline when determining whether an adverse event is related: Yes There is a plausible temporal relationship between the onset of the adverse event and the study intervention, and the adverse event cannot be readily explained by the participant’s clinical state, intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern of response to the study intervention; and/or the adverse event abates or resolves upon discontinuation of the study intervention or dose reduction and, if applicable, reappears upon re-challenge. No Evidence exists that the adverse event has an etiology other than the study intervention (e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the adverse event has no plausible temporal relationship to study intervention. Intensity of Adverse Event The intensity of an adverse event will be rated on a three-point scale: (1) mild, (2) moderate, or (3) severe. It is emphasized that the term severe is a measure of intensity: thus a severe adverse event is not necessarily serious. For example, itching for several days may be rated as severe, but may not be clinically serious. MILD: Usually transient, requires no special treatment, and does not interfere with the participant’s daily activities. MODERATE: Usually causes a low level of inconvenience or concern to the participant and may interfere with daily activities, but is usually ameliorated by simple therapeutic measures. SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic drug therapy or other treatment. Coding of Adverse Events Adverse events will be coded using the MedDRA dictionary. Adverse events that continue after the participant’s discontinuation or completion of the study will be followed until their medical outcome is determined or until no further change in the condition is expected. Outcome of Adverse Event The outcome of each reportable adverse event will be classified by the investigator as follows: • RESOLVED – The participant recovered from the AE/SAE without sequelae. Record the AE/SAE stop date. • RESOLVED WITH SEQUELAE – The event persisted and had stabilized without change in the event anticipated. Record the AE/SAE stop date. • FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the event that was the cause of death should be reported as fatal. AEs/SAEs that were ongoing at the time of death; however, were not the cause of death, will be recorded as “resolved” at the time of death. • UNKNOWN – An unknown outcome is defined as an inability to access the participant or the participant’s records to determine the outcome (for example, a participant that was lost to follow-up). • ONGOING – An ongoing AE/SAE is defined as the event was ongoing with an undetermined outcome. An ongoing outcome will require follow-up by the site in order to determine the final outcome of the AE/SAE. The outcome of an ongoing event at the time of death that was not the cause of death, will be updated and recorded as “resolved” with the date of death recorded as the stop date. All clinically significant abnormalities of clinical laboratory measurements or adverse events occurring during the study and continuing at study termination should be followed by the participant’s physician and evaluated with additional tests (if necessary) until diagnosis of the underlying cause, or resolution. Follow-up information should be recorded on source documents. If any reported adverse events are present when a participant completes the study, or if a participant is withdrawn from the study due to an adverse event, the participant will be contacted for re-evaluation within 2 weeks. If the adverse event has not resolved, additional follow-up will be performed as appropriate. Every effort should be made by the Investigator or delegate to contact the participant until the adverse event has resolved or stabilized. Reportable Device Issues All UADEs, ADEs, device complaints, and device malfunctions will be reported irrespective of whether an adverse event occurred, except in the following circumstances. The following device issues are anticipated and will not be reported on a Device Issue Form but will reported as an Adverse Event if the criteria for AE reporting described above are met: • Component disconnections • CGM sensors lasting fewer than 7 days • CGM tape adherence issues • Pump infusion set occlusion not leading to ketosis • Battery lifespan deficiency due to inadequate charging or extensive wireless communication • Intermittent device component disconnections/communication failures not leading to system replacement • Device issues clearly addressed in the user guide manual that do not require additional troubleshooting • Skin reactions from CGM sensor placement or pump infusion set placement that don’t meet criteria for AE reporting Pregnancy Reporting If pregnancy occurs, the participant will be discontinued from the study, and the occurrence of pregnancy will be reported on an AE Form. Timing of Event Reporting Serious or unexpected device-related adverse events must be reported to the PI within 24 hours via completion of the online serious adverse event form. Other reportable adverse events and device malfunctions (with or without an adverse event) will be reported within 3 days of the investigator becoming aware of the event by completion of an electronic case report form. Device complaints not associated with device malfunction or an adverse event must be reported within 7 days of the investigator becoming aware of the event. The PI is responsible for reporting serious study-related adverse events and abiding by any other reporting requirements. Upon receipt of a UADE report, the PI will investigate the UADE and if indicated, report the results of the investigation to the IRB and the FDA within 10 working days of becoming aware of the UADE per 21CFR 812.46(b) (2). The PI must determine if the UADE presents an unreasonable risk to participants. If so, the PI must ensure that all investigations, or parts of investigations presenting that risk, are terminated as soon as possible but no later than 5 working days after the PI makes this determination and no later than 15 working days after first receipt notice of the UADE. Interim Safety Analyses The study statistician will perform an analysis of the hypoglycemia and hyperglycemia endpoints for the purpose of safety monitoring. These results with be shared with the DSMB but not with study investigators. There will not be a formal interim analysis and there will be no plans to stop the study or change sample size unless the DSMB believes that safety concerns mandate changes to the protocol. Data and Safety Monitoring Board This study will be monitored by an independent Data Safety Monitoring Board (DSMB). The DSMB will consist of 3 members: one physician specializing in diabetes in pregnancy, one physician with expertise in maternal fetal medicine/high risk obstetrics, and 1 additional member. The DSMB will be informed of all serious adverse events and any unanticipated adverse device events that occur during the study and will review compiled safety data at periodic intervals. The responsibilities of this board will include: • Review of the research protocol and any amendments, informed consent documents, and plans for data and safety analysis. • Evaluation of the progress of the study, including assessment of data quality and timeliness of data entry, participant recruitment, accrual and retention, and any other factors that may affect the successful and timely conclusion of the study. • Review of any factors external to the study, such as scientific or therapeutic developments, which may impact the safety of the subjects or the ethical continuation of the trial. • Review of interim safety analyses. • Data and Research Material Sharing • Sending Data/Materials to Research Collaborators outside Mass General Brigham The study data may be shared with collaborators outside of MGB, but only in a form in which all personally identifiable information has been removed (e.g. combined database including blood glucose values, Dexcom CGM glucose data, record of insulin and glucagon delivered by the device, logs of activity, exercise, and food, etc.). Shared data will be in the form of a database in which only a number identifies subjects. • Receiving Data/Materials from Research Collaborators outside Mass General Brigham Not applicable. • Privacy and Confidentiality ☒ Study procedures will be conducted in a private setting. ☒ Only data and/or specimens necessary for the conduct of the study will be collected. ☒ Data collected (paper and/or electronic) will be maintained in a secure location with appropriate protections such as password protection, encryption, physical security measures (locked files/areas) ☒ Specimens collected will be maintained in a secure location with appropriate protections (e.g. locked storage spaces, laboratory areas) ☒ Data and specimens will only be shared with individuals who are members of the IRB-approved research team or approved for sharing as described in this IRB protocol. ☒ Data and/or specimens requiring transportation from one location or electronic space to another will be transported only in a secure manner (e.g. encrypted files, password protection, using chain-of-custody procedures, etc.) ☒ All electronic communication with participants will comply with Mass General Brigham secure communication policies. ☒ Identifiers will be coded or removed as soon as feasible and access to files linking identifiers with coded data or specimens will be limited to the minimal necessary members of the research team required to conduct the research. ☒ All staff are trained on and will follow the Mass General Brigham policies and procedures for maintaining appropriate confidentiality of research data and specimens. ☒ The PI will ensure that all staff implement and follow any Research Information Service Office (RISO) requirements for this research. ☐ Additional privacy and/or confidentiality protections 13. 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The following characteristics describe the DMC/DSMB convened for this study (Check all that apply): ☒ The DMC/DSMB is independent from the study team and study sponsor. ☒ A process has been implemented to ensure absence of conflicts of interest by DMC/DSMB members. ☒ The DMC/DSMB has the authority to intervene on study progress in the event of safety concerns, e.g., to suspend or terminate a study if new safety concerns have been identified or need to be investigated. ☒ Describe number and types of (i.e., qualifications of) members: One physician specializing in diabetes in pregnancy, one physician with expertise maternal fetal medicine/high risk obstetrics, and 1 additional member ☒ Describe planned frequency of meetings: One meeting prior to enrollment of the first participant; one meeting after completion of half of the sample; final meeting after study completion ☒ DMC/DSMB reports with no findings (i.e., “continue without modifications”) will be submitted to the IRB at the time of Continuing Review. ☒ DMC/DSMB reports with findings/modifications required will be submitted promptly (within 5 business days/7 calendar days of becoming aware) to the IRB as an Other Event.