Individualizing Automated Closed Loop Glucose Control Through Pharmacokinetic Profiling in an Insulin-Only Bionic Pancreas

• ClinicalTrials.gov Identifier: NCT03262116
• Recruitment Status: Terminated
• First Posted: August 25, 2017
• Results First Posted: December 9, 2022
• Last Update Posted: December 9, 2022
• Sponsor: Massachusetts General Hospital
• Collaborator: Boston University
• Information provided by (Responsible Party): Steven J. Russell, MD, PhD, Massachusetts General Hospital

Study Description

Brief Summary:

Subjects will participate in three weeks of the bionic pancreas in the insulin-only configuration. Each week, subjects will use a different rapid acting insulin analog -- Humalog, Novolog, or BC222 insulin lispro -- in a randomized cross-over order.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes Mellitus	Drug: Humalog; Drug: Novolog; Drug: BC222 insulin lispro; Device: Bionic Pancreas	Phase 2; Phase 3

Detailed Description:

The investigators hypothesize that differences in the PK characteristics of insulin analogs will lead to differences in glycemic outcomes when delivered by the insulin-only configuration of the bionic pancreas. Specifically, the investigators predict that insulin analogs that have faster absorption (numerically lower Tmax and/or T½max) and insulin analogs that have faster clearance (numerically lower terminal half-life) will result in lower mean glucose and/or a lower percentage of time in the hypoglycemic range.

Up to 30 subjects will participate in three 7-day study arms using insulin lispro, insulin aspart, and BC222 lispro in the bionic pancreas in random order. The co-primary outcomes will be mean CGMG and fraction of time spent with CGMG <54 mg/dl with comparisons made between arms for individual participants. Secondary analyses will include time in glycemic ranges (<50, <60, <70, 70-120, 70-180, >180, >250 mg/dl), coefficient of variation, mean postprandial excursion (difference in CGMG from the time of meal announcement to the peak CGMG in the first 4 hours after the meal announcement) for both mixed meal challenges, number of symptomatic hypoglycemic events, grams of carbohydrate consumed to treat hypoglycemia, and TDD of insulin, between arms for individual subjects.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Masking Description: Participants will be blinded to the type of insulin used in the iLet bionic pancreas each arm of the study.
• Primary Purpose: Treatment
• Official Title: Individualizing Automated Closed Loop Glucose Control Through Pharmacokinetic Profiling in an Insulin-Only Bionic Pancreas
• Actual Study Start Date: March 19, 2019
• Actual Primary Completion Date: July 23, 2019
• Actual Study Completion Date: July 23, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Bionic Pancreas - Humalog; Subjects will participate in one week of wearing the insulin only bionic pancreas using humalog as the rapid acting insulin.	Drug: Humalog; Subjects will participate in one week of wearing the insulin only bionic pancreas using humalog as the rapid acting insulin.; Other Name: insulin; Device: Bionic Pancreas; The insulin-only bionic pancreas will be used in all three arms of the study
Experimental: Bionic Pancreas - Novolog; Subjects will participate in one week of wearing the insulin only bionic pancreas using novolog as the rapid acting insulin.	Drug: Novolog; Subjects will participate in one week of wearing the insulin only bionic pancreas using novolog as the rapid acting insulin.; Other Name: insulin; Device: Bionic Pancreas; The insulin-only bionic pancreas will be used in all three arms of the study
Experimental: Bionic Pancreas - BC222 insulin lispro; Subjects will participate in one week of wearing the insulin only bionic pancreas using BC222 insulin lispro as the rapid acting insulin.	Drug: BC222 insulin lispro; Subjects will participate in one week of wearing the insulin only bionic pancreas using BC222 insulin lispro as the rapid acting insulin.; Other Name: insulin; Device: Bionic Pancreas; The insulin-only bionic pancreas will be used in all three arms of the study

Outcome Measures

Primary Outcome Measures :

1. Average Continuous Glucose Monitor (CGM) Glucose [ Time Frame: 7 days ]
   The average glucose achieved by the bionic pancreas as measured by the continuous glucose monitor during each arm
2. Percentage of Time Spent With CGM Glucose < 54 mg/dl [ Time Frame: 7 days ]
   The amount of time the subject spent in the hypoglycemic range < 54 mg/dl as measured by the continuous glucose monitor during each arm

Secondary Outcome Measures :

1. Percentage of Time Spent Within Each of the Following Ranges: [ Time Frame: 7 days ]
   The amount of time subject's spent in each of the listed glucose ranges as measured by the continuous glucose monitor during each bionic pancreas arm
2. Within Day Coefficient of Variation [ Time Frame: 7 days ]
   A measure of dispersion of glucose values around the mean
3. Mean Post Prandial Excursion [ Time Frame: 7 days ]
   Difference in CGMG from the beginning of the meal challenge to the peak CGMG in the 4 hours after the meal, for both mixed meal challenges.
4. Number of Symptomatic Hypoglycemic Events Per Day [ Time Frame: 7 days ]
   The number of times subjects report experiencing symptoms of hypoglycemia during each bionic pancreas arm
5. Grams of Carbohydrates Consumed to Treat Hypoglycemia Per Day [ Time Frame: 7 days ]
   The total amount of grams of carbohydrates subjects report having to take in for treatment of hypoglycemia
6. Total Daily Dose of Insulin [ Time Frame: 7 days ]
   The average total amount of insulin delivered daily by the bionic pancreas during each bionic pancreas arm.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Age ≥ 18 years and have had clinical type 1 diabetes for at least one year
• Diabetes managed using an insulin pump for ≥ 6 months
• Have used a CGM for at least one cumulative month over the last 12 months
• Prescription medication regimen stable for > 1 month (except for medications that will not affect the safety of the study and are not expected to affect any outcome of the study, in the judgment of the principal investigator)
• Willing to remain within a 250 mile radius of MGH. No air travel will be allowed, and subjects will still be expected to follow the visit schedule as described.
• Willing to wear one Dexcom CGM sensor, and one leur-lock compatible infusion set that must be replaced every other day
• Have a mobile phone they will have access to at all times during the study for making contact with study staff

Exclusion Criteria:

• Unable to provide informed consent (e.g. impaired cognition or judgment)
• Unable to safely comply with study procedures and reporting requirements (e.g. impairment of vision or dexterity that prevents safe operation of the bionic pancreas, impaired memory, unable to speak and read English)
• Current participation in another diabetes-related clinical trial that, in the judgment of the principal investigator, will compromise the results of this study or the safety of the subject
• Pregnancy (positive urine HCG), breast feeding, plan to become pregnant in the immediate future, or sexually active without use of contraception Subjects must use acceptable contraception for the two weeks prior to the study, throughout the study and for the two weeks following the study.

Acceptable contraception methods include: Oral contraceptive pill (OCP), Intrauterine Device (IUD, hormonal or copper), Male condoms, Female condoms, Diaphragm or cervical cap with spermicide, Contraceptive patch (such as OrthoEvra), Contraceptive implant (such as Implanon, Nexplanon), Vaginal ring (such as NuvaRing), Progestin shot (such as Depo-Provera), Male partner with a vasectomy proven to be effective by semen analysis

• Current alcohol abuse (intake averaging > 3 drinks daily in last 30 days) or other substance abuse (use within the last 6 months of controlled substances other than marijuana without a prescription)
• Unwilling or unable or to avoid use of drugs that may dull the sensorium, reduce sensitivity to symptoms of hypoglycemia, or hinder decision making during the period of participation in the study (use of beta blockers will be allowed as long as the dose is stable and the subject does not meet the criteria for hypoglycemia unawareness while taking that stable dose, but use of benzodiazepines or narcotics or other central nervous system depressants, even if by prescription, may be excluded according to the judgment of the principal investigator)
• Renal failure requiring dialysis
• Estimated Glomerular filtration rate <15 mL/min/1.732
• Personal history of cystic fibrosis, severe pancreatitis, pancreatic tumor, pancreatectomy or any other pancreatic disease leading to diabetes mellitus.
• Any known history of coronary artery disease including, but not limited to, history of myocardial infarction, stress test showing ischemia, history of angina, or history of intervention such as coronary artery bypass grafting, percutaneous coronary intervention, or enzymatic lysis of a presumed coronary occlusion)
• Abnormal EKG consistent with coronary artery disease or increased risk of malignant arrhythmia including, but not limited to, evidence of active ischemia, prior myocardial infarction, proximal LAD critical stenosis (Wellen's sign), prolonged QT interval (> 440 ms). Non-specific ST segment and T wave changes are not grounds for exclusion in the absence of symptoms or history of heart disease. A reassuring evaluation by a cardiologist after an abnormal EKG finding may allow participation.
• Congestive heart failure (established history of CHF, lower extremity edema, paroxysmal nocturnal dyspnea, or orthopnea)
• History of TIA or stroke15. Recent history of diabetic ketoacidosis (DKA) or severe hypoglycemia in the last 6 months. Severe hypoglycemia is defined as an event that 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.
• History of more than 1 episode of DKA requiring hospitalization in the last 2 years
• History of more than 1 episode of severe hypoglycemia in the last year.
• Untreated or inadequately treated mental illness (indicators would include symptoms such as psychosis, hallucinations, mania, and any psychiatric hospitalization in the last year), or treatment with anti-psychotic medications that are known to affect glucose regulation.
• Electrically powered implants (e.g. cochlear implants, neurostimulators) that might be susceptible to RF interference
• Unable to completely avoid acetaminophen for duration of study
• Established history of allergy or severe reaction to adhesive or tape that must be used in the study
• History of eating disorder within the last 2 years, such as anorexia, bulimia, or diabulemia or omission of insulin to manipulate weight
• History of intentional, inappropriate administration of insulin leading to severe hypoglycemia requiring treatment
• Use of oral (e.g. thiazolidinediones, biguanides, sulfonylureas, glitinides, DPP-4 inhibitors, SGLT-2 inhibitors) or non-insulin injectable (GLP-1 agonists, amylin) anti-diabetic medications
• Any diagnosed allergy to insulin lispro or insulin aspart
• Lives in or frequents areas with poor Verizon wireless network coverage (which would prevent study staff from contacting subjects)
• Any factors that, in the opinion of the principal investigator would interfere with the safe completion of the study

Contacts and Locations

Locations

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Sponsors and Collaborators

Massachusetts General Hospital

Boston University

Investigators

• Principal Investigator: Steven J Russell, MD, PhD; Massachusetts General Hospital

  Study Documents (Full-Text)

Documents provided by Steven J. Russell, MD, PhD, Massachusetts General Hospital:

Study Protocol and Statistical Analysis Plan  [PDF] June 17, 2019

More Information

• Responsible Party: Steven J. Russell, MD, PhD, Principal Investigator, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT03262116
• Other Study ID Numbers: 2017P001778
• First Posted: August 25, 2017
• Results First Posted: December 9, 2022
• Last Update Posted: December 9, 2022
• Last Verified: November 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

Keywords provided by Steven J. Russell, MD, PhD, Massachusetts General Hospital:

bionic pancreas; insulin; continuous glucose monitor; type 1 diabetes; insulin pharmacokinetics

Additional relevant MeSH terms:

Diabetes Mellitus, Type 1; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Insulin; Insulin, Globin Zinc; Insulin Lispro; Insulin Aspart; Pancrelipase; Hypoglycemic Agents; Physiological Effects of Drugs; Gastrointestinal Agents