A Multicenter Study of Outpatient Automated Blood Glucose Control With a Bihormonal Bionic Pancreas

• ClinicalTrials.gov Identifier: NCT02092220
• Recruitment Status: Completed
• First Posted: March 20, 2014
• Results First Posted: October 20, 2017
• Last Update Posted: November 22, 2017
• Sponsor: Massachusetts General Hospital
• Collaborator: Boston University
• Information provided by (Responsible Party): Steven J. Russell, MD, PhD, Massachusetts General Hospital

Study Description

Brief Summary:

This study will test the hypothesis that a wearable bionic pancreas system that automatically delivers insulin and glucagon can provide superior regulation of glycemia versus usual care for adults with type 1 diabetes.

Please note that all participants must work or attend school at one of the following campuses: Massachusetts General Hospital in Boston, MA; University of Massachusetts Medical Center in Worcester, MA; University of North Carolina in Chapel Hill, NC; Stanford University in Palo Alto, CA.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus Type 1	Device: Bionic Pancreas; Device: Insulin pump with or without CGM	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter Study of Outpatient Automated Blood Glucose Control With a Bihormonal Bionic Pancreas
• Actual Study Start Date: April 2014
• Actual Primary Completion Date: July 2015
• Actual Study Completion Date: December 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Bionic Pancreas; Bionic Pancreas diabetes management, a wearable bionic pancreas system that automatically delivers insulin and glucagon using a continuous glucose monitoring (CGM) device, for 11 days.	Device: Bionic Pancreas
Active Comparator: Usual Care; Usual Care diabetes management, standard of care for diabetes including use of an insulin pump with or without CGM according to the participant's usual practice, for 11 days.	Device: Insulin pump with or without CGM

Outcome Measures

Primary Outcome Measures :

1. Mean Continuous Glucose Monitoring Glucose (CGMG) Values During Days 2 to 11 [ Time Frame: Days 2 to 11 of each period ]
   Glucose reading were taken every 5 minutes by the CGM. The glucose results on Days 2 to 11 were averaged.
2. Percentage of Time Spent With CGMG Concentration < 60 mg/dL During Days 2 to 11 [ Time Frame: Days 2 to 11 of each period ]
   Glucose reading were taken every 5 minutes by the CGM.The percentage of time that the glucose concentration was less than 60 mg/dL [3.3 millimoles/liter (mmol/L)] during Days 2 to 11 was calculated.

Secondary Outcome Measures :

1. Mean CGMG Values [ Time Frame: Day 1 and Days 1 to 11 in each period ]
   Glucose reading were taken every 5 minutes by the CGM. The glucose results on Days 1 and Days 1 to 11 were averaged.
2. Percentage of Time With CGMG Concentration by Ranges During Day 1 [ Time Frame: Day 1 of each period ]

   Glucose reading were taken every 5 minutes by the CGM.The percentage of time that the glucose concentration was less than the following ranges were calculated:

   < 50 mg/dL (2.8 mmol/L) < 60 mg/dL (3.3 mmol/L) < 70 mg/dL (3.9 mmol/L) 70 to 120 mg/dL (3.9 to 6.7 mmol/L) 70 to180 mg/dl (3.9 to 10.0 mmol/L) > 180 mg/dL (10.0 mmol/L) > 250 mg/dL (13.9 mmol/L)

3. Percentage of Time With CGMG Concentration by Ranges During Days 1 to 11 [ Time Frame: Days 1 to 11 of each period ]

   Glucose reading were taken every 5 minutes by the CGM.The percentage of time that the glucose concentration was less than the following ranges were calculated:

   < 50 mg/dL (2.8 mmol/L) < 70 mg/dL (3.9 mmol/L) 70 to 120 mg/dL (3.9 to 6.7 mmol/L) 70 to180 mg/dl (3.9 to 10.0 mmol/L) > 180 mg/dL (10.0 mmol/L) > 250 mg/dL (13.9 mmol/L)

4. Percentage of Time With CGMG Concentration by Ranges During Days 2 to 11 [ Time Frame: Days 2 to 11 of each period ]

   Glucose reading were taken every 5 minutes by the CGM.The percentage of time that the glucose concentration was less than the following ranges were calculated:

   < 50 mg/dL (2.8 mmol/L) < 70 mg/dL (3.9 mmol/L) 70 to 120 mg/dL (3.9 to 6.7 mmol/L) 70 to180 mg/dl (3.9 to 10.0 mmol/L) > 180 mg/dL (10.0 mmol/L) > 250 mg/dL (13.9 mmol/L)

5. Percentage of Participants With Mean CGMG < 154 mg/dl [ Time Frame: Day 1, Days 2 to11, Days 1 to11 of each period ]
   Glucose reading were taken every 5 minutes by the CGM. The glucose readings were averaged. 154 mg/dL was the estimated average glucose corresponding to a Glycosylated Hemoglobin A1C of 7%.
6. Number of Hypoglycemic Events (< 70 mg/dL, < 60 mg/dL, <50 mg/dL) [ Time Frame: Days 1-11 ]
   A series of hypoglycemic measurements is defined as a single event until there is a break of ≥ 30 minutes between measurements below the defined thresholds of < 70, < 60, and <50 mg/dL.
7. Percentage of Days That CGM Was Used by Participants as Part of Their Usual Care [ Time Frame: Days 1-11 of each period ]
   The percentage of days that participants reported the CGM device was being worn and working properly is reported.
8. Glycated Albumin on Day 12 [ Time Frame: Day 12 of each period ]
9. 1,5-anhydroglucitol on Day 12 [ Time Frame: Day 12 of each period ]
10. Anti-Insulin and Anti-Glucagon Antibodies on Day 12 [ Time Frame: Day 12 of each period ]
11. Number of Participants With Severe Hypoglycemic Events [ Time Frame: 11 days of each period ]
    A severe hypoglycemic event is an event where the participant is unable to self-treat and requires the assistance of another person.
12. Number of Episodes of Symptomatic Hypoglycemia [ Time Frame: Day 1, Days 1 to 11 and Days 2 to 11 of each period ]
    The number of episodes of symptomatic hypoglycemia were reported daily by the participant. The average number of episodes of symptomatic hypoglycemia per day was calculated.
13. Number of Reported Carbohydrate Interventions for Hypoglycemia [ Time Frame: Day 1, Days 1 to 11 and Days 2 to 11 of each period ]
    The number of carbohydrate interventions for hypoglycemia were reported daily by the participant. The average number of carbohydrate interventions per day is reported.
14. Total Grams of Carbohydrate Taken for Hypoglycemia [ Time Frame: Day 1, Days 1 to 11 and Days 2 to 11 of each period ]

    The total grams of carbohydrate taken for hypoglycemia as reported daily by the participant were averaged.

    The total number of grams of carbohydrate taken for hypoglycemia were reported daily by the participant. The total number of grams of carbohydrate taken are reported.

15. Insulin Total Daily Dose [ Time Frame: Day 1, Days 1 to 11, Days 2 to 11 of each period ]
    Insulin total daily dose is reported in units per kilogram per day (U/kg/day).
16. Glucagon Total Daily Dose Levels in the Bionic Pancreas Arm [ Time Frame: Day 1, Days 2 to 11, Days 1 to 11 of each period ]
    Glucagon dose level is reported in micrograms per kilogram of body mass per day (µg/kg/day).
17. Mean Glucose Target Set by User (Time-weighted Average Over Study Period) in the Bionic Pancreas Arm [ Time Frame: Day 1, Days 2 to 11, Days 1 to11, Overall, Daytime, Nighttime of each period ]
18. Percentage of Time Bionic Pancreas Off-line or Not Functioning Properly [ Time Frame: 11 days ]
    Not functioning properly includes issues due to system crash, communication problems between CGM and bionic pancreas, communication problems between bionic pancreas and pumps and pump malfunction.
19. Mean Nausea Index Score Using a Visual Analog Scale (VAS) [ Time Frame: Day 1, Days 1 to 11, Days 2 to 11 and each individual day 2 to 11 of each period ]
    Participants rated their nausea using a 0 to 10 centimeter (cm) VAS where 0=least severe nausea to 10=most severe nausea. The average nausea index scores during Days 1 to 11 and Days 2 to 11 were calculated.
20. Change From Baseline in Body Weight [ Time Frame: Baseline and Day 12 of each period ]
    The change in body weight collected at Day 12 relative to Baseline. A negative change from Baseline indicates a reduction in body weight and a positive change from Baseline indicates an increase in body weight.
21. Change From Baseline in Hemoglobin [ Time Frame: Baseline and Day 12 of each period ]
    The change in the value of hemoglobin collected at Day 12 relative to Baseline. A negative change from Baseline indicates a reduction in hemoglobin and a positive change from Baseline indicates an increase in hemoglobin.
22. Number of Participants With Skin Rash [ Time Frame: 11 days of each period ]

Other Outcome Measures:

1. Reliability Index, Calculated as Percent of Possible Values Actually Recorded by CGM [ Time Frame: 11 days ]
2. Number of Unscheduled Infusion Set Replacements [ Time Frame: 11 days ]
3. Mean Daily Basal Insulin Dose [ Time Frame: Day 1, Days 2 to 11, each individual day 2 to 11 of each period ]
   Daily basal insulin dose reported in Units per kilogram per day (U/kg/day).
4. Mean Daily Bolus Insulin Dose [ Time Frame: Day 1, Days 1 to 11, Days 2 to 11, each individual day 2 to 11 of each period ]
   Daily bolus insulin dose reported in Units per kilogram per day (U/kg/day).
5. CGM Mean Absolute Relative Differences (MARD) Versus Time-stamped Blood Glucose (BG) Values From Meter Downloads [ Time Frame: 11 days ]
   This outcome measure compares the time stamped PG values from the glucose meter to the corresponding CGM glucose value to determine the overall accuracy of the CGM.

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
• 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 judgement of the site principal investigator).
• Employee or student working or studying during most of the week at one of the participating campuses (Massachusetts General Hospital in Boston, MA; University of Massachusetts Medical Center in Worcester, MA; University of North Carolina in Chapel Hill, NC; Stanford University in Palo Alto, CA)
• Lives within a 30 minute drive-time radius of the central monitoring location for one of the study sites
• Willing to remain within a 60 minute drive-time radius of the central monitoring location for one of the study sites during each of the 11-day study arms
• Have someone over 18 years of age who lives with them, has access to where they sleep, is willing to be in the house when the subject is sleeping, and is willing to receive calls from the study staff and check the welfare of the study subject if telemetry shows a technical problem or severe biochemical hypoglycemia without subject response and the subject does not answer their telephone (up to two individuals can share this role, but they must be willing to carefully coordinate with each other and the subject so that one of them is clearly designated as having this responsibility at any given time)
• Willing to wear two infusion sets and continuous glucose monitor (CGM) sensor and change sets frequently (at least one new glucagon infusion set daily)

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 human chorionic gonadotropin (HCG)] breast feeding, plan to become pregnant in the immediate future, or sexually active without use of contraception
• Need to go outside of the designated geographic boundaries during either arm of the study
• Current alcohol abuse (intake averaging > 3 drinks daily in last 30 days), use of marijuana within 1 month of enrollment, or other substance abuse (use within the last 6 months of controlled substances other than marijuana without a prescription)
• Unwilling or unable to refrain from drinking more than 2 drinks in an hour or more than 4 drinks in a day or use of marijuana during the trial
• 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, even if by prescription, may be excluded according to the judgment of the principal investigator)
• History of liver disease that is expected to interfere with the anti-hypoglycemia action of glucagon (e.g. liver failure or cirrhosis). Other liver disease (i.e. active hepatitis, steatosis, active biliary disease, any tumor of the liver, hemochromatosis, glycogen storage disease) may exclude the subject if it causes significant compromise to liver function or may do so in an unpredictable fashion.
• Renal failure on dialysis
• Personal history of cystic fibrosis, pancreatitis, pancreatic tumor, or any other pancreatic disease besides type 1 diabetes
• 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 electrocardiogram (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 left anterior descending coronary artery (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 (CHF) [established history of CHF, lower extremity edema, paroxysmal nocturnal dyspnea, or orthopnea]
• History of transient ischaemic attack (TIA) or stroke
• Seizure disorder, history of any non-hypoglycemic seizure within the last two years, or ongoing treatment with anticonvulsants
• History of hypoglycemic seizures or coma in the last year

• History of pheochromocytoma: fractionated metanephrines will be tested in patients with history increasing the risk for a catecholamine secreting tumor:

  • episodic or treatment refractory (requiring 4 or more medications to achieve normotension) hypertension
  • paroxysms of tachycardia, pallor, or headache
  • personal or family history of multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B (MEN 2B), neurofibromatosis, or von Hippel-Lindau disease
• History of adrenal disease or tumor
• Hypertension with systolic blood pressure (BP) ≥160 mm Hg or diastolic BP ≥100 despite treatment
• 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 radio-frequency (RF) interference
• Unable to completely avoid acetaminophen for duration of study
• History of adverse reaction to glucagon (including allergy) besides nausea and vomiting
• Established history of allergy or severe reaction to adhesive or tape that must be used in the study
• History of eating disorder 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 oral [e.g. thiazolidinediones, biguanides, sulfonylureas, glitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter 2 (SGLT-2) inhibitors] anti-diabetic medications
• Lives in or frequents areas with poor Verizon wireless network coverage (which would prevent remote monitoring)
• Any factors that, in the opinion of the site principal investigator or overall principal investigator, would interfere with the safe completion of the study

Contacts and Locations

Locations

United States, California

Stanford University

Stanford, California, United States, 94305

United States, Massachusetts

Massachusetts General Hospital (MGH) Diabetes Research Center

Boston, Massachusetts, United States, 02114

UMass Medical Center

Worcester, Massachusetts, United States, 01655

United States, North Carolina

University of North Carolina Chapel Hill

Chapel Hill, North Carolina, United States, 27514

Sponsors and Collaborators

Massachusetts General Hospital

Boston University

Investigators

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

More Information

Publications of Results:

El-Khatib FH, Balliro C, Hillard MA, Magyar KL, Ekhlaspour L, Sinha M, Mondesir D, Esmaeili A, Hartigan C, Thompson MJ, Malkani S, Lock JP, Harlan DM, Clinton P, Frank E, Wilson DM, DeSalvo D, Norlander L, Ly T, Buckingham BA, Diner J, Dezube M, Young LA, Goley A, Kirkman MS, Buse JB, Zheng H, Selagamsetty RR, Damiano ER, Russell SJ. Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial. Lancet. 2017 Jan 28;389(10067):369-380. doi: 10.1016/S0140-6736(16)32567-3. Epub 2016 Dec 20. Erratum In: Lancet. 2017 Jan 28;389(10067):368. Lancet. 2017 Feb 4;389(10068):e2.

• Responsible Party: Steven J. Russell, MD, PhD, Assistant Professor of Medicine, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02092220
• Other Study ID Numbers: Multicenter Study
• First Posted: March 20, 2014
• Results First Posted: October 20, 2017
• Last Update Posted: November 22, 2017
• Last Verified: October 2017

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

Bionic Pancreas; Insulin; Glucagon; Continuous Glucose Monitor

Additional relevant MeSH terms:

Diabetes Mellitus, Type 1; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Pancrelipase; Gastrointestinal Agents