Hypoglycemia
Conditions
Keywords
glucagon, continuous glucose monitorering (CGM), artificial pancreas, hypoglycemia, post-bariatric hypoglycemia, bionic pancreas, bariatric surgery
Brief summary
This study is to test our automated hypoglycemia prevention and treatment device (glucagon-only bionic pancreas) in subjects that have undergone post-bariatric surgery that are experiencing symptoms of hypoglycemia.
Interventions
DEVICEGlucagon-only bionic pancreas - glucagon
A computer algorithm will automatically deliver glucagon based on the signal from a minimally invasive continuous glucose monitor.
DEVICEGlucagon-only bionic pancreas - placebo
A computer algorithm will automatically deliver placebo based on the signal from a minimally invasive continuous glucose monitor.
Sponsors
Joslin Diabetes Center
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Glucagon and placebo were blinded by the research pharmacy. Subjects were given bags of blinded medication labeled with which day they were to be used, and then were asked to label the bags with which day the medication was actually used. The contents of the bags were verified with the research pharmacy's blinding key upon completion of the study.
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Age 21 years or older with a gastric bypass for more than 1 year. * Post-bariatric hypoglycemia with prior episodes of neuroglycopenia, unresponsive to dietary intervention (low glycemic index, controlled carbohydrate portions) and trial of acarbose therapy at the maximally tolerated dose. Other therapies will not exclude a subject as long as the therapy is continued during the study. * Otherwise healthy (mild chronic disease such as asthma, hypertension, and depression will be allowed if well controlled). * Self-reported frequency of documented hypoglycemia (BG \< 60 mg/dl verified by capillary blood glucose measurements) of at least 2 times per week.
Exclusion criteria
* Unable to provide informed consent. * Unable to comply with study procedures. * Current participation in another hypoglycemia related clinical trial other than one that is primarily observational in nature. * Pregnancy (positive urine HCG), breast feeding, plan to become pregnant in the immediate future, or sexually active without use of contraception. * Use of insulin and/or insulin secretogues as sulfonylurea, metglitides, and glitazones. * History of cystic fibrosis, pancreatitis, type 1 diabetes or other pancreatic disease. * End stage renal disease on dialysis (hemodialysis or peritoneal dialysis). * Any known liver or biliary disease including cirrhosis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, any form of viral hepatitis. * Congestive heart failure (established history of CHF, paroxysmal nocturnal dyspnea, or orthopnea). * Acute illness or exacerbation of chronic illness at the time of the study. * Known insulinoma or predominantly fasting pattern of hypoglycemia * Adrenal insufficiency. Congenital hyperinsulinemia presenting with hypoglycemia during infancy. * History of pheochromocytoma. Fractionated metanephrines will be tested in patients with history increasing the risk for a catecholamine secreting tumor: * Paroxysms of tachycardia, pallor, or headache. * Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or von Hippel-Lindau disease. * Episodic or treatment refractory (requiring 4 or more medications to achieve normotension) hypertension. * Untreated or inadequately treated mental illness (indicators would include symptoms such as psychosis, hallucinations, mania, and/or any psychiatric hospitalization in the last year). * Current alcohol abuse (intake averaging \> 3 drinks daily in last 30 days) or substance abuse (any use within the last 6 months of controlled substances without a prescription). * Unwilling or unable to refrain from drinking more than two drinks in an hour or more than four drinks in a day during the trial. * Electrically powered implants (e.g. cochlear implants, neurostimulators) that might be susceptible to RF interference. * History of adverse reaction to glucagon (including allergy) besides nausea and vomiting. * Unwilling or unable to completely avoid acetaminophen during the study period. * Any factors that, in the opinion of the principal investigator, would interfere with the safe completion of the study procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Over the Curve and <60 mg/dl (CGM) Measured in mg/dl *Min | 14 days | The measure for area over the curve is used when an integrated assessment (e.g., a measurement of something over a specific amount of time) is more useful in understanding a phenomenon. To calculate this measure, a method of approximation is often used. One way would be to estimate the curve via curve-fitting techniques. For this outcome, using area over the curve and \<60mg/dl provides a more robust method of calculating amount of hypoglycemia (by including more severe degrees of hypoglycemia in the product of mg/dl\*min as opposed to percentage of time below 60mg/dl. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Time With CGM Glucose Less Than 60 mg/dl Overnight (11:00 PM - 7:00 AM) | 14 days | — |
| Percentage of Time With CGM Glucose Less Than 60 mg/dl During Daytime ( 7:00 AM-11:00 PM) | 14 days | — |
| Percentage of Time Spent Within the Glucose Range 70-120 mg/dl | 14 days | — |
| Percentage of Time Spent Within the Glucose Range 70-180 mg/dl | 14 days | — |
| Percentage of Time Spent Within the Glucose Range >180 mg/dl | 14 days | — |
| Fraction of Time Spent Within the Glucose Range >250 mg/dl | 2 weeks | — |
| Mean Absolute Relative Deviation (MARD) of CGM vs. All StatStrip Xpress BG Measurements | 14 days | MARD is computed using the difference between the CGM readings and the values measured at the same time by the reference measurement system. The mean (or average) of all the absolute relative deviations produces the MARD. In this study, the reference measurement system was the StatStrip Xpress meter, to which the CGM values were compared. |
| Mean Continuous Glucose Monitor (CGM) Glucose | 2 weeks | — |
| Total Number of Grams of Carbohydrate Taken for Hypoglycemia Per Day | 14 days | Calculated from daily email survey |
| Total Glucagon Dosing (mcg/kg/24 Hours) | 2 weeks | — |
| Number of Symptomatic Hypoglycemia Events Per Day | 14 days | Number of symptomatic hypoglycemia events per day calculated from daily email survey |
| Percentage of Days When Participants Correctly Guessed Intervention (Glucagon vs Placebo) Out of a Total of 14 Days. | 2 weeks | — |
| Number of Days With Nausea | 14 days | Number of days with nausea calculated from daily survey |
| Severity of Nausea on Daily E-mail Survey | 14 days | The visual analog scale (VAS) is a psychometric response scale which can be used in questionnaires. We used a simple VAS is a straight horizontal line of fixed length measuring 0-100mm with subscale markings every 10mm. The ends are defined as the extreme limits of the parameter to be measured (nausea) orientated from the left (least severity or 0) to the right (most severity or 100mm). Subjects can mark their response anywhere from 0 to 100mm. The mean severity of nausea for the group in each arm was calculated by averaging all responses in either arm. |
| Number of Carbohydrate Interventions for Hypoglycemia Per Day | 14 days | Number of carbohydrate interventions for hypoglycemia per day calculated from daily email survey |
Countries
United States
Participant flow
Pre-assignment details
10 participants were enrolled in the trial and participated in the study
Participants by arm
| Arm | Count |
|---|---|
| Glucagon-only Bionic Pancreas Subjects will use the device every day and will fill the reservoir daily with either glucagon or placebo (randomized, double blinded allocation for each day) for 14 days.
Glucagon-only Bionic Pancreas: A computer algorithm will automatically deliver glucagon or placebo based on the signal from a minimally invasive continuous glucose monitor. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Glucagon-only Bionic Pancreas |
|---|---|
| Age, Continuous | 56.2 years STANDARD_DEVIATION 7.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 10 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
Area Over the Curve and <60 mg/dl (CGM) Measured in mg/dl *Min
The measure for area over the curve is used when an integrated assessment (e.g., a measurement of something over a specific amount of time) is more useful in understanding a phenomenon. To calculate this measure, a method of approximation is often used. One way would be to estimate the curve via curve-fitting techniques. For this outcome, using area over the curve and \<60mg/dl provides a more robust method of calculating amount of hypoglycemia (by including more severe degrees of hypoglycemia in the product of mg/dl\*min as opposed to percentage of time below 60mg/dl.
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Area Over the Curve and <60 mg/dl (CGM) Measured in mg/dl *Min | 1066.30 mg/dl *minute | Standard Deviation 2100.17 |
| Glucagon-only Bionic Pancreas - Placebo | Area Over the Curve and <60 mg/dl (CGM) Measured in mg/dl *Min | 2004.80 mg/dl *minute | Standard Deviation 3076.93 |
Secondary
Fraction of Time Spent Within the Glucose Range >250 mg/dl
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Fraction of Time Spent Within the Glucose Range >250 mg/dl | 0.35 percentage of time | Standard Deviation 0.66 |
| Glucagon-only Bionic Pancreas - Placebo | Fraction of Time Spent Within the Glucose Range >250 mg/dl | 0.10 percentage of time | Standard Deviation 0.16 |
Secondary
Mean Absolute Relative Deviation (MARD) of CGM vs. All StatStrip Xpress BG Measurements
MARD is computed using the difference between the CGM readings and the values measured at the same time by the reference measurement system. The mean (or average) of all the absolute relative deviations produces the MARD. In this study, the reference measurement system was the StatStrip Xpress meter, to which the CGM values were compared.
Time frame: 14 days
Population: The 2 arms are combined for this analysis as subjects switched arms either daily or every other day through the 14 days. During this period, subjects wore 2 sensors in total (1 sensor lasts 7 days). We do not expect a difference in accuracy resulting from switching arms this frequently or relating to glucagon vs placebo.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Mean Absolute Relative Deviation (MARD) of CGM vs. All StatStrip Xpress BG Measurements | 14.2 percent difference | Standard Deviation 12.5 |
Secondary
Mean Continuous Glucose Monitor (CGM) Glucose
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Mean Continuous Glucose Monitor (CGM) Glucose | 112.3 mg/dl | Standard Deviation 10 |
| Glucagon-only Bionic Pancreas - Placebo | Mean Continuous Glucose Monitor (CGM) Glucose | 110.2 mg/dl | Standard Deviation 11.74 |
Secondary
Number of Carbohydrate Interventions for Hypoglycemia Per Day
Number of carbohydrate interventions for hypoglycemia per day calculated from daily email survey
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Number of Carbohydrate Interventions for Hypoglycemia Per Day | 1.17 interventions/day | Standard Deviation 1.25 |
| Glucagon-only Bionic Pancreas - Placebo | Number of Carbohydrate Interventions for Hypoglycemia Per Day | 1.32 interventions/day | Standard Deviation 0.94 |
Secondary
Number of Days With Nausea
Number of days with nausea calculated from daily survey
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Number of Days With Nausea | 1.1 days | Standard Deviation 1.6 |
| Glucagon-only Bionic Pancreas - Placebo | Number of Days With Nausea | 1.1 days | Standard Deviation 2 |
Secondary
Number of Symptomatic Hypoglycemia Events Per Day
Number of symptomatic hypoglycemia events per day calculated from daily email survey
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Number of Symptomatic Hypoglycemia Events Per Day | 1.37 events per day | Standard Deviation 1.05 |
| Glucagon-only Bionic Pancreas - Placebo | Number of Symptomatic Hypoglycemia Events Per Day | 1.56 events per day | Standard Deviation 0.94 |
Secondary
Percentage of Days When Participants Correctly Guessed Intervention (Glucagon vs Placebo) Out of a Total of 14 Days.
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Percentage of Days When Participants Correctly Guessed Intervention (Glucagon vs Placebo) Out of a Total of 14 Days. | 1.9 percentage of days | Standard Deviation 1.5 |
| Glucagon-only Bionic Pancreas - Placebo | Percentage of Days When Participants Correctly Guessed Intervention (Glucagon vs Placebo) Out of a Total of 14 Days. | 1.4 percentage of days | Standard Deviation 1.1 |
Secondary
Percentage of Time Spent Within the Glucose Range >180 mg/dl
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Percentage of Time Spent Within the Glucose Range >180 mg/dl | 4.27 percentage of time | Standard Deviation 4.48 |
| Glucagon-only Bionic Pancreas - Placebo | Percentage of Time Spent Within the Glucose Range >180 mg/dl | 4.81 percentage of time | Standard Deviation 4.41 |
Secondary
Percentage of Time Spent Within the Glucose Range 70-120 mg/dl
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Percentage of Time Spent Within the Glucose Range 70-120 mg/dl | 66.53 percentage of time | Standard Deviation 13.15 |
| Glucagon-only Bionic Pancreas - Placebo | Percentage of Time Spent Within the Glucose Range 70-120 mg/dl | 63.41 percentage of time | Standard Deviation 15 |
Secondary
Percentage of Time Spent Within the Glucose Range 70-180 mg/dl
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Percentage of Time Spent Within the Glucose Range 70-180 mg/dl | 92.67 percentage of time | Standard Deviation 7.07 |
| Glucagon-only Bionic Pancreas - Placebo | Percentage of Time Spent Within the Glucose Range 70-180 mg/dl | 89.31 percentage of time | Standard Deviation 8.22 |
Secondary
Percentage of Time With CGM Glucose Less Than 60 mg/dl During Daytime ( 7:00 AM-11:00 PM)
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Percentage of Time With CGM Glucose Less Than 60 mg/dl During Daytime ( 7:00 AM-11:00 PM) | 1.43 percentage of time | Standard Deviation 2.4 |
| Glucagon-only Bionic Pancreas - Placebo | Percentage of Time With CGM Glucose Less Than 60 mg/dl During Daytime ( 7:00 AM-11:00 PM) | 1.47 percentage of time | Standard Deviation 1.85 |
Secondary
Percentage of Time With CGM Glucose Less Than 60 mg/dl Overnight (11:00 PM - 7:00 AM)
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Percentage of Time With CGM Glucose Less Than 60 mg/dl Overnight (11:00 PM - 7:00 AM) | 0.93 percentage of time | Standard Deviation 1.41 |
| Glucagon-only Bionic Pancreas - Placebo | Percentage of Time With CGM Glucose Less Than 60 mg/dl Overnight (11:00 PM - 7:00 AM) | 3.95 percentage of time | Standard Deviation 5.5 |
Secondary
Severity of Nausea on Daily E-mail Survey
The visual analog scale (VAS) is a psychometric response scale which can be used in questionnaires. We used a simple VAS is a straight horizontal line of fixed length measuring 0-100mm with subscale markings every 10mm. The ends are defined as the extreme limits of the parameter to be measured (nausea) orientated from the left (least severity or 0) to the right (most severity or 100mm). Subjects can mark their response anywhere from 0 to 100mm. The mean severity of nausea for the group in each arm was calculated by averaging all responses in either arm.
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Severity of Nausea on Daily E-mail Survey | 0.5 millimeters | Standard Deviation 0.7 |
| Glucagon-only Bionic Pancreas - Placebo | Severity of Nausea on Daily E-mail Survey | 0.5 millimeters | Standard Deviation 0.7 |
Secondary
Total Glucagon Dosing (mcg/kg/24 Hours)
Time frame: 2 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Total Glucagon Dosing (mcg/kg/24 Hours) | 8.34 mcg/kg/day | Standard Deviation 3.76 |
| Glucagon-only Bionic Pancreas - Placebo | Total Glucagon Dosing (mcg/kg/24 Hours) | 10.1 mcg/kg/day | Standard Deviation 4.3 |
Secondary
Total Number of Grams of Carbohydrate Taken for Hypoglycemia Per Day
Calculated from daily email survey
Time frame: 14 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucagon-only Bionic Pancreas - Glucagon | Total Number of Grams of Carbohydrate Taken for Hypoglycemia Per Day | 24.09 grams | Standard Deviation 26.1 |
| Glucagon-only Bionic Pancreas - Placebo | Total Number of Grams of Carbohydrate Taken for Hypoglycemia Per Day | 22.56 grams | Standard Deviation 22.07 |