Conditions: Hypoglycemia Complications of Bariatric Procedures
Keywords: hypoglycemia glucagon glucose metabolism disorders hormones gastrointestinal agents bariatric surgery incretins
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
The primary objective of this study is to test an optimized control system for sensor-guided (physician administered) delivery of glucagon, and test Proof-of-Concept (POC) in a clinical setting in patients with severe hypoglycemia following bariatric surgery.

Detailed description:
This is a Phase 2a, single-center, open-label, proof-of-concept study designed to test the ability of the control algorithm to detect and direct timing of G-Pump™ glucagon infused from an OmniPod® pump to prevent hypoglycemia in patients with post-bariatric hypoglycemia syndrome. While the algorithm will provide an alert as to when glucagon should be dosed to prevent hypoglycemia, there will be no automation in this clinical trial and it will ultimately be up to the physician to initiate dosing via the OmniPod® controller.

Participant on continuous glucose monitoring will arrive at the clinic and IV line will be inserted for venous access. Subject will then be asked to drink a liquid mixed meal containing 60 g of carbohydrates, e.g. Boost® Nutritional Drink, over 10 minutes. Blood samples will be collected for glucose and hormone measurement.

The open-loop system will be set to recognize low sensor glucose values, triggering an alert to the physician, who will deliver a bolus of 150 or 300 µg of glucagon via the pump, with the goal of preventing further decline in glucose values. Depending on response, a second bolus dose of 150 or 300 µg of glucagon may be administered. Plasma glucose will be measured after glucagon administration to ensure successful treatment and glucose stability, and glucagon levels will be analyzed concurrently to determine magnitude of increase above baseline. Sensors will be downloaded for subsequent analysis of appropriateness of alert timing and trigger for glucagon bolus delivery.

Arms:
arm 1: 0.15 or 0.3 mg G-Pump™ (glucagon infusion) administered from OmniPod® pump

Interventions: intervention 1: G-Pump™ (glucagon infusion)
Intervention descriptions: intervention 1: 0.15 or 0.3 mg G-Pump™ (glucagon infusion) administered from OmniPod® pump

Protocol document:
Prot_000.pdf: 
XSGO-PB01 Clinical Protocol 
 
 
G-Pump™ (glucagon infusion) 
 
 
Official Protocol Title: A Phase 2 Proof-of-Concept Study of Sensor-Guided, 
Clinician-Administered Delivery of G-Pump™ (Glucagon Infusion) From an 
OmniPod® to Prevent Post-Prandial Hypoglycemia in Post-Bariatric Surgery 
Patients  
NCT02733588 
Document Date: February 13, 2017 
 
 
 


XSGO-PB01 Clinical Protocol 
 
 
G-Pump™ (glucagon infusion) 
 
 
1 
TITLE PAGE 
PROTOCOL XSGO-PBO1 
 
A PHASE 2 PROOF-OF-CONCEPT STUDY OF SENSOR-
GUIDED, CLINICIAN-ADMINISTERED DELIVERY OF 
G-PUMP™ (GLUCAGON INFUSION) FROM AN 
OMNIPOD® TO PREVENT POST-PRANDIAL 
HYPOGLYCEMIA IN POST-BARIATRIC SURGERY 
PATIENTS 
 
 
 
 
 
 
 
 
 
 
Version 1.2 
February 13, 2017 
 
 
 
 


XSGO-PB01 Clinical Protocol 
 
 
G-Pump™ (glucagon infusion) 
 
 
Protocol Number XSGO-PB01 
A Phase 2 Proof-of-Concept Study of Sensor-Guided, Clinician-Administered Delivery of G-
Pump™ (glucagon infusion) from an OmniPod® to Prevent Post-Prandial Hypoglycemia in 
Post-Bariatric Surgery Patients 
Principal 
Investigators:   
Mary-Elizabeth Patti, MD 
IND: 
120653 
Project phase: 
Phase 2a 
Compound(s):   
G-Pump™ (glucagon infusion)  
Objectives: 
The primary objective of this study is to test an optimized control system 
for sensor-guided delivery and test Proof-of-Concept (POC) in a clinical 
setting in patients with severe hypoglycemia following bariatric surgery 
The primary endpoint for this study will be validation of the controller 
algorithm, defined as ability to detect and direct timing of the glucagon 
dose as programmed.   
The secondary objectives include the following: 
• Prevention of severe hypoglycemia (defined as glucose levels 
below 60 mg/dl) 
• Prevention of rebound hyperglycemia (defined as glucose levels 
above 180 mg/dl) 
• Time in goal range (60-180 mg/dl), reported in minutes. 
Study design:   
As a first step to developing new glucagon infusion delivery strategies for 
hypoglycemia, development of computer algorithms to predict timing and 
severity of hypoglycemia onset has been initiated, in collaboration with 
computational scientists at Harvard University School of Engineering.  We 
have analyzed data collected from clinically-indicated diagnostic 
continuous glucose monitoring systems (iPRO CGMS) obtained from 
patients enrolled in the hypoglycemia clinic at the Joslin Diabetes Center. 
Extracted data, including continuous glucose monitoring sensor glucose 
values, age, gender, and body mass index, and food and activity logs, were 
used to develop computational algorithms to allow prediction of 
hypoglycemia.  
This will be a Phase 2a, single-center, open-label, proof-of-concept study 
designed to test the ability of the control algorithm to detect and direct 
timing of G-Pump™ glucagon infused from an OmniPod® pump to 
prevent hypoglycemia in patients with post-bariatric hypoglycemia 
syndrome.  While the algorithm will provide an alert as to when glucagon 


XSGO-PB01 Clinical Protocol 
 
 
G-Pump™ (glucagon infusion) 
 
 
should be dosed to prevent hypoglycemia, there will be no automation in 
this clinical trial and it will ultimately be up to the physician to initiate 
dosing via the OmniPod® controller.   
Study location: 
Joslin Diabetes Center, Boston, MA USA.   
Study duration: 
The total length of the study will be approximately one week per patient, 
and involve up to two infusions of G-Pump™ glucagon at a single visit.  
The total time for enrollment and treatment will be approximately 3 
months. 
Sample size: 
For this proof-of-concept study, success will be defined as meeting the 
primary endpoint in 3 of 5 participants.  If this is not achieved, the 
algorithm will be revised, and an additional 5 participants may be recruited 
for additional study.  
Subjects: 
Adult male or female patients with post-bariatric hypoglycemia syndrome 
Inclusion 
Criteria: 
1. Males or females diagnosed with ongoing 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.   
2. Age 18-65 years of age, inclusive, at screening.   
3. Willingness to provide informed consent and follow all study 
procedures, including attending all scheduled visits. 
Exclusion 
Criteria: 
1. Documented hypoglycemia occurring in the fasting state (> 12 hours 
fast);  
2.Chronic kidney disease stage 4 or 5;  
3. Hepatic disease, including serum ALT or AST greater than or equal to 3 
times the upper limit of normal; hepatic synthetic insufficiency as 
defined as serum albumin < 3.0 g/dL; or serum bilirubin > 2.0;  
4. Congestive heart failure, NYHA class II, III or IV;  
5. History of myocardial infarction, unstable angina or revascularization 
within the past 6 months; 
6. History of a cerebrovascular accident;  
7. Seizure disorder (other than with suspect or documented 
hypoglycemia);  
8. Active treatment with any diabetes medications except for acarbose;  
9. Active malignancy, except basal cell or squamous cell skin cancers;  
10. Personal or family history of pheochromocytoma or disorder with 
increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von 


XSGO-PB01 Clinical Protocol 
 
 
G-Pump™ (glucagon infusion) 
 
 
Hippel-Lindau disease);  
11. Known insulinoma; 
12. Major surgical operation within 30 days prior to screening; 
13. Hematocrit  ≤33%; 
14. Bleeding disorder, treatment with warfarin, or platelet count <50,000; 
15. Blood donation (1 pint of whole blood) within the past 2 months; 
16. Active alcohol abuse or substance abuse; 
17. Current administration of oral or parenteral corticosteroids; 
18. Pregnancy and/ or Lactation: For women of childbearing potential: 
there is a requirement for a negative urine pregnancy test and for 
agreement to use contraception during the study and for at least 1 month 
after participating in the study. Acceptable contraception includes birth 
control pill / patch / vaginal ring, Depo-Provera, Norplant, an IUD, the 
double barrier method (the woman uses a diaphragm and spermicide and 
the man uses a condom), or abstinence. 
19. Use of an investigational drug within 30 days prior to screening. 
20. There will be no involvement of special vulnerable populations such as 
pregnant women, prisoners, institutionalized or incarcerated individuals, or 
others who may be considered vulnerable populations. 
Brief outline of 
treatments: 
 
Methods: 
Visit Day 1 - Screening: 
• Adult male or female patients with PBH will be recruited from the 
hypoglycemia clinic at Joslin.   
• Patients will undergo a history and physical examination, with 
particular emphasis on inclusion and exclusion criteria.   
• Blood and urine samples will be obtained for screening laboratory 
testing including hemoglobin A1c, CBC, comprehensive chemistry,  
urinalysis, and pregnancy test (if applicable).   
• Consent forms will be reviewed in detail with potential 
participants.   
Visit Day 2 - CGM Sensor Placement: 
• Two continuous glucose monitor sensors (Dexcom® G4 Platinum) 
will be placed on the anterior abdominal wall (to ensure sensor 
availability and calibration for visit day 3).  Participants will be 
provided a glucometer and instructed in both sensor insertion and 
calibration techniques.   
• If patient has prior experience with sensor insertion and calibration 


XSGO-PB01 Clinical Protocol 
 
 
G-Pump™ (glucagon infusion) 
 
 
then this visit may occur concurrent with visit 1.  
Visit Day 3 – Mixed Meal Testing (</= 3 days following Visit 2): 
• Subjects will arrive in the morning after an overnight fast.   
• An intravenous line will be inserted for blood sampling and to 
provide intravenous access.  Placement of the Dexcom sensor will 
be verified, and calibration verified using at least 2 venous blood 
glucose samples obtained 15 minutes apart.   
• An OmniPod® containing G-Pump™ glucagon will be inserted.  
• Two blood samples will be obtained for measurement of plasma 
glucose (via YSI analytical device) immediately and for subsequent 
hormonal assays.   
• The subject will then be asked to drink a liquid mixed meal 
containing 60 g of carbohydrates, e.g. Boost® Nutritional Drink, 
over 10 minutes.   
• Blood samples will be collected for immediate (in room) glucose 
measurements (YSI) every 10 minutes, and hormonal profiles at 
10, 20, 30, 60, 90, 120, 150, and 180 minutes.  Once venous 
glucose levels fall below 90 mg/dl, glucose will be measured at 5 
minute intervals (YSI).  This blood sampling series will conclude 
once sensor glucose levels fall to <75 mg/dl.  (See below for 
subsequent sample timing after clock is reset when glucagon is 
delivered.) 
• The open-loop system will be set to recognize sensor glucose 
values <75 mg/dl, triggering an alert to the physician, who will 
deliver a bolus of 150 or 300 µg of glucagon via the pump, with the 
goal of preventing further decline in glucose values.  Time will be 
reset to 0 at the time of glucagon delivery. 
• Plasma glucose will be measured (YSI)  at 5, 10, 20, 30, 45, 60, 90, 
and 120 minutes after glucagon administration  to ensure successful 
treatment and glucose stability, and glucagon levels will be 
analyzed concurrently to determine magnitude of increase above 
baseline.  
• If the open-loop algorithm issues a predictive alert or detects a 
sensor glucose level under 75 mg/dl within 30-120 minutes after 
the first dose of glucagon, a second dose of glucagon (either 150 
micrograms if a predicted hypoglycemia alert, or 300 micrograms 
if sensor glucose is under 75 mg/dl) will be administered.  If a 
second dose of glucagon is given, glucose levels will be monitored 
every 15 minutes for an additional 60 minutes. 
• At time of alarm trigger and before each administration of 
glucagon, the Edinburgh Hypoglycemia Symptoms Score will be 


XSGO-PB01 Clinical Protocol 
 
 
G-Pump™ (glucagon infusion) 
 
 
assessed.  This will be repeated at 15, 30 and 60 minutes following 
glucagon infusion. 
• Thirty minutes after the last glucagon treatment, the OmniPod® 
pump will be removed, and lunch will be provided. 
• Venous blood glucose will be monitored every 15 minutes for at 
least 2 hours to ensure stability prior to discharge from the clinical 
research unit. Prior to discharge, the pump insertion site will be 
examined, and sensors will be removed.  Patient will be given a 
snack on discharge. 
• Sensors will be downloaded for subsequent analysis of 
appropriateness of alert timing and trigger for glucagon bolus 
delivery. 
• Blood samples collected during this visit will be processed and 
stored at -80 until analysis for insulin and incretin hormone levels 
(to verify typical patterns in response to meal ingestion), for 
baseline levels of cortisol, and for glucagon, to assess endogenous 
responses as well as post-bolus plasma levels. 
Follow-Up Phone Call (1 to 3 days following Visit 3) 
Biostatistical 
Considerations: 
All subjects who have received at least one dose of glucagon will be 
included in the data analysis set.  Adverse events, vital signs, physical 
examination, laboratory safety variables (Screening to Final Visit), EKG 
(Screening to Final Visit), and local tolerability data will be reviewed and 
summarized on an ongoing basis during the study to evaluate the safety of 
subjects.  Safety data will be presented in tabular and/or graphical format 
and summarized descriptively, where appropriate.   
Sensor and glucagon delivery request will be collected and evaluated for 
specificity and response time.  
Glucagon, insulin, and incretin plasma concentration profiles will be 
analyzed with commercially available analytical methods and examined 
using repeated-measures ANOVA.   
Success will be defined as meeting the primary endpoint in 3 of 5 
participants.  If this is not achieved, the algorithm will be revised, and an 
additional 5 participants may be recruited for additional study. 
 

SAP_001.pdf: 
Official Protocol Title: A Phase 2 Proof-of-Concept Study of Sensor-Guided, 
Clinician-Administered Delivery of G-Pump™ (Glucagon Infusion) From an 
OmniPod® to Prevent Post-Prandial Hypoglycemia in Post-Bariatric Surgery 
Patients  
NCT02733588 
Document Date: February 13, 2017 
 
 
 
 
 


Statistical Analysis Plan for Protocol XSGO-PB01 
 
Analysis Population. Participants with a history of RYGB surgery and PBH with neuroglycopenia, 
uncontrolled on medical nutrition therapy and medications, were recruited from the hypoglycemia 
clinic. Exclusion criteria included fasting hypoglycemia, known insulinoma, major systemic illness, 
pregnancy, substance or alcohol abuse, recent steroid or investigational drug exposure, and use of 
medications (beyond hypoglycemia treatment) known to affect insulin secretion or action. The Joslin 
Diabetes Center Committee on Human Studies approved the study. Written informed consent was 
obtained from all participants.  Six females and one male were enrolled. Two participants enrolled twice, 
in different stages of system development. All enrolled participants were included in the analysis. 
 
Study endpoints. This iterative development clinical study was designed to evaluate the primary 
endpoints of safety and feasibility of the proposed system to predict and prevent severe hypoglycemia 
in patients with PBH. Secondary outcomes included prediction of imminent hypoglycemia by the 
automatic monitoring algorithm, minimization of time below a prespecified threshold (<75 mg/dL) using 
glucagon delivery, prevention of severe postprandial hypoglycemia (plasma glucose <60 mg/dL), and 
prevention of rebound hyperglycemia (plasma glucose >180 mg/dL) after glucagon delivery.  
 
Statistics. As an algorithm iterative development study, sample size was not determined by a power 
calculation. Statistical analyses were performed using GraphPad Prism (GraphPad Software, La Jolla, CA). 
Normally distributed data were expressed as mean ± standard deviation and skewed data were 
expressed as median with interquartile range. Normality was determined using the Shapiro-Wilk test1. 
Statistical significance was determined with the Wilcoxon signed-rank test2. 
 
References. 
1. Shapiro SS, Wilk MB. An analysis of variance test for normality (complete samples). Biometrika 1965; 
52: 591–611. 
2. Wilcoxon F. Individual Comparisons by Ranking Methods. Biom Bull 1945; 1: 80–3.