Closed-Loop Glucagon Pump for Treatment of Post-Bariatric Hypoglycemia

To assess the efficacy of a closed loop glucagon system to prevent and treat hypoglycemia occurring in patients with Post-Bariatric Hypoglycemia (PBH) in response to meals and exercise.

A control system for sensor-guided delivery was previously developed and tested in a Proof-of-Concept (POC) study in a clinical research setting during 9 mixed meal tolerance tests in 8 unique patients with severe hypoglycemia following bariatric surgery. This optimized algorithm will now be implemented to deliver stable glucagon in a closed-loop system.

A randomized, placebo-controlled, masked trial will be conducted to assess the efficacy of the closed loop system to prevent and treat hypoglycemia occurring in patients with PBH in response to meals (part 1). Part 2 will test whether the closed loop system can also prevent and treat hypoglycemia in patients with PBH in response to exercise. A manufacturing program from our collaborating team at Xeris Pharmaceuticals will continue to produce supplies of glucagon for the clinical trial in a current good manufacturing practice (cGMP) facility, with continued shelf-life stability testing.

Eligibility Criteria:
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 (including end-stage renal disease);
3. Hepatic disease, including serum alanine transaminase (ALT) or aspartate aminotransferase (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, New York Heart Association (NYHA )class II, III or IV;
5. History of myocardial infarction, unstable angina or revascularization within the past 6 months or 2 or more risk factors for coronary artery disease including diabetes, uncontrolled hypertension, uncontrolled hyperlipidemia, and active tobacco use;
6. History of cardiac arrhythmia or arrhythmia detected by EKG during the screening visit;
7. History of syncope (unrelated to hypoglycemia) or diagnosed cardiac arrhythmia
8. Concurrent administration of β-blocker therapy;
9. History of a cerebrovascular accident;
10. Seizure disorder (other than with suspect or documented hypoglycemia);
11. Active treatment with any diabetes medications except for acarbose;
12. Active malignancy, except basal cell or squamous cell skin cancers;
13. Personal or family history of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease);
14. Known insulinoma or glucagonoma;
15. Major surgical operation within 30 days prior to screening;
16. Hematocrit \< 33%;
17. Bleeding disorder, treatment with warfarin, or platelet count \<50,000;
18. Blood donation (1 pint of whole blood) within the past 2 months;
19. Active alcohol abuse or substance abuse;
20. Current administration of oral or parenteral corticosteroids;
21. 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 intrauterine device (IUD), the double barrier method (the woman uses a diaphragm and spermicide and the man uses a condom), or abstinence;
22. Use of an investigational drug within 30 days prior to screening;
23. Current use of anticholinergic medications;
24. Allergy to a component of the study drug.