Clinical trial NCT03255629: Closed-Loop Glucagon Pump for Treatment of Post-Bariatric Hypoglycemia
Official title: Closed-Loop Glucagon Pump for Treatment of Post-Bariatric Hypoglycemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Post-bariatric Hypoglycemia
Lead sponsor: Joslin Diabetes Center
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Xeris Pharmaceuticals
name: Harvard University
First posted: 2017-08-21
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: A randomization scheme will be devised to assign half the subjects to receive glucagon during their first challenge visit and the other half to receive vehicle during their first challenge visit. At their second challenge subjects will be assigned to the product not received during their first challenge. The label will include a subject randomization number and information as to which vial should be administered during the first challenge and which should be administered during the second challenge.
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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.

Primary outcomes:
measure: Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <65 mg/dL
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <65 mg/dL
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
Secondary outcomes:
measure: Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <60 mg/dL
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Number of Participants With Rebound Hyperglycemia (Defined as Glucose Levels Above 180 mg/dl).
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge will be conducted within two weeks of the first.
measure: Number of Participants With Hypoglycemia Rescue Administered
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <60 mg/dL
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <55 mg/dL
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <55 mg/dL
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Percent Time Plasma Glucose in Range After the Final Dose of Study Drug or Vehicle, Which Was Either 1 or 2 Doses Depending on Patient Response
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Percent Time Sensor Glucose in Range After Drug Delivery After the Final Dose of Study Drug or Vehicle, Which Was Either 1 or 2 Doses Depending on Patient Response
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Meal Provoked Nadir Plasma Glucose
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Meal Provoked Nadir Sensor Glucose
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Time to Nadir Plasma Glucose After Mixed Meal (Min)
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Time to Nadir Sensor Glucose After Mixed Meal (Min)
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Time to Alarm During Mixed Meal Testing (Minutes)
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Time to Delivery (Min)
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Sensor Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Capillary Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Sensor Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Capillary Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)
timeFrame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.
measure: Pain Score at Time of First Dose Delivery of Study Drug, Versus Pain Score at Time of First Dose Delivery of Placebo (Comparing First Delivery Pain Scores for Visit Where Participant Received Study Drug vs. Visit Where Participant Received Placebo).
timeFrame: The two study visits where participants were administered either study drug or placebo took place over 2 weeks (there was a 1 to 2 week washout period between visits).
measure: Pain Score at Time of Second Dose Delivery of Study Drug, Versus Pain Score at Time of Second Dose Delivery of Placebo (Comparing Second Delivery Pain Scores for Visit Where Participant Received Study Drug vs. Visit Where Participant Received Placebo).
timeFrame: The two study visits where participants were administered either study drug or placebo took place over 2 weeks (there was a 1 to 2 week washout period between visits).
Other outcomes:
Locations:
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
Study officials:
affiliation: Joslin Diabetes Center
name: Mary E Patti, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mulla CM, Zavitsanou S, Laguna Sanz AJ, Pober D, Richardson L, Walcott P, Arora I, Newswanger B, Cummins MJ, Prestrelski SJ, Doyle FJ, Dassau E, Patti ME. A Randomized, Placebo-Controlled Double-Blind Trial of a Closed-Loop Glucagon System for Postbariatric Hypoglycemia. J Clin Endocrinol Metab. 2020 Apr 1;105(4):e1260-71. doi: 10.1210/clinem/dgz197.