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Completed

NCT Number: NCT03255629

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.

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Key information

Conditions

Post-bariatric Hypoglycemia

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Joslin Diabetes Center

Boston, Massachusetts, 02215, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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.
  • Age 18-65 years of age, inclusive, at screening.
  • Willingness to provide informed consent and follow all study procedures, including attending all scheduled visits.

Exclusion criteria

  • Documented hypoglycemia occurring in the fasting state (> 12 hours fast);
  • Chronic kidney disease stage 4 or 5 (including end-stage renal disease);
  • 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;
  • Congestive heart failure, New York Heart Association (NYHA )class II, III or IV;
  • 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;
  • History of cardiac arrhythmia or arrhythmia detected by EKG during the screening visit;
  • History of syncope (unrelated to hypoglycemia) or diagnosed cardiac arrhythmia
  • Concurrent administration of β-blocker therapy;
  • History of a cerebrovascular accident;
  • Seizure disorder (other than with suspect or documented hypoglycemia);
  • Active treatment with any diabetes medications except for acarbose;
  • Active malignancy, except basal cell or squamous cell skin cancers;
  • Personal or family history of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease);
  • Known insulinoma or glucagonoma;
  • Major surgical operation within 30 days prior to screening;
  • Hematocrit < 33%;
  • Bleeding disorder, treatment with warfarin, or platelet count <50,000;
  • Blood donation (1 pint of whole blood) within the past 2 months;
  • Active alcohol abuse or substance abuse;
  • Current administration of oral or parenteral corticosteroids;
  • 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;
  • Use of an investigational drug within 30 days prior to screening;
  • Current use of anticholinergic medications;
  • Allergy to a component of the study drug.

Treatment and study plan

glucagon

Drug

novel, stable non-aqueous glucagon formulation provided by Xeris Pharmaceuticals

Closed loop glucagon pump

Device

a novel closed-loop glucagon system (CLG) incorporating a novel, stable non-aqueous glucagon formulation together with an infusion pump system (Omnipod) guided by real-time continuous glucose monitoring (Dexcom) that is triggered by a hypoglycemia alert algorithm.

Primary outcomes

  1. Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <65 mg/dL

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    A primary endpoint for this study is the prevention of meal provoked hypoglycemia, defined as sensor glucose levels below <65 mg/dl, comparing study drug to control.

  2. Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <65 mg/dL

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    A primary endpoint for this study is prevention of meal provoked hypoglycemia, defined as plasma glucose levels below <65 mg/dl, comparing study drug to control

Secondary outcomes

  1. Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <60 mg/dL

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below <60 mg/dl, comparing vehicle to control

  2. Number of Participants With Rebound Hyperglycemia (Defined as Glucose Levels Above 180 mg/dl).

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge will be conducted within two weeks of the first.

    Compare outcomes for glucagon versus vehicle infusions for prevention of rebound hyperglycemia (defined as glucose levels above 180 mg/dl).

  3. Number of Participants With Hypoglycemia Rescue Administered

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    Protocol-specified rescue delivery of IV glucose was performed if plasma glucose <55 mg/dL and/or significant neuroglycopenia developed.

  4. Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <60 mg/dL

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below <60 mg/dl, comparing vehicle to control

  5. Number of Participants With Meal-provoked Hypoglycemia, Defined as Plasma Glucose <55 mg/dL

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    Prevention of meal / provoked hypoglycemia, defined as plasma glucose levels below <55 mg/dl, comparing vehicle to control

  6. Number of Participants With Meal-provoked Hypoglycemia, Defined as Sensor Glucose <55 mg/dL

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    Prevention of meal / provoked hypoglycemia, defined as sensor glucose levels below <55 mg/dl, comparing vehicle to control

  7. 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

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    Compare outcomes for glucagon versus vehicle infusions for percent time plasma glucose in range (180-65mg/dL) after the final dose, which was either 1 or 2 doses depending on patient response

  8. 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

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    Compare outcomes for glucagon versus vehicle infusions for percent time sensor glucose in range (180-65mg/dL) after the final dose, which was either 1 or 2 doses depending on patient response

  9. Meal Provoked Nadir Plasma Glucose

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    Nadir plasma glucose (mg/dl) during meal testing, comparing vehicle to control

  10. Meal Provoked Nadir Sensor Glucose

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    Nadir sensor glucose (mg/dl) during meal testing, comparing vehicle to control

  11. Time to Nadir Plasma Glucose After Mixed Meal (Min)

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

  12. Time to Nadir Sensor Glucose After Mixed Meal (Min)

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

  13. Time to Alarm During Mixed Meal Testing (Minutes)

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    Time to alarm represents the time for the first alarm to occur during mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose < 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.

  14. Time to Delivery (Min)

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    Time to delivery (min) of study drug during mixed meal testing

  15. Sensor Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    This is the sensor glucose at which time the first alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose < 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.

  16. Capillary Glucose at Time of Alarm 1 During Mixed Meal Testing (mg/dL)

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    This is the capillary glucose at which time the first alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose < 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.

  17. Sensor Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    This is the sensor glucose at which time the second alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose < 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.

  18. Capillary Glucose at Time of Alarm 2 During Mixed Meal Testing (mg/dL)

    Time frame: Measured following 2 challenges: 1 with glucagon and 1 with vehicle. The second challenge was conducted within two weeks of the first.

    This is the capillary glucose at which time the second alarm occurred during the mixed meal testing. Alarms are triggered by hypoglycemia (sensor glucose < 65 mg/dL), or by the algorithm predicting that hypoglycemia will occur in less than 30 minutes (taking into account current sensor glucose level (between 65-150 mg/dL) and the rate of change of a rapidly falling sensor glucose level). In the latter case, the alarm is activated even if glucose levels are within the normoglycemic range to allow early detection and response. During both glucagon and vehicle treatment visits, all participants received either 300 μg of glucagon or the equivalent volume of vehicle with the first alarm.

  19. 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).

    Time frame: 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).

    Pain score was assessed verbally, 1 is the least pain (none), 10 is the most severe pain. Pain score at the time of the first administration was compared for the visit where the participant received the study drug vs. the visit where the participant received the placebo. A participant could receive 2 doses of the study drug or placebo at each visit. All 12 participants completed both the study drug phase and the placebo phase. The pain scores for the first administration of study drug vs. first administration of placebo for these two visits were compared. Whether the participant was assigned to the study drug glucagon (vs. placebo) at the first or second MMTT was determined by randomization.

  20. 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).

    Time frame: 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).

    Pain score was assessed verbally, 1 is the least pain (none), 10 is the most severe pain. Pain score at the time of the second administration was compared for the visit where the participant received the study drug vs. the visit where the participant received the placebo. A participant could receive 2 doses of the study drug or placebo at each visit. All 12 participants completed both the study drug phase and the placebo phase. The pain scores from the second administration of study drug vs. second administration of placebo for these two visits were compared. Whether the participant was assigned to the study drug glucagon (vs. placebo) at the first or second MMTT was determined by randomization.

Sponsors and collaborators

Lead sponsor

Joslin Diabetes Center

Other

Collaborators

  • Harvard University
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • National Institutes of Health (NIH)
  • Xeris Pharmaceuticals

Registry information

Important dates

Study start
2017
Primary completion
2018
Study completion
2018
First posted
Aug 21, 2017
Registry last updated
Sep 6, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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