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Glucagon Infusion in T1D Patients With Recurrent Severe Hypoglycemia: Effects on Counter-Regulatory Responses

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ClinicalTrials.gov Identifier: NCT03490942
Recruitment Status : Recruiting
First Posted : April 6, 2018
Last Update Posted : February 15, 2019
Sponsor:
Collaborator:
Integrated Medical Development
Information provided by (Responsible Party):
Xeris Pharmaceuticals

Brief Summary:
This is a prospective, randomized, controlled, double-blind, parallel 4-group trial with the primary analysis after 4 weeks of treatment with continuous subcutaneous glucagon infusion (CSGI) or placebo. After a 1-week qualification on continuous glucose monitoring (CGM), subjects will have their baseline hypoglycemia counter-regulatory response hormones quantified using a step-wise hypoglycemia induction procedure. Subjects meeting eligibility requirements will be randomized to 1 of 4 treatment groups, 2 glucagon, 2 placebo. Subjects will receive blinded study drug for 4 weeks, and they will be followed for an additional 26 weeks post-treatment. Subjects' counter-regulatory hormone response will be measured at baseline, the end of treatment (4 weeks), and 13 and 26 weeks after treatment ends.

Condition or disease Intervention/treatment Phase
Hypoglycemia Unawareness Diabetes Mellitus, Type 1 Drug: Glucagon Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a prospective, randomized, controlled, double-blind, parallel 4-group trial with the primary analysis after 4 weeks treatment with CSGI or placebo.
Masking: Double (Participant, Investigator)
Masking Description: double-blind, placebo-controlled
Primary Purpose: Treatment
Official Title: Fixed Rate Continuous Subcutaneous Glucagon Infusion (CSGI) vs Placebo in Type 1 Diabetes Mellitus Patients With Recurrent Severe Hypoglycemia: Effects on Counter-Regulatory Responses to Insulin-Induced Hypoglycemia
Actual Study Start Date : March 15, 2018
Estimated Primary Completion Date : March 31, 2019
Estimated Study Completion Date : September 30, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Glucagon

Arm Intervention/treatment
Experimental: CSGI high infusion rate
Glucagon given as a continuous subcutaneous infusion for 28 days
Drug: Glucagon
CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.
Other Names:
  • CSI-Glucagon
  • CGSI

Experimental: CSGI low infusion rate
Glucagon given as a continuous subcutaneous infusion for 28 days
Drug: Glucagon
CSI-Glucagon is a room temperature stable, non-aqueous, liquid formulation of glucagon.
Other Names:
  • CSI-Glucagon
  • CGSI

Placebo Comparator: Placebo high infusion rate
Placebo given as a continuous subcutaneous infusion for 28 days
Drug: Placebo
The placebo solution is a non-active formulation containing excipients only.

Placebo Comparator: Placebo low infusion rate
Placebo given as a continuous subcutaneous infusion for 28 days
Drug: Placebo
The placebo solution is a non-active formulation containing excipients only.




Primary Outcome Measures :
  1. Plasma Epinephrine [ Time Frame: 0-30 minutes ]
    Plasma epinephrine concentration after 30 minutes of induced hypoglycemia. Change from baseline to the end of treatment will be assessed.


Secondary Outcome Measures :
  1. Intravenous glucose infusion rate [ Time Frame: 0-30 minutes ]
    Cumulative glucose infusion rate required to maintain glucose during insulin-induced hypoglycemia. Change from baseline to the end of treatment will be assessed.

  2. Glucagon [ Time Frame: 0-30 minutes ]
    Plasma glucagon (PG) concentration after 30 minutes of induced hypoglycemia. Change from baseline to the end of treatment will be assessed.

  3. Cortisol [ Time Frame: 0-30 minutes ]
    Plasma cortisol concentration after 30 minutes of induced hypoglycemia. Change from baseline to the end of treatment will be assessed.

  4. Growth Hormone [ Time Frame: 0-30 minutes ]
    Plasma growth hormone concentration after 30 minutes of induced hypoglycemia. Change from baseline to the end of treatment will be assessed.

  5. Autonomic symptoms [ Time Frame: 0-45 minutes ]
    Scores will be summed from each of 4 autonomic symptoms (sweating, tremor, palpitations and feeling of nervousness) as assessed by the Hypoglycemia Symptom Scale during episodes of insulin-induced hypoglycemia. Each symptom will be scored from 1 (absent) to 6 (severe) and the total autonomic symptom score from 4-24 will be compared between baseline and the end of study.

  6. Neuroglycopenic symptoms [ Time Frame: 0-45 minutes ]
    Scores will be summed from each of 4 neuroglycopenic symptoms (dizziness, blurred vision, difficulty in thinking and faintness) as assessed by the Hypoglycemia Symptom Scale during episodes of insulin-induced hypoglycemia. Each symptom will be scored from 1 (absent) to 6 (severe) and the total neuroglycopenic symptom score from 4-24 will be compared between baseline and the end of study.

  7. Hypoglycemia awareness [ Time Frame: 0-28 days ]
    Level of hypoglycemia awareness will be assessed by the Gold Scale and scored as 1= always aware and 7 = never aware. Average scores will be compared between baseline and the end of study.

  8. Time below range [ Time Frame: 0-28 days ]
    Proportional time spent with glucose < 70, <60 and <50 mg/dl as assessed by a continuous glucose monitor.

  9. Time in range [ Time Frame: 0-28 days ]
    Proportional time spent with glucose 70 ≤ PG < 180 mg/dl, as assessed by a continuous glucose monitor.

  10. Time above range [ Time Frame: 0-28 days ]
    Proportional time spent with glucose > 180 mg/dl, as assessed by a continuous glucose monitor.

  11. Mean glucose [ Time Frame: 0-28 days ]
    Mean blood glucose concentration, as assessed by a continuous glucose monitor.

  12. Glucose standard deviation [ Time Frame: 0-28 days ]
    Standard deviation of blood glucose concentration, as assessed by a continuous glucose monitor.

  13. Hypoglycemic event frequency [ Time Frame: 0-28 days ]
    Rate of hypoglycemic event episodes at < 70, <60 and <50 mg/dl as reported by the subject

  14. Confirmed symptomatic hypoglycemia [ Time Frame: 0-28 days ]
    Frequency of symptomatic hypoglycemia events confirmed with self-monitored glucose < 70 mg/dl.

  15. Unconfirmed symptomatic hypoglycemia [ Time Frame: 0-28 days ]
    Frequency of symptomatic hypoglycemia events with no confirmatory glucose reading or with a confirmed glucose reading > 70 mg/dl.

  16. Asymptomatic hypoglycemia [ Time Frame: 0-28 days ]
    Frequency of asymptomatic hypoglycemia with a confirmatory glucose reading < 70 mg/dl.

  17. Severe hypoglycemia [ Time Frame: 0-28 days ]
    Frequency of severe hypoglycemia as defined by affected consciousness of hypoglycemic origin confirmed by a glucose meter reading or prompt recovery upon hypoglycemia treatment.



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Ages Eligible for Study:   21 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Males or females diagnosed with type 1 diabetes mellitus for at least 24 months.
  2. Random serum C-peptide concentration < 0.5 ng/ml at Screening.
  3. Current use of multiple daily dosing insulin treatment < 1 U/(kg*day) total daily dose either administered with subcutaneous injections or continuous subcutaneous insulin infusion (CSII).
  4. Recurrent severe hypoglycemia as defined by minimally two events during the last year and at least one the last six months requiring not merely receiving third party intervention and either confirmation with a measured glucose < 50 mg/dl, or prompt recovery from impaired consciousness. Events must be documented in patient chart prior to study entry. Events induced as a part of clinical diagnostics or experimentation do not qualify.
  5. Performs monitoring of glucose minimally 3 times a day. Patients using continuous glucose monitoring for monitoring should continue to do so during the course of the study.
  6. Age 21-64 years, inclusive, at screening.
  7. Willingness to provide informed consent and follow all study procedures, including using the Medtronic smart phone application "iPRO2mylog" for diabetes data logging and attending all scheduled visits.

Exclusion Criteria:

  1. Subjects using CSII, who do not use a Medtronic pump.
  2. Hemoglobin A1c ≥9.0% at Screening.
  3. Chronic kidney disease stage 4 or 5.
  4. Hepatic disease, including serum alanine transaminase (ALT) or aspartate transaminase (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.
  5. Hematocrit of less than or equal to 30% at Screening.
  6. Blood pressure (BP) reading at Screening where systolic BP <90 or >150 mm Hg, or diastolic BP <50 or >100 mm Hg.
  7. Clinically significant echocardiogram (ECG) abnormalities at Screening.
  8. Congestive heart failure, New York Heart Association (NYHA) class II, III or IV,
  9. History of myocardial infarction, unstable angina or revascularization within the past 6 months.
  10. History of a cerebrovascular accident.
  11. Current seizure disorder.
  12. History of pheochromocytoma or disorder with increased risk of pheochromocytoma (multiple endocrine neoplasia type 2, neurofibromatosis, or Von Hippel-Lindau disease).
  13. History of insulinoma.
  14. Active malignancy within 5 years from Screening, except basal cell or squamous cell skin cancers. History of breast cancer or malignant melanoma will be exclusionary.
  15. Major surgical operation within 30 days prior to Screening.
  16. Current bleeding disorder, treatment with warfarin, or platelet count below 50,000 at Screening.
  17. History of allergies to glucagon or glucagon-like products, or any history of significant hypersensitivity to glucagon or any related products or to any of the excipients in the investigational formulation.
  18. History of glycogen storage disease.
  19. Any concurrent illness, other than diabetes, that is not controlled by a stable therapeutic regimen.
  20. Whole blood donation of 1 pint (500 mL) within 8 weeks prior to Screening. Donations of plasma, packed red blood cells, platelets or quantities less than 500 mL are allowed at investigator discretion.
  21. Active substance or alcohol abuse (more than 21 drinks/wk. for males or 14 drinks/wk. for females). Subjects reporting active marijuana use and/or testing positive for tetrahydrocannabinol via rapid urine test will be allowed to participate in the study at the discretion of the investigator. Subjects positive for other drugs of abuse via rapid urine test who report use of a prescription or over-the-counter medication that would explain such a finding will be allowed to participate at the discretion of the investigator.
  22. Administration of glucagon within 14 days of Screening.
  23. Pregnant and/or Lactating. For subjects of childbearing potential, there is a requirement for a negative urine pregnancy test and for agreement to use contraception and to refrain from breast feeding 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 intra-uterine device, the double barrier method (the female uses a diaphragm and spermicide and the male uses a condom), or abstinence.
  24. Inadequate venous access.
  25. Participation in other studies involving administration of an investigational drug or interventional device within 30 days or 5 half-lives, whichever is longer, before Screening for the current study and during the four weeks of study product administration in the current study.
  26. Any reason the principal investigator deems exclusionary.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03490942


Contacts
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Contact: Khaled Junaidi, MD 815-593-2218 kjunaidi@xerispharma.com
Contact: Martin Cummins 806-282-2120 mcummins@xerispharma.com

Locations
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United States, Alabama
University of Alabama, Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Contact: Tammy Perkins    205-934-4112    tlperkins@uabmc.edu   
Contact: Fernando Ovalle, MD       fovalle@uabmc.edu   
Principal Investigator: Fernando Ovalle, MD         
United States, California
University of California, San Diego Recruiting
San Diego, California, United States, 92037
Contact: Adrienne Armstrong    858-246-2151    a3armstrong@ucsd.edu   
Principal Investigator: Robert Henry, MD         
VA San Diego Healthcare System Active, not recruiting
San Diego, California, United States, 92161
United States, Georgia
Emory University - Grady Memorial Hospital Recruiting
Atlanta, Georgia, United States, 30303
Contact: Saumeth Cardona    404-251-8957    emily.k.tamponi@emory.edu   
Principal Investigator: Guillermo Umpierrez, MD         
Atlanta Diabetes Associates Recruiting
Atlanta, Georgia, United States, 30318
Contact: Betsy Childs    404-355-4393 ext 864    BChilds@atlantadiabetes.com   
Principal Investigator: Bruce Bode, MD         
United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Cornelia Dalton-Bakes    215-746-2085    Cornelia.dalton-bakes@uphs.upenn.edu   
Principal Investigator: Michael Rickels, MD         
Sponsors and Collaborators
Xeris Pharmaceuticals
Integrated Medical Development

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Responsible Party: Xeris Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03490942     History of Changes
Other Study ID Numbers: XSGO-AF01
First Posted: April 6, 2018    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Xeris Pharmaceuticals:
glucagon
hypoglycemia counter-regulation

Additional relevant MeSH terms:
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Diabetes Mellitus
Hypoglycemia
Diabetes Mellitus, Type 1
Unconsciousness
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Consciousness Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Glucagon
Glucagon-Like Peptide 1
Gastrointestinal Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Incretins