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CompletedNCT03439072Updated Feb 17, 2020Results posted

G-Pen™ Compared to Lilly Glucagon for Hypoglycemia Rescue in Adults With Type 1 Diabetes

A Phase 3 interventional study of G-Pen and Lilly Glucagon in Insulin Hypoglycemia, Type 1 Diabetes Mellitus and Severe Hypoglycemia, sponsored by Xeris Pharmaceuticals. Completed at 6 sites in 2 countries. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2020-02-17.

Sponsored by Xeris Pharmaceuticals · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
81
Allocation
Randomized
Ages
18 Years to 75 Years
Sex
All
01

Study summary

This is a non-inferiority, multi-center, randomized, controlled, single-blind, two-way crossover efficacy and safety study in subjects with Type 1 diabetes mellitus. The study involves two daytime clinical research center (CRC) visits with random assignment to receive G-Pen™ glucagon 1 mg during one period and Lilly Glucagon 1 mg during the other. Each daytime visit is preceded by an overnight stay in the CRC. In the morning of the inpatient study visit, the subject is brought into a state of hypoglycemia through IV administration of regular insulin diluted in normal saline. After a hypoglycemic state with plasma glucose \< 50 mg/dL is verified, the subject is administered a dose of G-Pen or Lilly Glucagon via subcutaneous injection. Plasma glucose levels are monitored for up to 180 minutes post-dosing, with a value of >70.0 mg/dL within 30 minutes of glucagon administration indicating a positive response. After 3 hours, the subject is given a meal and discharged when medically stable. After a wash-out period of 7 to 28 days, subjects return to the CRC, and the procedure are repeated with each subject crossed over to the other treatment. A follow-up visit as a safety check is conducted 2-7 days following administration of the final dose of study drug.

02

Conditions studied

  • Insulin Hypoglycemia
  • Type 1 Diabetes Mellitus
  • Severe Hypoglycemia

Keywords

  • glucagon
  • hypoglycemia
03

Who can participate

Ages eligible
18 Years to 75 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Males and females diagnosed with type 1 diabetes mellitus for at least 24 months.
  2. Current usage of daily insulin treatment that includes having an assigned "correction factor" for managing hyperglycemia.
  3. Age 18-75 years, inclusive.
  4. Random serum C-peptide concentration \< 0.5 ng/mL.
  5. Willingness to follow all study procedures, including attending all clinic visits.
  6. Subject has provided informed consent as evidenced by a signed/dated informed consent form completed before any trial-related activities occur.

Exclusion criteria

Exclusion Criteria:

  1. Pregnancy: For women of childbearing potential, there is a requirement for a negative urine pregnancy test and for agreement to use contraception throughout the study and for 7 days after the last dose of study glucagon. 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.
  2. Breastfeeding: Nursing mothers will be allowed into the study. However, breast feeding during the during inpatient study visits and for 48 hours after each dose of study drug is not allowed.
  3. HbA1c >9.0% at Screening.
  4. BMI > 40 kg/m2.
  5. Renal insufficiency (serum creatinine greater than 3.0 mg/dL) or end-stage renal disease. requiring renal replacement therapy.
  6. Serum ALT or AST equal to or greater than 3 times the upper limit of normal.
  7. Hepatic synthetic insufficiency as defined as a serum albumin of less than 3.0 g/dL.
  8. Hematocrit of less than or equal to 30%.
  9. BP readings at Screening where SBP \<90 or >150 mm Hg, and DBP \<50 or >100 mm Hg.
  10. Clinically significant ECG abnormalities.
  11. Use of > 2.0 U/kg total insulin dose per day.
  12. Inadequate venous access.
  13. Congestive heart failure, NYHA class III or IV.
  14. History of myocardial infarction, unstable angina, or revascularization within the past 6 months.
  15. History of a cerebrovascular accident in past 6 months or with major neurological deficits.
  16. 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.
  17. Major surgical operation within 30 days prior to Screening.
  18. Current seizure disorder (other than with suspect or documented hypoglycemia).
  19. Current bleeding disorder, treatment with warfarin, or platelet count below 50 x 10e9 per liter.
  20. History of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease).
  21. History of insulinoma.
  22. 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 (DMSO \& trehalose) in the investigational formulation.
  23. History of glycogen storage disease.
  24. Subject tests positive for HIV, HCV or HBV infection (HBsAg+) at Screening.
  25. Active substance or alcohol abuse (more than 21 drinks/wk. for males or 14 drinks/wk. for females). Subjects reporting active marijuana use or testing positive for tetrahydrocannabinol (THC) via rapid urine test will be allowed to participate in the study at the discretion of the Investigator.
  26. Administration of glucagon within 28 days of Screening.
  27. Participation in other studies involving administration of an investigational drug or device within 30 days or 5 half-lives, whichever is longer, before Screening for the current study and during participation in the current study.
  28. Any reason the Investigator deems exclusionary.
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Crossover assignment
Masking
Single (Participant)
Enrollment
81 participants (actual)

Study arms

  • Other
    G-Pen followed by Lilly Glucagon

    1 mg G-Pen at the first treatment visit followed by 1 mg Lilly Glucagon at the second treatment visit

    Drug: G-Pen · Drug: Lilly Glucagon

  • Other
    Lilly Glucagon followed by G-Pen

    1 mg Lilly Glucagon at the first treatment visit followed by 1 mg G-Pen at the second treatment visit

    Drug: G-Pen · Drug: Lilly Glucagon

Interventions

  • DrugG-Pen

    1 mg subcutaneous injection of G-Pen (glucagon injection) administered via auto-injector

    Also known as: glucagon

  • DrugLilly Glucagon

    1 mg subcutaneous injection of Lilly Glucagon (glucagon injection \[RNDA Origin\])

    Also known as: GEK

05

What researchers measure

Primary outcomes

  1. Number of Subjects With a Positive Glucose Response

    Increase in plasma glucose concentration from below 50.0 mg/dL to greater than 70.0 mg/dL within 30 minutes after receiving glucagon

    Time frame: 0 to 30 minutes post dose

Secondary outcomes

  1. Time for Positive Glucose Response

    Time from administration of glucagon for plasma glucose to rise from below 50.0 mg/dL to above 70.0 mg/dL

    Time frame: 0 to 180 minutes post dose

  2. Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Positive Glucose Increase

    A positive response for this endpoint is a return of plasma glucose to \> 70 mg/dL or an increase in plasma glucose by ≥20 mg/dL within 30 minutes after receiving glucagon

    Time frame: 0 to 30 minutes post dose

  3. Number of Subjects With a Positive Glucose Increase

    Increase in plasma glucose by ≥ 20.0 mg/dL within 30 minutes after receiving glucagon

    Time frame: 0 to 30 minutes post dose

  4. Time for Positive Glucose Increase

    Time from administration of glucagon for plasma glucose to increase by ≥20 mg/dL from baseline

    Time frame: 0 to 180 minutes post dose

  5. Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Relief of Neuroglycopenic Symptoms

    A positive response for this endpoint is a return of plasma glucose to \> 70 mg/dL or clearance of all neuroglycopenic symptoms of hypoglycemia within 30 minutes after receiving glucagon. Four symptoms were assessed: dizziness, blurred vision, difficulty in thinking and faintness.

    Time frame: 0 to 30 minutes post dose

  6. Number of Subjects With Relief of Neuroglycopenic Symptoms

    Clearance of all neuroglycopenic symptoms of hypoglycemia within 30 minutes after receiving glucagon. Four symptoms were assessed: dizziness, blurred vision, difficulty in thinking and faintness.

    Time frame: 0 to 30 minutes post dose

  7. Time to Resolution of Autonomic Symptoms

    Time from administration of glucagon to complete resolution of 4 autonomic symptoms of hypoglycemia. Symptoms included: sweating, tremor, palpitations and feeling of nervousness.

    Time frame: 0 to 180 minutes post dose

  8. Time to Resolution of Neuroglycopenic Symptoms

    Time from administration of glucagon to complete resolution of 4 neuroglycopenic symptoms of hypoglycemia. Four symptoms were assessed: dizziness, blurred vision, difficulty in thinking and faintness.

    Time frame: 0 to 180 minutes post dose

  9. Time to Resolution of the Feeling of Hypoglycemia

    Time from administration of glucagon to resolution of the overall sensation of hypoglycemia. Subjects were asked to answer yes/no to the question, "Do you feel hypoglycemic?" The time point as which the subject first answered "no" was considered the time of resolution.

    Time frame: 0 to 180 minutes post dose

  10. Glucose AUC

    Area under the curve for plasma glucose.

    Time frame: 0 to 180 minutes post dose - Blood samples for assessment of blood glucose concentration were collected every 5 minutes post-dose to 90 minutes, and then at 120, 150 and 180 minutes post dose.

  11. Glucose Cmax

    Maximum concentration of plasma glucose.

    Time frame: 0 to 180 minutes post dose - Blood samples for assessment of blood glucose concentration were collected every 5 minutes post-dose to 90 minutes, and then at 120, 150 and 180 minutes post dose.

  12. Glucose Tmax

    Time to maximum concentration of plasma glucose. Blood samples for assessment of blood glucose concentration were collected every 5 minutes post-dose to 90 minutes, and then at 120, 150 and 180 minutes post dose.

    Time frame: 0 to 180 minutes post dose

  13. Glucagon Preparation and Administration Time

    Time required to prepare and inject glucagon as measured between a "decision to dose" and completion of the injection

    Time frame: 0 to 5 minutes pre-dose

06

Results

Posted May 30, 2019

Participant flow

The recruitment period began 08 Jan 2018 and ran through 02 Apr 2018. Subjects were screened for study eligibility at one of the six clinical sites up to 30 days prior to randomization.

Participant flow — Overall Study
MilestoneG-Pen Followed by Lilly GlucagonLilly Glucagon Followed by G-Pen
Started4140
Completed3936
Not completed24
Withdrew: Withdrawal by subject23
Withdrew: Physician decision01

Outcome measures

PrimaryNumber of Subjects With a Positive Glucose Response

Increase in plasma glucose concentration from below 50.0 mg/dL to greater than 70.0 mg/dL within 30 minutes after receiving glucagon

Time frame:
0 to 30 minutes post dose
Reported as:
Count of participants · Participants
Number of Subjects With a Positive Glucose Response
ParticipantsG-PenLilly Glucagon
Number of Subjects With a Positive Glucose Response7678
SecondaryTime for Positive Glucose Response

Time from administration of glucagon for plasma glucose to rise from below 50.0 mg/dL to above 70.0 mg/dL

Time frame:
0 to 180 minutes post dose
Reported as:
Mean · minutes
Time for Positive Glucose Response
minutesG-PenLilly Glucagon
Time for Positive Glucose Response12.17 ± 3.6048.58 ± 2.026
SecondaryNumber of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Positive Glucose Increase

A positive response for this endpoint is a return of plasma glucose to \> 70 mg/dL or an increase in plasma glucose by ≥20 mg/dL within 30 minutes after receiving glucagon

Time frame:
0 to 30 minutes post dose
Reported as:
Count of participants · Participants
Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Positive Glucose Increase
ParticipantsG-PenLilly Glucagon
Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Positive Glucose Increase7678
SecondaryNumber of Subjects With a Positive Glucose Increase

Increase in plasma glucose by ≥ 20.0 mg/dL within 30 minutes after receiving glucagon

Time frame:
0 to 30 minutes post dose
Reported as:
Count of participants · Participants
Number of Subjects With a Positive Glucose Increase
ParticipantsG-PenLilly Glucagon
Number of Subjects With a Positive Glucose Increase7678
SecondaryTime for Positive Glucose Increase

Time from administration of glucagon for plasma glucose to increase by ≥20 mg/dL from baseline

Time frame:
0 to 180 minutes post dose
Reported as:
Mean · minutes
Time for Positive Glucose Increase
minutesG-PenLilly Glucagon
Time for Positive Glucose Increase11.36 ± 3.3458.02 ± 1.856
SecondaryNumber of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Relief of Neuroglycopenic Symptoms

A positive response for this endpoint is a return of plasma glucose to \> 70 mg/dL or clearance of all neuroglycopenic symptoms of hypoglycemia within 30 minutes after receiving glucagon. Four symptoms were assessed: dizziness, blurred vision, difficulty in thinking and faintness.

Time frame:
0 to 30 minutes post dose
Reported as:
Count of participants · Participants
Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Relief of Neuroglycopenic Symptoms
ParticipantsG-PenLilly Glucagon
Number of Subjects With a Positive Response for the Combination Endpoint: Positive Glucose Response/Relief of Neuroglycopenic Symptoms7678
SecondaryNumber of Subjects With Relief of Neuroglycopenic Symptoms

Clearance of all neuroglycopenic symptoms of hypoglycemia within 30 minutes after receiving glucagon. Four symptoms were assessed: dizziness, blurred vision, difficulty in thinking and faintness.

Time frame:
0 to 30 minutes post dose
Reported as:
Count of participants · Participants
Number of Subjects With Relief of Neuroglycopenic Symptoms
ParticipantsG-PenLilly Glucagon
Number of Subjects With Relief of Neuroglycopenic Symptoms7477
SecondaryTime to Resolution of Autonomic Symptoms

Time from administration of glucagon to complete resolution of 4 autonomic symptoms of hypoglycemia. Symptoms included: sweating, tremor, palpitations and feeling of nervousness.

Time frame:
0 to 180 minutes post dose
Reported as:
Mean · minutes
Time to Resolution of Autonomic Symptoms
minutesG-PenLilly Glucagon
Time to Resolution of Autonomic Symptoms13.8 ± 10.8912.0 ± 7.44
SecondaryTime to Resolution of Neuroglycopenic Symptoms

Time from administration of glucagon to complete resolution of 4 neuroglycopenic symptoms of hypoglycemia. Four symptoms were assessed: dizziness, blurred vision, difficulty in thinking and faintness.

Time frame:
0 to 180 minutes post dose
Reported as:
Mean · minutes
Time to Resolution of Neuroglycopenic Symptoms
minutesG-PenLilly Glucagon
Time to Resolution of Neuroglycopenic Symptoms14.2 ± 15.1212.2 ± 8.85
SecondaryTime to Resolution of the Feeling of Hypoglycemia

Time from administration of glucagon to resolution of the overall sensation of hypoglycemia. Subjects were asked to answer yes/no to the question, "Do you feel hypoglycemic?" The time point as which the subject first answered "no" was considered the time of resolution.

Time frame:
0 to 180 minutes post dose
Reported as:
Mean · minutes
Time to Resolution of the Feeling of Hypoglycemia
minutesG-PenLilly Glucagon
Time to Resolution of the Feeling of Hypoglycemia11.6 ± 6.4513.1 ± 7.86
SecondaryGlucose AUC

Area under the curve for plasma glucose.

Time frame:
0 to 180 minutes post dose - Blood samples for assessment of blood glucose concentration were collected every 5 minutes post-dose to 90 minutes, and then at 120, 150 and 180 minutes post dose.
Reported as:
Mean · mg∙min/dL
Glucose AUC
mg∙min/dLG-PenLilly Glucagon
Glucose AUC33686.04 ± 5300.20433538.60 ± 5705.219
SecondaryGlucose Cmax

Maximum concentration of plasma glucose.

Time frame:
0 to 180 minutes post dose - Blood samples for assessment of blood glucose concentration were collected every 5 minutes post-dose to 90 minutes, and then at 120, 150 and 180 minutes post dose.
Reported as:
Mean · mg/dL
Glucose Cmax
mg/dLG-PenLilly Glucagon
Glucose Cmax238.32 ± 45.626228.11 ± 46.567
SecondaryGlucose Tmax

Time to maximum concentration of plasma glucose. Blood samples for assessment of blood glucose concentration were collected every 5 minutes post-dose to 90 minutes, and then at 120, 150 and 180 minutes post dose.

Time frame:
0 to 180 minutes post dose
Reported as:
Mean · minutes
Glucose Tmax
minutesG-PenLilly Glucagon
Glucose Tmax125.67 ± 33.513113.89 ± 31.908
SecondaryGlucagon Preparation and Administration Time

Time required to prepare and inject glucagon as measured between a "decision to dose" and completion of the injection

Time frame:
0 to 5 minutes pre-dose
Reported as:
Mean · seconds
Glucagon Preparation and Administration Time
secondsG-PenLilly Glucagon
Glucagon Preparation and Administration Time27.3 ± 19.6697.2 ± 45.06

Adverse events

Collected over Adverse events were collected for up to 9 weeks, from the time of consent through the follow-up visit.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
G-Pen0/76 (0%)0/76 (0%)46/76 (60.5%)
Lilly Glucagon0/78 (0%)0/78 (0%)34/78 (43.6%)
Most frequent other events
Most frequent other events
EventG-PenLilly Glucagon
NauseaGastrointestinal disorders29/7626/78
VomitingGastrointestinal disorders20/7611/78
HeadacheNervous system disorders6/764/78

Baseline characteristics

All randomized subjects

Age, Continuous
Age, Continuous(years)All Randomized Subjects
Mean38.2 ± 14.6
Sex: Female, Male
Sex: Female, Male(Participants)All Randomized Subjects
Female37
Male44
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)All Randomized Subjects
Hispanic or Latino6
Not Hispanic or Latino75
Unknown or Not Reported0
Race (NIH/OMB)
Race (NIH/OMB)(Participants)All Randomized Subjects
American Indian or Alaska Native0
Asian6
Native Hawaiian or Other Pacific Islander0
Black or African American0
White71
More than one race3
Unknown or Not Reported1
Region of Enrollment
Region of Enrollment(participants)All Randomized Subjects
North America81
07

Study locations

6 sites
  • ProSciento, Inc.
    Chula Vista, California 91911, United States
  • Diablo Clinical Research, Inc.
    Walnut Creek, California 94598, United States
  • Atlanta Diabetes Associates
    Atlanta, Georgia 30318, United States
  • Rainier Clinical Research Center, Inc.
    Renton, Washington 98057, United States
  • LMC ESD, Inc.
    Toronto, Ontario M4G 3E8, Canada
  • Altasciences Algorithme Pharma
    Montréal, Quebec H3P 3P1, Canada
08

References and documents

Publications

  • Christiansen MP, Cummins M, Prestrelski S, Close NC, Nguyen A, Junaidi K. Comparison of a ready-to-use liquid glucagon injection administered by autoinjector to glucagon emergency kit for the symptomatic relief of severe hypoglycemia: two randomized crossover non-inferiority studies. BMJ Open Diabetes Res Care. 2021 Oct;9(1):e002137. doi: 10.1136/bmjdrc-2021-002137. PubMed 34620618 ↗

Study documents

  • Study protocol · Jan 29, 2018
  • Statistical analysis plan · May 3, 2018

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

09

Registry details

Key details

Study ID
NCT03439072
Lead sponsor
Xeris Pharmaceuticals
Collaborators
SGS S.A., Integrated Medical Development
Responsible party
Sponsor
First posted
Feb 20, 2018
Start date
Jan 23, 2018
Primary completion
Apr 18, 2018
Completion
May 3, 2018
Results posted
May 30, 2019
Last update
Feb 17, 2020

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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