Post Bariatric Hypoglycemia
Conditions
Keywords
Bariatric surgery complications, Glucose Metabolism Disorders, Exendin (9-39), GLP-1
Brief summary
This study is designed to evaluate the efficacy, safety and pharmacokinetics of subcutaneous exendin (9-39) in subjects with post-bariatric hypoglycemia. Development of this subcutaneous formulation of exendin (9-39) would represent a targeted therapeutic approach for this rare disease with unmet clinical need.
Detailed description
Post-Bariatric Hypoglycemia (PBH) is a rare, but increasingly reported disease occurring after bariatric surgery, characterized by severe hypoglycemic episodes accompanied by symptoms of hypoglycemia. At the moment, no medical therapies have been developed for this disorder, but the clinical need is great. The major contributory factor is thought to be an exaggerated secretion of glucagon-like peptide-1 (GLP-1) due to altered nutrient transit after bariatric surgery. GLP-1 is an incretin hormone secreted primarily by the distal ileum that contributes to postprandial glucose regulation. Exendin (9-39) is a specific GLP-1 receptor antagonist, that when given via continuous IV infusion, has been shown to effectively prevent postprandial hypoglycemia and reduce symptoms of hypoglycemia in patients with PBH. This study is designed to assess the efficacy, safety and pharmacokinetic profile of a novel subcutaneous formulation of exendin (9-39).
Interventions
DRUGLyo avexitide
Lyophilized avexitide (Lyo avexitide) administered subcutaneously (sc)
DRUGLiq avexitide
Liquid avexitide (Liq avexitide) administered subcutaneously (sc)
Sponsors
Eiger BioPharmaceuticals
Tracey McLaughlin
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Post-bariatric surgery more than 6 months prior to signing the informed consent * Reported history of Whipple's triad: the occurrence of hypoglycemic symptoms associated with a capillary blood glucose of ≤55 mg/dL, and resolution with glucose or carbohydrate administration. * Symptomatic hypoglycemia during the baseline/screening oral glucose tolerance test (OGTT), as defined by the presence of plasma glucose ≤55 mg/dL with concomitant autonomic and/or neuroglycopenic symptoms.
Exclusion criteria
* Patients currently using sulfonylureas or other medications that may interfere with glucose metabolism within 5 half-lives of drug. * Participation in any clinical investigation within 4 weeks prior to dosing * History of or current insulinoma * Active infection or significant acute illness within 2 weeks prior to dosing * Female patients who are pregnant or lactating * Women of childbearing potential and not utilizing effective contraceptive methods * Inadequate end organ function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Nadir Glucose | Day 3 (time zero then every 30 minutes until 180 minutes or gylcemic rescue was required) | Nadir glucose at baseline and at Day 3 of treatment during oral glucose tolerance test (OGTT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Composite Symptom Score as a Measure of Treatment Effect | Baseline, Day 3 | Symptoms of hypoglycemia were assessed using the Edinburgh Hypoglycemia Symptom Scale that measures the intensity of 13 commonly experienced hypoglycemic symptoms, each severity graded on a 6-point Likert scale (0 = not present, 5 = severe). Scores are summed for a composite score ranging from 0 to 65, with higher scores corresponding to more severe hypoglycemia symptoms. |
| Pharmacokinetics of Subcutaneous Avexitide: Plasma Concentration Prior to Dosing (Co) | Day 3 (Predose) | Pharmacokinetics of subcutaneous avexitide were assessed on Day 3 of twice daily dosing. |
| Pharmacokinetics of Subcutaneous Avexitide: Maximum Plasma Concentration (Cmax) | Day 3 (Predose, and 60, 120, 150, 180, 210, 240, 270, 300, 330, 450, 720 minutes post-dose) | Pharmacokinetics of subcutaneous avexitide were assessed on Day 3 of twice daily dosing. |
| Pharmacokinetics of Subcutaneous Avexitide: Time of Maximum Plasma Concentration (Tmax) | Day 3 (Predose, and 60, 120, 150, 180, 210, 240, 270, 300, 330, 450, 720 minutes post-dose) | Pharmacokinetics of subcutaneous avexitide were assessed on Day 3 of twice daily dosing. |
| Pharmacokinetics of Subcutaneous Avexitide: Area Under the Plasma Concentration Versus Time Curve (AUC) | Day 3 (Predose, and 60, 120, 150, 180, 210, 240, 270, 300, 330, 450, 720 minutes post-dose) | Pharmacokinetics of subcutaneous avexitide were assessed on Day 3 of twice daily dosing. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A: Lyo Avexitide 0.05 mg/kg Lyo avexitide administered sc twice daily for 3 days | 3 |
| Part A: Lyo Avexitide 0.15 mg/kg Lyo avexitide administered sc twice daily for 3 days | 5 |
| Part A: Lyo Avexitide 0.35 mg/kg Lyo avexitide administered sc twice daily for 3 days | 3 |
| Part A: Lyo Avexitide 0.46 mg/kg Lyo avexitide administered sc twice daily for 3 days | 3 |
| Part B: Liq Avexitide 0.38 mg/kg Liq avexitide administered sc twice daily for 3 days | 5 |
| Total | 19 |
Baseline characteristics
| Characteristic | Part A: Lyo Avexitide 0.05 mg/kg | Part A: Lyo Avexitide 0.15 mg/kg | Part A: Lyo Avexitide 0.35 mg/kg | Part A: Lyo Avexitide 0.46 mg/kg | Part B: Liq Avexitide 0.38 mg/kg | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 5 Participants | 3 Participants | 3 Participants | 5 Participants | 19 Participants |
| Age, Continuous | 46.0 years STANDARD_DEVIATION 14.1 | 50.2 years STANDARD_DEVIATION 12.7 | 41.3 years STANDARD_DEVIATION 14.6 | 44.7 years STANDARD_DEVIATION 10.6 | 48.0 years STANDARD_DEVIATION 13.8 | 46.7 years STANDARD_DEVIATION 12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 4 Participants | 1 Participants | 3 Participants | 2 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 3 Participants | 2 Participants | 5 Participants | 18 Participants |
| Region of Enrollment United States | 3 participants | 5 participants | 3 participants | 3 participants | 5 participants | 19 participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 3 Participants | 3 Participants | 5 Participants | 19 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 5 | 0 / 3 | 0 / 3 | 0 / 5 |
| other Total, other adverse events | 1 / 3 | 0 / 5 | 2 / 3 | 2 / 3 | 0 / 5 |
| serious Total, serious adverse events | 0 / 3 | 0 / 5 | 0 / 3 | 0 / 3 | 0 / 5 |
Outcome results
Primary
Nadir Glucose
Nadir glucose at baseline and at Day 3 of treatment during oral glucose tolerance test (OGTT).
Time frame: Day 3 (time zero then every 30 minutes until 180 minutes or gylcemic rescue was required)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Lyo Avexitide 0.5 mg/kg | Nadir Glucose | Baseline | 41 mg/dL | Standard Deviation 5 |
| Part A: Lyo Avexitide 0.5 mg/kg | Nadir Glucose | Day 3 | 45 mg/dL | Standard Deviation 6 |
| Part A: Lyo Avexitide 0.15 mg/kg | Nadir Glucose | Day 3 | 46 mg/dL | Standard Deviation 12 |
| Part A: Lyo Avexitide 0.15 mg/kg | Nadir Glucose | Baseline | 43 mg/dL | Standard Deviation 7 |
| Part A: Lyo Avexitide 0.35 mg/kg | Nadir Glucose | Day 3 | 51 mg/dL | Standard Deviation 3 |
| Part A: Lyo Avexitide 0.35 mg/kg | Nadir Glucose | Baseline | 39 mg/dL | Standard Deviation 7 |
| Part A: Lyo Avexitide 0.46 mg/kg | Nadir Glucose | Day 3 | 59 mg/dL | Standard Deviation 14 |
| Part A: Lyo Avexitide 0.46 mg/kg | Nadir Glucose | Baseline | 42 mg/dL | Standard Deviation 4 |
| Part A: Lyo Avexitide 0.35 mg/kg and 0.46 mg/kg Groups | Nadir Glucose | Baseline | 41 mg/dL | Standard Deviation 5 |
| Part A: Lyo Avexitide 0.35 mg/kg and 0.46 mg/kg Groups | Nadir Glucose | Day 3 | 55 mg/dL | Standard Deviation 10 |
| Part B: Liq Avexitide 0.38 (±0.03) mg/kg | Nadir Glucose | Day 3 | 60 mg/dL | Standard Deviation 13 |
| Part B: Liq Avexitide 0.38 (±0.03) mg/kg | Nadir Glucose | Baseline | 41 mg/dL | Standard Deviation 9 |
Secondary
Change in Composite Symptom Score as a Measure of Treatment Effect
Symptoms of hypoglycemia were assessed using the Edinburgh Hypoglycemia Symptom Scale that measures the intensity of 13 commonly experienced hypoglycemic symptoms, each severity graded on a 6-point Likert scale (0 = not present, 5 = severe). Scores are summed for a composite score ranging from 0 to 65, with higher scores corresponding to more severe hypoglycemia symptoms.
Time frame: Baseline, Day 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Lyo Avexitide 0.5 mg/kg | Change in Composite Symptom Score as a Measure of Treatment Effect | Baseline | 25 score on a scale | Standard Deviation 7 |
| Part A: Lyo Avexitide 0.5 mg/kg | Change in Composite Symptom Score as a Measure of Treatment Effect | Day 3 | 25 score on a scale | Standard Deviation 11 |
| Part A: Lyo Avexitide 0.15 mg/kg | Change in Composite Symptom Score as a Measure of Treatment Effect | Baseline | 12 score on a scale | Standard Deviation 4 |
| Part A: Lyo Avexitide 0.15 mg/kg | Change in Composite Symptom Score as a Measure of Treatment Effect | Day 3 | 12 score on a scale | Standard Deviation 9 |
| Part A: Lyo Avexitide 0.35 mg/kg | Change in Composite Symptom Score as a Measure of Treatment Effect | Baseline | 22 score on a scale | Standard Deviation 13 |
| Part A: Lyo Avexitide 0.35 mg/kg | Change in Composite Symptom Score as a Measure of Treatment Effect | Day 3 | 15 score on a scale | Standard Deviation 11 |
| Part A: Lyo Avexitide 0.46 mg/kg | Change in Composite Symptom Score as a Measure of Treatment Effect | Baseline | 15 score on a scale | Standard Deviation 1 |
| Part A: Lyo Avexitide 0.46 mg/kg | Change in Composite Symptom Score as a Measure of Treatment Effect | Day 3 | 7 score on a scale | Standard Deviation 3 |
| Part A: Lyo Avexitide 0.35 mg/kg and 0.46 mg/kg Groups | Change in Composite Symptom Score as a Measure of Treatment Effect | Baseline | 19 score on a scale | Standard Deviation 9 |
| Part A: Lyo Avexitide 0.35 mg/kg and 0.46 mg/kg Groups | Change in Composite Symptom Score as a Measure of Treatment Effect | Day 3 | 11 score on a scale | Standard Deviation 8 |
| Part B: Liq Avexitide 0.38 (±0.03) mg/kg | Change in Composite Symptom Score as a Measure of Treatment Effect | Baseline | 17 score on a scale | Standard Deviation 12 |
| Part B: Liq Avexitide 0.38 (±0.03) mg/kg | Change in Composite Symptom Score as a Measure of Treatment Effect | Day 3 | 9 score on a scale | Standard Deviation 8 |
Secondary
Pharmacokinetics of Subcutaneous Avexitide: Area Under the Plasma Concentration Versus Time Curve (AUC)
Pharmacokinetics of subcutaneous avexitide were assessed on Day 3 of twice daily dosing.
Time frame: Day 3 (Predose, and 60, 120, 150, 180, 210, 240, 270, 300, 330, 450, 720 minutes post-dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Lyo Avexitide 0.5 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Area Under the Plasma Concentration Versus Time Curve (AUC) | 21151 ng/mL*min | Standard Deviation 9877 |
| Part A: Lyo Avexitide 0.15 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Area Under the Plasma Concentration Versus Time Curve (AUC) | 51765 ng/mL*min | Standard Deviation 2134 |
| Part A: Lyo Avexitide 0.35 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Area Under the Plasma Concentration Versus Time Curve (AUC) | 77849 ng/mL*min | Standard Deviation 23670 |
| Part A: Lyo Avexitide 0.46 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Area Under the Plasma Concentration Versus Time Curve (AUC) | 129427 ng/mL*min | Standard Deviation 31325 |
| Part A: Lyo Avexitide 0.35 mg/kg and 0.46 mg/kg Groups | Pharmacokinetics of Subcutaneous Avexitide: Area Under the Plasma Concentration Versus Time Curve (AUC) | 147417 ng/mL*min | Standard Deviation 57722 |
Secondary
Pharmacokinetics of Subcutaneous Avexitide: Maximum Plasma Concentration (Cmax)
Pharmacokinetics of subcutaneous avexitide were assessed on Day 3 of twice daily dosing.
Time frame: Day 3 (Predose, and 60, 120, 150, 180, 210, 240, 270, 300, 330, 450, 720 minutes post-dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Lyo Avexitide 0.5 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Maximum Plasma Concentration (Cmax) | 61 ng/mL | Standard Deviation 21 |
| Part A: Lyo Avexitide 0.15 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Maximum Plasma Concentration (Cmax) | 156 ng/mL | Standard Deviation 54 |
| Part A: Lyo Avexitide 0.35 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Maximum Plasma Concentration (Cmax) | 228 ng/mL | Standard Deviation 57 |
| Part A: Lyo Avexitide 0.46 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Maximum Plasma Concentration (Cmax) | 331 ng/mL | Standard Deviation 125 |
| Part A: Lyo Avexitide 0.35 mg/kg and 0.46 mg/kg Groups | Pharmacokinetics of Subcutaneous Avexitide: Maximum Plasma Concentration (Cmax) | 359 ng/mL | Standard Deviation 195 |
Secondary
Pharmacokinetics of Subcutaneous Avexitide: Plasma Concentration Prior to Dosing (Co)
Pharmacokinetics of subcutaneous avexitide were assessed on Day 3 of twice daily dosing.
Time frame: Day 3 (Predose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Lyo Avexitide 0.5 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Plasma Concentration Prior to Dosing (Co) | 11 ng/mL | Standard Deviation 7 |
| Part A: Lyo Avexitide 0.15 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Plasma Concentration Prior to Dosing (Co) | 16 ng/mL | Standard Deviation 11 |
| Part A: Lyo Avexitide 0.35 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Plasma Concentration Prior to Dosing (Co) | 4 ng/mL | Standard Deviation 2 |
| Part A: Lyo Avexitide 0.46 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Plasma Concentration Prior to Dosing (Co) | 71 ng/mL | Standard Deviation 62 |
| Part A: Lyo Avexitide 0.35 mg/kg and 0.46 mg/kg Groups | Pharmacokinetics of Subcutaneous Avexitide: Plasma Concentration Prior to Dosing (Co) | 204 ng/mL | Standard Deviation 91 |
Secondary
Pharmacokinetics of Subcutaneous Avexitide: Time of Maximum Plasma Concentration (Tmax)
Pharmacokinetics of subcutaneous avexitide were assessed on Day 3 of twice daily dosing.
Time frame: Day 3 (Predose, and 60, 120, 150, 180, 210, 240, 270, 300, 330, 450, 720 minutes post-dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Lyo Avexitide 0.5 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Time of Maximum Plasma Concentration (Tmax) | 270 minutes | Standard Deviation 30 |
| Part A: Lyo Avexitide 0.15 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Time of Maximum Plasma Concentration (Tmax) | 252 minutes | Standard Deviation 16 |
| Part A: Lyo Avexitide 0.35 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Time of Maximum Plasma Concentration (Tmax) | 240 minutes | Standard Deviation 60 |
| Part A: Lyo Avexitide 0.46 mg/kg | Pharmacokinetics of Subcutaneous Avexitide: Time of Maximum Plasma Concentration (Tmax) | 190 minutes | Standard Deviation 46 |
| Part A: Lyo Avexitide 0.35 mg/kg and 0.46 mg/kg Groups | Pharmacokinetics of Subcutaneous Avexitide: Time of Maximum Plasma Concentration (Tmax) | 396 minutes | Standard Deviation 183 |