Efficacy, Tolerability and Pharmacokinetics of Subcutaneous Exendin (9-39) in Patients With Post Bariatric Hypoglycemia

Study Overview
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Brief Summary
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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
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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).

Official Title
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A Phase 2 Multi-Ascending Dose Trial to Assess the Efficacy, Tolerability and Pharmacokinetic Profile of Exendin (9-39) in Patients With Post-bariatric Hyperinsulinemic Hypoglycemia

Conditions
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Post Bariatric Hypoglycemia

Intervention / Treatment
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* Drug: Lyo avexitide
* Drug: Liq avexitide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Lyo avexitide 0.05 mg/kg<br>Participants will receive lyophilized avexitide (Lyo avexitide) twice daily for 3 days | Drug: Lyo avexitide<br>* Lyophilized avexitide (Lyo avexitide) administered subcutaneously (sc)<br>* Other names: Exendin (9-39);|
| Experimental: Part A: Lyo avexitide 0.15 mg/kg<br>Participants will receive Lyo avexitide twice daily for 3 days | Drug: Lyo avexitide<br>* Lyophilized avexitide (Lyo avexitide) administered subcutaneously (sc)<br>* Other names: Exendin (9-39);|
| Experimental: Part A: Lyo avexitide 0.35 mg/kg<br>Participants will receive Lyo avexitide twice daily for 3 days | Drug: Lyo avexitide<br>* Lyophilized avexitide (Lyo avexitide) administered subcutaneously (sc)<br>* Other names: Exendin (9-39);|
| Experimental: Part A: Lyo avexitide 0.46 mg/kg<br>Participants will receive Lyo avexitide twice daily for 3 days | Drug: Lyo avexitide<br>* Lyophilized avexitide (Lyo avexitide) administered subcutaneously (sc)<br>* Other names: Exendin (9-39);|
| Experimental: Part B: Liq avexitide 0.38 (±0.03) mg/kg<br>Participants will receive liquid avexitide (Liq avexitide) twice daily for 3 days | Drug: Liq avexitide<br>* Liquid avexitide (Liq avexitide) administered subcutaneously (sc)<br>* Other names: Exendin (9-39);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nadir Glucose | Nadir glucose at baseline and at Day 3 of treatment during oral glucose tolerance test (OGTT). | Day 3 (time zero then every 30 minutes until 180 minutes or gylcemic rescue was required) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Day 3 | 
| Pharmacokinetics of Subcutaneous Avexitide: Plasma Concentration Prior to Dosing (Co) | Pharmacokinetics of subcutaneous avexitide were assessed on Day 3 of twice daily dosing. | Day 3 (Predose) | 
| Pharmacokinetics of Subcutaneous Avexitide: Maximum Plasma Concentration (Cmax) | Pharmacokinetics of subcutaneous avexitide were assessed on Day 3 of twice daily dosing. | Day 3 (Predose, and 60, 120, 150, 180, 210, 240, 270, 300, 330, 450, 720 minutes post-dose) | 
| Pharmacokinetics of Subcutaneous Avexitide: Time of Maximum Plasma Concentration (Tmax) | Pharmacokinetics of subcutaneous avexitide were assessed on Day 3 of twice daily dosing. | Day 3 (Predose, and 60, 120, 150, 180, 210, 240, 270, 300, 330, 450, 720 minutes post-dose) | 
| 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. | Day 3 (Predose, and 60, 120, 150, 180, 210, 240, 270, 300, 330, 450, 720 minutes post-dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bariatric surgery complications, Glucose Metabolism Disorders, Exendin (9-39), GLP-1