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

• ClinicalTrials.gov Identifier: NCT02771574
• Recruitment Status: Completed
• First Posted: May 13, 2016
• Results First Posted: August 14, 2020
• Last Update Posted: August 14, 2020
• Sponsor: Tracey McLaughlin
• Collaborator: Eiger BioPharmaceuticals
• Information provided by (Responsible Party): Tracey McLaughlin, Stanford University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Post Bariatric Hypoglycemia	Drug: Lyo avexitide; Drug: Liq avexitide	Phase 2

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 19 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: May 2016
• Actual Primary Completion Date: June 2017
• Actual Study Completion Date: June 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Nadir Glucose [ Time Frame: 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 Outcome Measures :

1. Change in Composite Symptom Score as a Measure of Treatment Effect [ Time Frame: 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.
2. Pharmacokinetics of Subcutaneous Avexitide: Plasma Concentration Prior to Dosing (Co) [ Time Frame: Day 3 (Predose) ]
   Pharmacokinetics of subcutaneous avexitide were assessed on Day 3 of twice daily dosing.
3. Pharmacokinetics of Subcutaneous Avexitide: Maximum Plasma Concentration (Cmax) [ Time Frame: 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.
4. Pharmacokinetics of Subcutaneous Avexitide: Time of Maximum Plasma Concentration (Tmax) [ Time Frame: 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.
5. Pharmacokinetics of Subcutaneous Avexitide: Area Under the Plasma Concentration Versus Time Curve (AUC) [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Stanford University School of Medicine

Stanford, California, United States, 94305

Sponsors and Collaborators

Tracey McLaughlin

Eiger BioPharmaceuticals

Investigators

• Principal Investigator: Marilyn Tan, MD; Clinical Assistant Professor

  Study Documents (Full-Text)

Documents provided by Tracey McLaughlin, Stanford University:

Study Protocol  [PDF] May 6, 2016

Statistical Analysis Plan  [PDF] July 20, 2020

More Information

Publications of Results:

Tan M, Lamendola C, Luong R, McLaughlin T, Craig C. Safety, efficacy and pharmacokinetics of repeat subcutaneous dosing of avexitide (exendin 9-39) for treatment of post-bariatric hypoglycaemia. Diabetes Obes Metab. 2020 Aug;22(8):1406-1416. doi: 10.1111/dom.14048. Epub 2020 May 4.

• Responsible Party: Tracey McLaughlin, Associate Professor of Medicine (Endocrinology), Stanford University
• ClinicalTrials.gov Identifier: NCT02771574
• Other Study ID Numbers: 36673
• First Posted: May 13, 2016
• Results First Posted: August 14, 2020
• Last Update Posted: August 14, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Tracey McLaughlin, Stanford University:

Bariatric surgery complications; Glucose Metabolism Disorders; Exendin (9-39); GLP-1

Additional relevant MeSH terms:

Hypoglycemia; Glucose Metabolism Disorders; Metabolic Diseases