Clinical trial NCT02771574
Conditions: Post Bariatric Hypoglycemia
Keywords: Bariatric surgery complications Glucose Metabolism Disorders Exendin (9-39) GLP-1
Sponsor: Tracey McLaughlin
Start date: 2016-05-01; Completion date: 2017-06-01
Enrollment: 19 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

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).

Arms: arm 1: Participants will receive lyophilized avexitide (Lyo avexitide) twice daily for 3 days arm 2: Participants will receive Lyo avexitide twice daily for 3 days arm 3: Participants will receive Lyo avexitide twice daily for 3 days arm 4: Participants will receive Lyo avexitide twice daily for 3 days arm 5: Participants will receive liquid avexitide (Liq avexitide) twice daily for 3 days
Interventions: intervention 1: Lyo avexitide intervention 2: Liq avexitide
Intervention descriptions: intervention 1: Lyophilized avexitide (Lyo avexitide) administered subcutaneously (sc) intervention 2: Liquid avexitide (Liq avexitide) administered subcutaneously (sc)

Protocol documents:
Prot_002.pdf: 
NCT02771574 
 
Document Date (IRB Approval Date): May 6, 2016 
 
 
 
A Phase 2a Multi-Ascending Dose Trial to assess the efficacy, tolerability and pharmacokinetic profile  
of BID Exendin (9-39) in patients with post-bariatric hyperinsulinemic hypoglycemia 
 
 
Background and Study Rationale.  
Post-Bariatric Hyperinsulinemic Hypoglycemia (PBHH) is a rare, but increasingly reported complication of bariatric surgery, 
characterized by severe hypoglycemic episodes with neuroglycopenic symptoms.  At the moment, no medical therapies have been 
developed for this disorder, but the clinical need is great.  While the underlying cause is not known, the major contributory factor is 
thought to be an exaggerated postprandial 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) (Ex9) is a specific GLP-1 receptor antagonist, that when given via continuous IV infusion, effectively prevents 
postprandial hypoglycemia in patients with PBHH (1).  A single dose of subcutaneous (SC) Ex9 has been shown to effectively reverse 
postprandial hypoglycemia and substantially reduce symptoms in patients with hyperinsulinemic hypoglycemia (2).  Based upon the 
results of this single ascending dose study designed to examine the pharmacokinetics, pharmacodynamics, and local tolerability of 
SC Ex9, relatively low doses of Ex9, up to only 37,500 pmol/kg have been shown to effectively prevent hypoglycemia and reduce 
associated symptoms.  Building upon the success of these results, the proposed 3-day MAD study is a critical next step that will 
elucidate the pharmacokinetic and pharmacodynamic dose-response of BID SC Ex9.  
 
Study objectives and endpoints. 
Objective 
Endpoint 
Primary: 
 
 
To evaluate the treatment effect on plasma 
glucose of SC BID Ex9 
Response rate in plasma glucose nadir, defined as proportion of 
patients in each dose arm with no plasma glucose ≤50 mg/dL at any 
timepoint from 0-180 minutes during OGTT on Day 3 of treatment vs. 
on Day 0. 
Secondary: 
 
 
To evaluate the treatment effect on symptoms 
of hypoglycemia of SC BID Ex9 
Improvement in composite symptom score as compared to baseline 
during OGTT on Day 3 of treatment vs. on Day 0. 
 
 
To assess the pharmacokinetics of SC BID Ex9 at 
each dose level 
Plasma PK parameters include AUC0-12h, Cmax, Tmax, T1/2, and Ctrough, 
after SC injection. 
 
To assess the safety and tolerability of SC BID 
Ex9 at each dose level 
AEs, laboratory parameters, vital signs; NMR score, VAS score. 
 
 


 
Study Design. 
Overview: This is a single-blinded, dose-randomized, cross-over design study that will be conducted at the Stanford University School 
of Medicine.  All subject visits will take place in the Clinical and Translational Research Unit (CTRU).   Sixteen eligible subjects will be 
assigned to 1 of 4 dose levels to receive BID Ex9 over 3 days.  After a baseline Oral Glucose Tolerance Test (OGTT) is conducted on 
Day 0 wherein metabolic and symptomatic analyses will occur, subjects will return to the research clinic on Day 1 to initiate a BID 
dosing schedule for 3 days.  During this time, subjects will return daily for fasting labs in the morning, a morning dose, PK sampling, 
and an evening trough sample, followed immediately by the second daily dose at T+720 min. Safety, tolerability, and 
pharmacokinetic parameters will be measured on a daily basis for the full 3 day duration of the study, after which a repeat OGTT is 
performed on the morning of Day 3 after the morning dose to evaluate for efficacy (no hypoglycemia and reduction in composite 
symptom score).  Day 4 will consist solely of clinical safety monitoring with a plasma trough drawn 1440 minutes after the last Day 3 
injection.  This study if properly conducted is expected to demonstrate that BID dosing can result in meaningful therapeutic activity 
in each dosing arm. 
 
Randomization/Blinding: Computer-generated block randomization will be employed for the first 8 subjects, such that 2 subjects are 
randomized to each of 4-dose levels.  If no clinical efficacy is seen at a given level after 2 subjects have been tested at that level, that 
dose level will be removed and remaining subjects will be randomized to one of the remaining doses.  Otherwise, a total of 4 
subjects will be evaluated in each of 4 dose levels.  All subjects will remain blinded throughout.  With the exception of the PI and 
sub-investigator who will remain un-blinded for safety purposes, all site personnel including nurses and study coordinators, who 
conduct patient symptom surveys, will remain masked to treatment assignment.  
 
Study drug preparation and dispensation: All doses will be 
prepared by the Stanford Investigational Drug Services, and 
dispensed at the Stanford Clinical and Translational 
Research Unit by qualified staff, as previously described 
 
 
 
Oral Glucose Tolerance Test (OGTT): The OGTT will consist 
of administration of one 75 gram glucola drink with 1 gram 
of crushed acetaminophen to be consumed over 20 
minutes.   
 
Assays: Metabolic: glucose, c-peptide, insulin, GLP-1, GIP, 
glucagon; PK: AUC0-720, Cmax, Tmax, T1/2, Ctrough 
 
 
   
 


Overview of Visits. 
Day 0: Baseline OGTT with Metabolic analysis 
Timepoints:  
 
Plasma samples obtained at: T-10, T+30, 60, 90, 120, 150, 180. 
Metabolic Assays:  
Glucose, c-peptide, insulin, GLP-1, GIP, glucagon 
Days 1-3: SC injections at T=0 min and T=720 min, PK plasma samples with PK analysis 
Timepoints:  
 
Plasma samples at T-1, T+60, 120, 180, 210, 240, 300, 360, 480, 720 
Assays:   
 
AUC0-720, Cmax, Tmax, T1/2, Ctrough 
Day 3: Repeat OGTT after 5 SC injections with metabolic and PK analyses 
Timepoints:  
 
Plasma samples at T-1, +150, 180, 210, 240, 270, 300, 330, 480, 720 
Assays:   
 
Metabolic: Glucose, c-peptide, insulin, GLP-1, GIP, glucagon; PK: AUC0-720, Cmax, Tmax, T1/2, Ctrough 
Day 4: Safety monitoring, PK trough draw 
  
Timepoints: 
 
Plasma samples at T-1, T+60, 120, 180, 210, 240, 300, 360, 480, 720 
 
A schedule of all laboratory and clinical assessments by visits are outlined in detail on Table 4 below. 
 


Table 4.  Visit evaluation schedule 
 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Screening/Enrollment 
 
 
 
 
 
Obtain Informed 
consent 
X 
 
 
 
 
Patient history 
X 
 
 
 
 
Demography 
X 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
Prior/concomitant 
medications 
X 
 
 
 
 
Physical exam 
X 
 
 
X 
 
Height 
X 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
Pulse rate 
X 
X 
X 
X 
X 
Blood pressure 
X 
X 
X 
X 
X 
Oral Glucose 
Tolerance Test 
X 
 
 
X 
 
Hypoglycemic 
symptom assessment 
X 
 
 
X 
 
Metabolic assays:  
Glucose, c-peptide, 
insulin, GLP-1, GIP, 
glucagon 
X 
 
 
X 
 
Ex9 injection 
 
X (AM), X (PM) 
X (AM), X (PM) 
X (AM), X (PM) 
 
Tolerability 
assessment 
 
X (AM), X (PM) 
X (AM), X (PM) 
X (AM), X (PM) 
 
PK plasma samples  
 
X 
X 
X 
X 
Assessment for AEs 
Ongoing 
Laboratory 
assessments: 
 
 
 
 
 
Urine pregnancy test 
X 
 
 
 
 
CBC 
X 
 
 
 
X 
Comprehensive 
Chemistry 
X 
 
 
 
X 
 
 
 


Subjects. 
N=16 subjects 
 
Inclusion criteria.  
1. Male or female patients 18-70 years of age  
2. Post-bariatric surgery more than 6 months prior to signing the informed consent 
3. Documented history of hyperinsulinemic hypoglycemia 
4. Hypoglycemia during the baseline/screening OGTT on Visit Day 0, as defined by the presence of Whipple’s triad: the 
occurrence of hypoglycemic symptoms associated with a plasma glucose of ≤55 mg/dL, and resolution with glucose or 
carbohydrate administration.  
Exclusion criteria. 
1. Patients currently using sulfonylureas or other medications that may interfere with glucose metabolism within 5 half-lives 
of drug. 
2. Participation in any clinical investigation involving an experimental drug within 4 weeks prior to dosing 
3. History of or current insulinoma 
4. Active infection or significant acute illness within 2 weeks prior to dosing 
5. Female patients who are pregnant or lactating 
6. Women of childbearing potential and not utilizing effective contraceptive methods 
7. Inadequate end organ function as defined by: 
a. Serum creatinine >2.0 mg/dL 
b. ALT and AST > 3 x ULN 
 
 
   
 
 
 
 
 


Strategy proposed for interim data analysis. 
 
 
   
 
Dose cohort modification. 
No efficacy: In instances wherein no clinical efficacy is observed in the first two subjects at a given dose level (plasma glucose on Day 
3 repeat OGTT reaches 50 mg/dL or less), no further subjects will be assigned to that dose level.  Remaining subjects will be 
randomized to 1 of the remaining dose levels, as depicted in Figure 4 below. 
 
 
 
 
 
 

SAP_001.pdf: 
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   
Statistical Analysis Plan 
NCT02771574 
 July 20, 2020 
 
Data are presented as mean ± SD. Insulin sensitivity was estimated by homeostatic model assessment of 
insulin resistance (HOMA-IR). Area under the curve (AUC) calculations were performed using the 
trapezoidal rule. Because of the potential cancelling effect of the early rise and late fall in plasma 
glucose and insulin when considered as AUC over 180 minutes, AUC values were partitioned into 0 to 90 
(pre-glycaemic-peak) and 90 to 180 (post-glycaemic peak) minutes. Rate of glucose decline was 
calculated as (glucosepeak − glucosepeak + 30 min)/30 min. When the OGTT was stopped early because 
of hypoglycaemia requiring glycaemic rescue, the last glucose value recorded prior to rescue was carried 
forward. Plasma avexitide concentrations were collected twice daily for 3 days immediately prior to 
dosing, and over a 12-hour period on days 1 and 3 of dosing. Pharmacokinetic variables assessed include 
C0 (pre-dose concentration), Cmax (peak post-dose concentration), Tmax (time of Cmax), and AUC over 
a 12-hour period.