Clinical trial NCT04652479
Conditions: Acquired Hyperinsulinemic Hypoglycemia
Keywords: Post Bariatric Hypoglycemia avexitide Post-Bariatric Hypoglycemia Post-gastrectomy hypoglycemia Post gastrectomy hypoglycemia Post-esophagectomy hypoglycemia Post esophagectomy hypoglycemia Post-Nissen Fundoplication hypoglycemia Post Nissen Fundoplication hypoglycemia Exendin (9-39) Exendin 9-39
Sponsor: Dr. Tracey McLaughlin, MD
Start date: 2021-06-21; Completion date: 2022-06-30
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary goal of this study is to evaluate the safety and efficacy of two different dosing regimens of an investigational drug called Avexitide in treating low blood sugar in patients with Acquired Hyperinsulinemic Hypoglycemia.

Detailed description:

Arms: arm 1: Patients will receive one of the two dosing regimens of avexitide for 14 days followed by the other dosing regimen of avextide for 14 days arm 2: Patients will receive one of the two dosing regimens of avexitide for 14 days followed by the other dosing regimen of avextide for 14 days
Interventions: intervention 1: Avexitide
Intervention descriptions: intervention 1: Avexitide (exendin 9-39) is a competitive antagonist of GLP-1 at its receptor

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 
NCT04652479 
 CLINICAL STUDY PROTOCOL 52880 
 
Study Title: 
A Phase 2, Open-Label, Cross-over Study to Assess the Safety 
and Efficacy of Avexitide in Acquired Hyperinsulinemic 
Hypoglycemia 
Investigational Product 
Avexitide Injection 
IND Number  
; 
 by cross-reference 
Sponsor: 
Stanford University School of Medicine 
Principal Investigator 
Marilyn Tan, MD 
Date: 
20 November, 2020 
Amendment No.: 
0001 
Amendment submission date: 
13 May, 2021 
 
 
 


Page 2 
 
Sponsor: 
Stanford University School of 
Medicine 
Investigational Product:  
Avexitide Injection 
Developmental Phase: 
Phase 2 
Title of Study  
A Phase 2, Open-Label, Cross-over Study to Assess the Safety and Efficacy of Avexitide in Acquired 
Hyperinsulinemic Hypoglycemia 
Protocol Number:  52880 
 
INTRODUCTION AND BACKGROUND 
Hyperinsulinemic Hypoglycemia (HH) is a rare but growing disease state characterized by frequent 
episodes of severe symptomatic hyperinsulinemic hypoglycemia, with glucose concentrations low 
enough (<54 mg/dL) to cause seizures, altered mental status, loss of consciousness, cognitive 
dysfunction, disability, and possibly death. The predominant form of HH is post-bariatric 
hypoglycemia (PBH), which occurs in some 29-39% of patients undergoing Roux-en-Y gastric bypass 
(RYGB) and 10-23% of those undergoing vertical sleeve gastrectomy (VSG) (1-4). HH can also occur 
as a complication of other upper-gastrointestinal procedures, including esophagectomy (5), 
gastrectomy (6), and Nissen fundoplication (7). Currently, there are no effective medical therapies for 
patients with HH. 
 
The mechanisms mediating PBH and other forms of HH that occur after gastrointestinal procedures 
have long been debated, though excessive postprandial secretion of the incretin gut hormone, 
glucagon-like peptide-1 (GLP-1), has been shown to play a critical role in mediating hyperinsulinism 
(5-6,8-10). Avexitide is a specific, competitive antagonist of the GLP-1 receptor formed by the 
terminal deletion of the 8 N-terminus amino acids from exenatide (commercial name Byetta), a GLP-1 
agonist. Prior studies conducted by our laboratory and others involving either intravenous (7, 11-13) or 
subcutaneous (14-16) administration of avexitide have shown normalization of postprandial insulin 
concentrations with reduction in the occurrence and severity of hypoglycemia and associated 
symptoms.  
 
The most recent study in which our laboratory participated, the PREVENT study (16), was a Phase 2, 
randomized, placebo-controlled crossover study evaluating two dosing regimens of avexitide (30 mg 
BID and 60 mg QD) in 18 patients with diet-refractory PBH. In this study, 18 participants received 
placebo injections for 14 days followed by avexitide 30 mg BID and avexitide 60 mg QD, each for 14 
days in random order. The primary outcome was glucose nadir during mixed meal tolerance testing 
(MMTT) at the end of each 14-day treatment period. In addition, hypoglycemic events captured by 
SMBG, eDiary, and blinded continuous glucose monitoring (CGM) were captured. The primary and 
secondary endpoints were met by both avexitide regimens. Compared to placebo, avexitide 30 mg BID 
and 60 mg QD raised the plasma glucose nadir by 21% (p=0.001) and 26% (p=0.0002) and lowered the 
insulin peak by 23% (p=0.029) and 21% (p=0.042), corresponding to 50% and 75% fewer participants 
requiring rescue, respectively. Significant reductions in outpatient rates of Levels 1-3 hypoglycemia 
were observed, defined, respectively, as SMBG<70 mg/dL, SMBG<54 mg/dL, and a severe event 
characterized by altered mental and/or physical function requiring assistance. Blinded CGM 
demonstrated reductions in hypoglycemia without induction of clinically relevant hyperglycemia. 
Avexitide was well-tolerated, with no increase in adverse events.  
 


Page 3 
Based on the safety and tolerability profile of avexitide and the dose-response relationship observed 
with higher daytime avexitide exposure in the PREVENT trial, we seek to evaluate whether higher 
dosing regimens of avexitide may confer greater yet protection against hypoglycemia. In addition, 
given that GLP-1 excursions are also known to occur in forms of HH other than PBH, we seek to 
evaluate for the first time whether subcutaneous injection of avexitide may provide protection against 
hypoglycemia in this expanded cohort of patients with HH. Thus, we seek to extend upon the the 
previously conducted studies by investigating the safety, tolerability and efficacy of avexitide 
administered as 45 mg BID and 90 mg QD dosing regimens in patients with HH occurring after 
RYGB, VSG, esophagectomy, gastrectomy, and Nissen fundoplication. 
 
OBJECTIVES 
Primary Efficacy Objective  
Evaluate the effect of avexitide injection on the number of diurnal Level 2 hypoglycemia events 
(ADA, <54 mg/dL) as measured by CGM in patients with severe HH 
Secondary Efficacy Objectives  
Evaluate the effect of avexitide injection on the: 
• 
Rate of Level 2 hypoglycemia (ADA, <54 mg/dL) as measured by SMBG 
• 
Rate of Level 3 hypoglycemia (ADA, severe hypoglycemia) 
• 
Percent diurnal time <54 mg/dL as measured by CGM 
• 
Postprandial glycemia during standardized mixed meal consumption 
 
Exploratory Efficacy Objectives 
Evaluate the effect of avexitide injection on: 
• 
Quality of life (QoL) 
• 
Rate of Level 1 hypoglycemia (ADA, <70 mg/dL) as measured by SMBG in patients with 
severe HH  
• 
Percent time >250 mg/dL as measured by CGM 
• 
Percent nocturnal time <54 mg/dL as measured by CGM 
• 
Number of nocturnal Level 2 hypoglycemia events (ADA, <54 mg/dL) as measured by CGM 
• 
Characterize the Pharmacokinetic/Pharmacodynamic (PK/PD) profile of avexitide 45 mg BID 
and 90 mg QD 
• 
Evaluate development of anti-drug antibodies (ADA) 
 
 
Primary Safety Objective 
• 
Evaluate the safety and tolerability of avexitide 
 
 
INVESTIGATIONAL PLAN 
 
Study Design 


P a ge 4 
O ver vie w — T his is a P hase 2 b , si n gle ce nter, o pe n -la bel, cr oss-o ver st u d y of a ve xiti de i njecti o n  i n 
patie nts wit h s ur gicall y-i n d uce d se vere, diet-refract or y H H. Eli gi ble partici pa nts m ust ha ve a 
c o nfir me d dia g n osis of s ur gicall y-i n d uce d H H  a n d de m o nstrate se v ere, diet refract or y H H , as 
d oc u me nte d b y prese nce  of at least t w o se vere h y p o g yce mia e ve nts fr o m w hic h at least o ne m ust be 
c haracterize d b y gl uc ose < 5 4 m g/ d L as meas ure d b y  C G M d uri n g t he 1 4-da y R u n -i n Peri o d w hile 
a d heri n g t o me dical n utri tio nal t hera p y . 
 
E li gi ble H H  i n dicati o ns i ncl u de h y p o gl yce mia occ urri n g after: 
•  
Bariatric S ur ger y:  
-R o u x -e n-Y Gastric B y pass ( R Y G B) or Vertical Slee ve Gastrect o m y ( V S G)  
•  
U p per -Gastr oi ntesti nal S ur ger y:  
-Gastrect o m y , Es o p ha gect o m y , or Nisse n F u n d o plicati o n 
 
Pr o visi o nall y eli gi ble  s u bjects will u n der g o a 14- da y R u n -I n c o nsisti n g of sta n dar d of care ( S O C) 
treat me nt ( me dical n utriti o n t hera p y) wit h  sta n dar dize d mi xe d meal c o ns u m pti o n a n d scree ni n g la bs 
a n d c ollecti o n of bl o o d t o test f or a nti-dr u g a nti b o d y ( A D A) at t he e n d of t he 1 4 -da y S O C R u n -I n t o 
c o nfir m eli gi bilit y a n d esta blis h a baseli ne wit hi n 9 0 da ys of ra n d o mizati o n . E nr olle d partici pa nts will 
be ra n d o mize d t o o ne of  tw o  1 4 -da y a ve xiti de d osi n g re gi me n or ders ( Fi g ure 1). D oses are t o be self -
a d mi nistere d i n t he o ut patie nt setti n g via s u bc uta ne o us ( S C) i njecti o n. T hr o u g h o ut t he st u d y d urati o n 
partici pa nts will c o nti n ue t o mai ntai n  S O C treat me nt f oll o wi n g sta n dar d dietar y g ui deli nes f or 
ma na ge me nt of P B H a n d will be e val uate d b y bli n de d C G M,  patie nt electr o nic diar y (e Diar y) a n d 
S M B G. At t he e n d of Treat me nt Peri o d s 1 a n d 2, partici pa nts will re peat baseli n e assess me nts wit h 
A D A a n d  tr o u g h P K sa m ples a d diti o nall y dra w n. At t he e n d of Treat me nt Peri o d 2, partici pa nts  will 
ret ur n use d a n d u n use d st u d y dr u g vials  d uri n g t he  safet y f oll o w-u p visit.  
 
St u d y D ur ati o n —  De pe n di n g o n w he n a patie nt c o m pletes t he R u n -I n Peri o d, t he ma xi m u m 
a ntici pate d ti me a n i n di vi d ual patie nt will partici pate i n t he st u d y will be ~ 1 2 0  da ys.  
Fi g ure 1 
Di a gr a m of St u d y Desi g n 
 


Page 5 
Number of Participants   
Up to 20 participants will be enrolled in a 1:1 ratio to each of the two dosing regimen orders shown in 
Figure 1. Of the enrolled population, at least 50% will be post-RYGB; the remainder will be post-VSG, 
-gastrectomy, -esophagectomy, or -Nissen fundoplication. Randomization will be stratified by type of 
surgery RYGB vs Others (including VSG, gastrectomy, esophagectomy, or Nissen fundoplication). 
Rationale for Dose and Dose Regimen Selection 
The dose levels of avexitide and the dosing intervals selected for this study are based on results from 
the Phase 2 PREVENT study, a randomized, placebo-controlled crossover study evaluating two dosing 
regimens (30 mg BID and 60 mg QD) in 18 patients with diet-refractory PBH. On the basis of the 
strength and consistency of study results from the PREVENT trial and the safety and tolerability 
profile associated with avexitide exposure, we seek to conduct a preliminary analysis of use of a 90 mg 
total daily dose administered as 45 mg BID and 90 mg QD, as it is of our opinion that higher total daily 
exposure may be well-tolerated and has the potential to result in even more robust clinical outcomes.  
 
STUDY POPULATION 
 
Inclusion Criteria                
Patients must meet all of the following inclusion criteria before study entry to be eligible for 
enrollment.  
1. Able to understand the purpose and risks of the study; willing and able to adhere to scheduled 
visits, treatment plans, laboratory tests, procedures, and provide written informed consent 
2. History of qualifying bariatric or upper-gastrointestinal surgery (RYGB, VSG, gastrectomy, 
esophagectomy, or Nissen fundoplication) at least 12 months prior to the start of Screening 
3. Male or female, at least 18 years old (inclusive) at Visit 1 (Screening) 
4. Body mass index (BMI) of up to 40 kg/m2 
5. Has stable body weight, i.e., not varying by >5% for at least 4 months prior to Visit 1 
(Screening), as documented by the investigator  
6. History of recurrent hypoglycemia refractory to bariatric dietary recommendations occurring 
after bariatric or upper-GI surgery, as documented in the medical record. 
7. At least two severe hypogycemia events from which at least one must be characterized by 
glucose <54 mg/dL as measured by CGM during the 14-day Run-in Period while adhering to 
medical nutritional therapy.  
8. If female, must meet the following criteria: 
a. Not breastfeeding or lactating 
b. Negative urine pregnancy test result at Visit 4 (Screening) (not applicable to 
hysterectomized females); urine pregnancy test at Screening must be confirmed negative 
prior to randomization and dosing. 
c. If of childbearing potential (including peri-menopausal women who have had a menstrual 
period within 1 year) must agree to use appropriate birth control (defined as a method 
which results in a low failure rate, i.e., less than 1% per year, when used consistently and 
correctly, such as implants, injectables, hormonal contraceptives, some intrauterine 


Page 6 
contraceptive devices, sexual abstinence, tubal ligation or occlusion, or a vasectomized 
partner) during the entire duration of the study. Subjects must practice appropriate birth 
control as stated above for 4 weeks after the last dose of study drug. 
• 
Nonchildbearing potential is defined as surgically sterile (documented hysterectomy, 
tubal ligation, or bilateral salpingo oophorectomy) or postmenopausal (defined as 12 
months of spontaneous amenorrhea).  
9. Has no clinically significant abnormal complete metabolic panel (CMP) as judged by the 
investigator. Note: CMP collected at Visit 4 unless assessed within 6 months prior to 
randomization. 
10. Has no clinically significant medical condition, as judged by the investigator, at Screening 
 
Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the study. 
General Exclusions 
1. Use of an investigational drug within 5 half-lives of the study drug before Screening. 
2. Donation or loss of >500 mL of blood or blood product within 56 days before the first dose of 
study drug. 
3. Clinically significant active infection within 14 days before the first dose of study drug. 
4. Any clinically relevant acute or chronic psychiatric, renal, hepatic, pancreatic, cardiovascular, 
neurological, hematological, or gastrointestinal abnormality (eg, inflammatory bowel disease) 
or active malignancy. 
5. Major surgery within 6 months before randomization. 
6. History of or current insulinoma or other cause of endogenous hyperinsulinism other than HH 
(e.g., insulin autoimmune hypoglycemia). Such causes must be ruled out if clinically suspected 
by the Investigator.  
Exclusions Based on Laboratory Values 
7. Abnormal laboratory values of clinical significance as assessed by the Investigator. Note:  
Exclusions Based on Recent or Concomitant Medication or Drug Use 
8. Use of agents that may interfere with glucose metabolism within 5 half-lives, as follows: 
a. Anti-hyperglycemic agents (eg, insulin, sulfonylureas, meglitinides, metformin, 
thiazolidinediones [TZDs], dipeptidyl-peptidase [DPP-4] inhibitors, sodium-glucose-
linked transporter 2 [SGLT2] inhibitors, GLP-1 agonists). 
b. Alcohol (eg, beer, wine, drinks containing distilled spirits) 
c. Fluoroquinolone antibiotics (eg, ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, 
norfloxacin, ofloxacin)  
d. Tramadol (chronic use of other opioids is permitted as long as dose remains stable 
throughout study) 
e. Current use of acarbose, verapamil, diazoxide and or somatostatin analogs (eg. octreotide, 
pasirotide, lanreotide) 


Page 7 
f. Systemic or inhaled glucocorticoids (eg, prednisone, prednisolone, methylprednisolone, 
beclomethasone, betamethasone, dexamethasone, hydrocortisone, triamcinolone) with 
exception of topically or nasally administered steroids  
Subject Restrictions 
Participants must report any new prescription medications or over-the-counter preparations or any 
changes to concomitant medications to study staff for the duration of study participation 
INVESTIGATIONAL PRODUCT, DOSAGE AND ADMINISTRATION 
Avexitide injection is a sterile, clear, colorless solution and is supplied in single-use 3 mL vials 
containing 0.5 mL solution.  The drug product composition consists of 90 mg/mL avexitide injection 
(active ingredient).  The avexitide investigation product should be stored refrigerated between 2°C to 
8°C (35.6°F to 46.4°F), inclusive. 
 
Dispensing and Administration of Study Drug 
Three kits of study drug (two containing 28 x 3mL vials and one containing 6 x 3mL vials of 90 mg/ml 
solution) will be dispensed by the Investigator on V4. Participants will be given written and oral 
instructions on how to store, draw up and safely administered study drug. The study drug will be 
administered as subcutaneous injections either once daily in the morning (90 mg QD), or twice daily 
(45 mg BID): once in the morning and the second daily dose approximately 12 hours later. During 
once daily dosing, the morning dosing will occur at least 60 minutes prior to the first morning meal. 
During twice daily dosing, the morning dosing will not be relative to the timing of the first meal of the 
day.  
Missed Doses 
If patients miss a dose or a dose is delayed, the dose should be taken as soon as the missed or delayed 
dose is noted. In the event a dose is missed and it is time for the next dose to be taken, the missed dose 
should be taken along with the scheduled dose. However no more than 3 doses should be administered 
within any given 24-hour period. 
Drug Accountability 
Drug accountability will be maintained by the principal investigator, who will ensure that a current 
record of investigational product disposition is maintained and that the investigational product is used 
only in accordance with the approved protocol.  
Patients will be instructed to return all used and unused vials of study drug when they come to the 
clinic for the final study visit. Adherence with the prescribed regimen for each study drug will be 
estimated by counting the number of used and unused vials. 
STUDY CONDUCT AND ASSESSMENTS 
 
Screening Procedures 
Patients providing written informed consent will be evaluated to determine eligibility to participate in 
the study. An initial eligibility review will be conducted, including: 
• 
review of medical history and concomitant medications 
• 
review of Level 2 and Level 3 hypoglycemia event rate (<54 mg/dL by CGM or Level 3 
hypoglycemia) during Run-In 
• 
review of clinical lab results  


Page 8 
• 
pregnancy testing (as applicable) 
The preliminary eligibility assessments may be performed up to 90 days prior to randomization, 
consisting of a 14-day Baseline Run-in period during which the following items will be supplied 
concurrent with training:  
• 
eDiary  
• 
dietary guidelines (describes SOC medical nutrition therapy) 
• 
glucometer, lancets and test strips 
• 
Dexcom G6PRO 
 
Study Schedule 
The screening period comprises: 
• 
Visit 1 (Zoom): Informed Consent, review of medical history, hypoglycemia questionnaire, 
concomitant medications, assessment of preliminary eligibility 
• 
Visit 2 (Zoom): training on patient eDiary, glucometer use, and Dexcom G6PRO application 
and activation. Participants begin 14-day Run-In Period 
• 
Visit 3 (Zoom): Check in with patient. 
• 
On day 10 of the Run-In Period, participants place a new Dexcom G6PRO sensor. 
• 
Visit 4 (SHC): On day 14 of the Run-In Period, participants go to SHC for a urine pregnancy 
test, an ADA draw, and CMP as applicable then consume a standardized liquid mixed meal 
over 10 minutes, with fingerstick glucose checks every 30 minutes for a total of 180 minutes. 
Eligible participants are then enrolled, randomized and dispensed study drug.  
Enrolled participants will be randomized 1:1 to one of 2 avexitide dosing regimen orders, and 
will be trained on study medication injection procedures. Avexitide should be injected 
subcutaneously either once daily in the morning, or twice daily; once in the morning and the 
second daily dose approximately 12 hours later. During once daily administration (avexitide 90 
mg QD), morning dosing will occur at least 60 minutes prior to the first morning meal. During 
twice daily administration (avexitide 45 mg BID) morning dosing will not be relative to the 
timing of the first meal of the day. Throughout, patients will follow currently accepted dietary 
guidelines for treatment of PBH. 
• 
Visit 5 (Zoom): Participants are trained on study drug injection; initiate Treatment Period 1. 
Place new Dexcom G6PRO device. 
• 
Day 10 of Treatment Period 1: Participants place a new Dexcom G6PRO device.  
• 
Visit 6 (SHC): On day 14 of Treatment Period 1 participants have a PK and an ADA draw, 
have their final Treatment Period 1 study drug injection and 90 minutes later consume a 
standardized mixed meal over 10 minutes, with fingerstick glucose checks every 30 minutes 
for 180 minutes. Participants are dispensed new study drug and initiate a 2-day washout 
period.  
• 
Day 4 of Treatment Period 2: Participants place a new Dexcom G6PRO device. 
• 
Visit 7 (SHC): On day 14 of Treatment Period 2 participants have a PK and an ADA draw, 
have their final Treatment Period 2 study drug injection and 90 minutes later participants 
consume a standardized mixed meal over 10 minutes, with fingerstick glucose checks every 30 
minutes for a total of 180 minutes. Participants then remove their Dexcom sensor/transmitter 
and return their used/unused study drug vials. 
 


Page 9 
Study Procedures 
eDiary and Glucometer 
Patients will be trained on the use of an eDiary on Visit 2 in which they will record all hypoglycemia 
signs, symptoms, and outcomes, any corrective actions taken for hypoglycemia, any assistance 
received related to an episode, and dietary intake. Patients will also receive a glucometer prior to Visit 
2 and be instructed to check fingerstick glucose concentrations whenever they experience 
hypoglycemic symptoms. Patients will also enter into the eDiary all SMBG glucose values obtained 
during consumption of the 3 standardized liquid meals. Study personnel will train participants on the 
use of the eDiary and glucometer. 
 
Blinded Continuous Glucose Monitoring (CGM) 
During the Run-In phase, a Dexcom Mobile G6 Pro Continuous Glucose Monitoring System in blinded 
mode (i.e., the CGM device) will be issued to potential study participants. Each participant will be 
trained on its use in accordance with the manufacturer’s instructions. Written instructions for CGM use 
and maintenance will be provided. The instructions will, if necessary, be repeated at site visits. The 
data from CGM will be downloaded after Run-In and at the end of each 14-day period for enrolled 
subjects. Each device will be blinded for use during the study. The Dexcom Mobile G6 Pro CGM 
System must be removed before magnetic resonance imaging (MRI), computed tomography (CT) scan, 
or high-frequency electrical heat (diathermy) treatment.  
 
Dietary Treatment 
All patients will be expected to follow accepted dietary treatment guidelines for PBH throughout the 
study including during the Run-In period. Guidelines provided include limiting dietary carbohydrates 
to no more than 30 g per meal or 15 g per snack, avoiding simple, high glycemic index carbohydrates, 
maintaining adequate protein intake, abstaining from consumption of alcohol, and maintaining post-
bariatric vitamin and mineral supplementation. A written description of guidelines will be provided to 
each participant for at-home reference. The site personnel will be responsible for reviewing the 
guidelines with patients at each study visit. Patients will report dietary adherence in their eDiary on a 
daily basis.  
 
Mixed Meal Tolerance Test 
At the end of each study period (Run-In, Treatment Periods 1 and 2), participants will consume a 
standardized liquid meal (e.g., Boost Nutritional Drink) over 10 minutes, with fingerstick glucose 
checks every 30 minutes for a total of 180 minutes. Participants will record glucose values in the 
eDiary. 
 
Figure 2 


Page 10 
 
 
 
Quality of Life Assessments 
The Short-Form (36) Health Survey (SF-36v2), EQ-5D, Hypoglycemia Fear Survey-II (HSF-II), and 
Hypoglycemia Confidence Scale (HSC) are patient-reported outcomes measures that enrolled patients 
will complete via RedCap survey at the end of the Run-In period and at the end of each of study 
period. 
 
Clinical Laboratory Tests 
A urine pregnancy test as applicable, a complete metabolic panel (unless assessed within the 6 months 
prior), and blood samples for ADA will be obtained. Any out of range laboratory results should be 
assessed for clinical significance with study entry eligibility at the discretion of the PI.  
 
Safety Assessments  
Safety assessments will consist of monitoring and recording adverse events (AEs) and serious adverse 
events (SAEs). The investigator will carefully monitor each subject throughout the study for possible 
AEs. Patients enrolled into this study have hypoglycemia and severe hypoglycemic events due to their 
disease state. Thus, hypoglycemia and severe hypoglycemic events are expected and captured as 
endpoints. Hypoglycemia will therefore not be captured as an AE, whereas consequences of 
hypoglycemia, such as loss of consciousness or seizure, may be reported as an AE.  
 
Stopping Parameters 
Participant Stopping Parameters: If a study participant experiences an SAE that is determined by the 
study investigator and medical monitor to be likely related to study drug, study drug may be 
discontinued for that participant. 
 
Study Stopping Parameters: If 2 subjects experience an SAE determined by the study investigator and 
medical monitor to be likely related to study drug, the study may be stopped. 
 
Pharmacokinetic Assessments 
Blood samples will be collected to determine the plasma concentration of avexitide at predose on Day 
14 of Treatment Periods 1 and 2. Trough PK samples will be obtained 12 hours after the last 45 mg 
BID dose and 24 hours after the last 90 mg QD dose. Additional PK samples may be collected. 


Page 11 
Criteria for Evaluation 
Primary Efficacy Endpoint 
• 
The primary endpoint is the baseline-adjusted number of diurnal Level 2 hypoglycemia events 
(ADA, <54 mg/dL) as measured by CGM and defined as the number of events captured by 
CGM with glucose measures <54 mg/dL during diurnal hours (8am-10pm) within each 
treatment period divided by number of days for a given treatment period, then normalized to 
duration of 14 days. The baseline-adjusted number of diurnal Level 2 hypoglycemia events 
during 14 days of avexitide treatment (Treatment Periods 1 and 2) and 14 days of standard of 
care treatment (Run-In Period) will be calculated and examined in a mixed-effect model, 
including treatment, treatment sequence, treatment period, and surgery type stratum (RYGB 
vs. Others) as fixed effect, and subject-within-sequence as random effect. The least squares 
(LS) mean, the standard error (SE), the 2-sided 95% confidence interval (CI), and the p-value 
will be derived from the mixed-effect model for each active treatment. No multiplicity 
adjustment is planned, and the primary endpoint will be evaluated through the nominal p-
values. P<0.05 is considered statistically significant.  
Secondary Endpoints 
The secondary endpoints include the following: 
• 
Rate of Level 2 hypoglycemia, defined as number of distinct episodes of Level 2 
hypoglycemia (SMBG glucose <54 mg/dL), divided by number of days for a given treatment 
period, then normalized to duration of 14 days. 
• 
Rate of Level 3 hypoglycemia (severe hypoglycemia), defined as the number of severe events 
during each treatment period characterized by altered mental and/or physical functioning that 
requires assistance from another person for recovery, divided by number of days for a given 
treatment period, then normalized to duration of 14 days. This applies regardless of whether a 
patient actually receives external assistance. Since the categorization of a severe hypoglycemia 
event can be subjective, particularly in cases where severe neuroglycopenic symptoms/signs 
occurred and external assistance was needed but was not received, all potential qualifying 
severe hypoglycemia events will be adjudicated by the principal investigator.  
• 
Percent diurnal time <54 mg/dL, defined as the percentage of CGM values <54 mg/dL during 
daytime hours (8am-10pm) within each treatment period, normalized to 14 days. 
• 
The magnitude of postprandial hypoglycemia, defined as the glucose nadir as measured by 
fingerstick glucose occurring within 3 hours of standardized liquid meal consumption. The 
plasma glucose nadir obtained during avexitide plus standard of care (Treatment Periods 1 and 
2) will be compared to during standard of care (Run-In). Particularly, the baseline-adjusted 
plasma glucose nadir will be calculated for each patient and evaluated. 
Secondary endpoints will be analyzed in the same manner as the primary efficacy endpoint.   
 
Exploratory Endpoints 
• 
QoL as measured by SF 36 v2, EQ-5D, HSF-II, and HCS. 
• 
Rate of hypoglycemia, defined as the number of distinct episodes of SMBG glucose 
<70 mg/dL divided by number of days for a given treatment period, then normalized to 
duration of 14 days. 


Page 12 
• 
Percent time >250 mg/dL, defined as the percentage of CGM values >250 mg/dL during each 
treatment period, normalized to 14 days 
• 
Percent nocturnal time <54 mg/dL as measured by CGM, defined as as the percentage of CGM 
values <54 mg/dL during nocturnal hours (12am-6am) within each treatment period, 
normalized to 14 days. 
• 
Number of nocturnal Level 2 hypoglycemia events (ADA, <54 mg/dL) as measured by CGM 
and defined as the number of events captured by CGM with glucose measures <54 mg/dL 
during nocturnal hours (12am-6am) within each treatment period divided by number of days 
for a given treatment period, then normalized to duration of 14 days. 
 
Safety Endpoints 
Safety endpoints include evaluation of adverse events 
 
References 
1. Lee CJ, Brown TT, Schweitzer M, Magnuson T, Clark JM. The incidence and risk factors 
associated with developing symptoms of hypoglycemia after bariatric surgery. Surg Obes 
Relat Dis 2018;14:797-802. 
2. Lee CJ, Clark JM, Schweitzer M, et al. Prevalence of and risk factors for hypoglycemic 
symptoms after gastric bypass and sleeve gastrectomy. Obesity (Silver Spring). 2015;23:1079-
84. 
3. Kefurt R, Langer FB, Schindler K, Shakeri-Leidenmühler S, Ludvik B, Prager G. 
Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose 
monitoring (CGM) versus mixed meal test. Surg Obes Relat Dis 2015;11:564-9. 
4. Brix JM, Kopp HP, Höllerl F, Schernthaner GH, Ludvik B, Schernthaner G. Frequency of 
Hypoglycaemia after Different Bariatric Surgical Procedures. Obes Facts 2019;12:397-406. 
5. Elliott JA, Docherty NG, Murphy CF, et al. Changes in gut hormones, glycaemic response and 
symptoms after oesophagectomy. Br J Surg 2019;106:735-46. 
6. Larraufie P, Roberts GP, McGavigan AK, et al. Important role of the GLP-1 axis for glucose 
homeostasis after bariatric surgery. Cell Rep 2019;26:1399-1408. 
8. Salehi M, Prigeon RL, D’Alessio DA. Gastric bypass surgery enhances glucagon-like peptide-
1 stimulated postprandial insulin secretion in humans. Diabetes 2011;60:2308-14.  
9. Korner J, Bessler M, Inabnet W, Taveras C, Holst JJ. Exaggerated glucagon-like peptide-1 and 
blunted glucose dependent insulinotropic peptide secretion are associated with Roux-en-Y 
gastric bypass but not adjustable gastric banding. Surg Obes Relat Dis 2007;3:597–601. 
10. Goldfine A, Mun E, Devine E, et al. Patients with neuroglycopenia after gastric bypass surgery 
have exaggerated incretin and insulin secretory responses to a mixed meal. J Clin Endocrinol 
Metab 2007;92:4678-85. 
11. Salehi M, Prigeon RL, D'Alessio DA. Gastric bypass surgery enhances glucagon-like peptide-
1 stimulated postprandial insulin secretion in humans. Diabetes 2011;60:2308-14.  
12. Craig CM, Liu LF, Deacon CF, Holst JJ, McLaughlin TL. Critical role for GLP-1 in 
symptomatic post bariatric hypoglycemia. Diabetologia 2017;60:531-40. 


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13. Calabria AC, Charles L, Givler S, De Leon DD. Postprandial hypoglycemia in children after 
gastric surgery: clinical characterization and pathophysiology. Horm Res Paediatr 
2016;85:140-6. 
14. Craig CM, Liu L, Nguyen T, Price C, Bingham J, McLaughlin T. Efficacy and 
pharmacokinetics of subcutaneous exendin (9-39) in patients with post-bariatric 
hypoglycaemia. Diabetes Obes Metab 2018;20:352-61. 
15. Tan M, Lamendola C, Luong R,  McLaughlin T, Craig CM. Safety, efficacy and 
pharmacokinetics of repeat subcutaneous dosing of avexitide (exendin 9-39) for treatment of 
post-bariatric hypoglycaemia. Diabetes Obes Metab 2020;22(8):1406-16 
16. Craig CM, Lawler HL, Lee CJE et al. PREVENT: A Randomized, Placebo-Controlled 
Crossover Trial of Avexitide for Treatment of Post-Bariatric Hypoglycemia. J Clin Endocrinol 
Metab. 2021 Feb 22:dgab103. doi: 10.1210/clinem/dgab103. Epub ahead of print. 
 


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Page 15 
APPENDIX A   
 
 
 
 
 
 
 
  
 
 
SCHEDULE OF EVENTS 
 
 
DAY-0 
 
 
 
ZOOM 
VISIT 1 
RUN-IN 
PERIOD 
(DAY-1) 
 
ZOOM  
VISIT 2 
RUN-IN 
PERIOD 
(DAY-4) 
 
ZOOM  
VISIT 3 
RUN-IN 
PERIOD 
(DAY-10) 
 
 
NO VISIT  
RUN-IN 
PERIOD 
(DAY-14)  
 
STANFORD  
VISIT 4 
TREATMENT 
PERIOD 1 
(DAY-1) 
 
ZOOM  
VISIT 5 
TREATMENT 
PERIOD 1 
(DAY-10) 
 
 
NO VISIT  
TREATMENT 
PERIOD 1 
(DAY-14)  
 
STANFORD 
VISIT 6 
TREATMENT 
PERIOD 2  
(DAY-1) 
 
 
NO VISIT 
TREATMENT 
PERIOD 2  
(DAY-4)  
 
 
NO VISIT 
TREATMENT 
PERIOD 2 
(DAY-14)  
 
STANFORD  
VISIT 7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Hypoglycemia 
Questionnaire  
X 
 
 
 
 
 
 
 
 
 
 
Quality of Life 
Assessments** 
 
 
 
 
X 
 
 
X* 
 
 
X* 
Physical Exam 
X 
 
 
 
 X* 
 
 
 
 
 
X* 
Preliminary Eligibility 
Determination 
X 
 
 
 
 
 
 
 
 
 
 
eDiary Training  
 
X 
 
 
 
 
 
 
 
 
 
Glucose Meter Training 
 
X 
 
 
 
 
 
 
 
 
 
Check-In with Patients  
 
 
X 
 
 
 
 
 
 
 
 
Review Dietary 
Guidelines and SOC 
Adherence 
X 
X 
X 
 
X 
X* 
 
X* 
 
 
X* 
Initiate eDiary and 
glucometer Use  
 
X 
 
 
 
 
 
 
 
 
 
CGM Training 
 
X 
 
 
 
 
 
 
 
 
 
CGM 
Placement/Activation 
 
X 
 
X 
 
X* 
X* 
 
 
X* 
 
Mixed Meal Tolerance 
Test 
 
 
 
 
X 
 
 
X* 
 
 
X* 
CGM Removal 
 
 
 
X 
 
 
X* 
 
 
X* 
X* 


Page 16 
 
* Procedures and activities are only applicable to enrolled participants (determined on Visit 4 at Stanford Health Clinic).  
** QoL assesements are not completed during the visit. 
*** CMP drawn at Visit 4 unless assessed within the prior 6 months. 
 
 
Trough PK Draw 
 
 
 
 
 
 
 
X* 
 
 
X* 
Blood Draw (CMP)*** 
 
 
 
 
X 
 
 
 
 
 
X* 
ADA Draw  
 
 
 
 
X 
 
 
X* 
 
 
X* 
Urine Pregnancy Test   as 
applicable 
 
 
 
 
X 
 
 
 
 
 
 
Final Eligibility 
Determination  
 
 
 
 
X 
 
 
 
 
 
 
Randomization 
 
 
 
 
X* 
 
 
 
 
 
 
Dispensing of Study 
Drug 
 
 
 
 
X* 
 
 
 
 
 
 
Study Drug Injection 
Training  
 
 
 
 
 
X* 
 
 
 
 
 
14-Day Treatment Period 
1 Starts 
 
 
 
 
 
X* 
 
 
 
 
 
2-Day Washout Period 
Starts 
 
 
 
 
 
 
 
X* 
 
 
 
14-Day Treatment Period 
2 Starts 
 
 
 
 
 
 
 
 
X* 
 
 
Concomitant Medications 
X 
X 
X 
 
X 
X* 
 
X* 
 
 
X* 
Adverse Events 
 
 
X 
 
X 
X* 
 
X* 
 
 
X* 
Return of Used and 
Unused Study Drug Vials  
 
 
 
 
 
 
 
 
 
 
X* 
Study Drug 
Accountability 
 
 
 
 
 
 
 
 
 
 
X*