Conditions: Postbariatric Hypoglycemia
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 18
Healthy volunteers: no

Brief summary:
This clinical study will evaluate whether taking an investigational drug called exendin 9-39 is safe, well-tolerated, and helps to prevent low blood sugar in people who have had bariatric surgery and later develop a rare condition called postbariatric hypoglycemia (PBH).

Detailed description:
This is a Phase 2, multicenter, randomized, single-blind, placebo-controlled cross-over study in patients with refractory PBH.

Participants will be randomized and assigned in a 1:1 ratio to one of two treatment arms. All participants will receive 2 dosing regimens of exendin 9-39 and matching placebo self-administered via subcutaneous (SC) injection.

Participants will undergo in-clinic mixed meal tolerance test (MMTT) provocation with concomitant blood draws and symptom assessments.

Arms:
arm 1: patients will receive two dose regimens of exendin 9-39 and one placebo arm 2: patients will receive two dose regimens of exendin 9-39 and one placebo (in a different sequence than Treatment Group 1)

Interventions: intervention 1: exendin 9-39 intervention 2: Placebo
Intervention descriptions: intervention 1: Exendin 9-39 is a competitive antagonist of GLP-1 at its receptor. intervention 2: Placebo solution is identical to the active drug product except for the absence of the active ingredient, Exendin 9-39.

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 4 
 
 
 
 
A Phase 2, Multicenter, Randomized, Single-Blind, 
Placebo-Controlled Cross-Over Study to Assess the 
Efficacy and Safety of Exendin 9-30 in Patients with 
Postbariatric Hypoglycemia 
 
NCT03373435 
 
Document date: March 31, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 2 of 4 
 
Protocol:  
Study Objective 
PREVENT is a multicenter, randomized placebo controlled Phase 2 trial to evaluate the 
efficacy of a pharmacologic agent: Avexitide for patients with postbariatric hypoglycemia 
(PBH) in the outpatient setting. 
Study design 
The PREVENT trial was a randomized, placebo-controlled, crossover study conducted 
at five U.S. academic centers. The study design, consisting of three 14-day treatment 
periods. After a run-in period during which eligibility was confirmed, 18 participants with 
severe, diet-refractory PBH were randomized 1:1 to one of two arms, each differing in 
the order of dosing regimen. For both groups, Treatment Period 1 consisted of 
subcutaneous placebo injections. During Treatment Periods 2 and 3, avexitide was 
administered 30 mg twice daily (BID) and 60 mg once daily (QD) in crossover design 
and random order. At the end of each treatment period, participants underwent 
standardized mixed-meal tolerance testing (MMTT) in the clinical research unit (CRU) 
with hormonal, metabolic, and symptomatic assessments. Throughout, participants 
were required to adhere to PBH dietary recommendations and document all 
hypoglycemic events in the outpatient setting using electronic diaries (eDiaries), self-
monitoring of blood glucose (SMBG), and blinded continuous glucose monitors (CGM).  
Participants 
Eligible participants were men or women ages 18-65 years old who had undergone 
RYGB surgery at least 12 months before screening and had a documented history of 
PBH defined as Whipple’s triad, with inappropriately elevated insulin (≥3 µU/mL) or C-
peptide (>0.6 ng/mL) at the time of hypoglycemia (≤54 mg/dL glucose).17 Eligible 
participants were further required to exhibit at least 2 episodes of hypoglycemic 
symptoms confirmed by SMBG≤54 mg/dL while following dietary guidelines during the 
run-in period. 
Patients who had any of the following criteria were excluded from study participation: 
• history of hypoglycemia predating RYGB surgery;  
• history of insulinoma or other cause ofendogenous hyperinsulinism; 
• clinically significant acute medical conditions;  
• pregnancy, lactation, and/or women of childbearing potential not using effective 
contraceptive methods;  
• and use of any agents known to interfere with glucose metabolism within 5 half 
lives at screening.  
Pregnancy status for individuals of childbearing potential was confirmed by 
documentation of negative plasma pregnancy test at screening and a negative urine 


Page 3 of 4 
 
pregnancy test on the first day of dosing. Nonchildbearing potential was defined as 
surgical sterility (documented hysterectomy, tubal ligation, or bilateral salpingo-
oophorectomy) or postmenopausal status (defined as 12 months of spontaneous 
amenorrhea) 
Randomization and masking 
Participants were informed that one treatment period would involve placebo injections 
and were blinded to treatment sequence and study drug composition. Participants 
received two subcutaneous injections daily throughout all three study periods to fulfill 
blinded conditions, with injections comprised of the appropriate combination of placebo 
and/or active avexitide 30 mg dose(s). Investigators and site staff were blinded to 
avexitide sequence during Treatment Periods 2 and 3 and to laboratory results. For 
safety reasons, investigators, but not participants, had access to point-of-care glucose 
results during the MMTTs to determine whether glycemic rescue was indicated. 
 
Procedures 
In-clinic MMTT procedures: At the end of each treatment period, subjects were admitted 
to the CRU after an overnight fast for a 180-minute MMTT. After a baseline blood draw, 
subjects consumed two Ensure® Compact Drinks containing 64g of carbohydrate over 
10 minutes, with labs drawn every 15 minutes (for plasma glucose, insulin, c-peptide, 
GLP-1 and glucagon) and bedside assessment of neuroglycopenic symptoms and 
point-of-care glucose via the HemoCue® Glucose 201 System every 30 minutes. If 
rescue parameters were met (the earlier of point-of-care glucose ≤50 mg/dL with 
documented neuroglycopenic symptoms or ≤40 mg/dL irrespective of symptoms), final 
blood samples were drawn and participants were rescued by intravenous dextrose. The 
primary outcome of plasma glucose nadir was based on plasma samples assayed per 
standard methods. 
Pharmacokinetic assessments: Blood samples for the determination of plasma avexitide 
concentrations were collected at the end of each 14-day avexitide treatment period at -
90, 0, 60, 180 and 330 min relative to the timing of study drug injection. 
At home procedures: Throughout all treatment periods subjects used an eDiary 
(internetconnected web application), a CONTOUR®Next One glucometer, and blinded 
Dexcom Mobile G4® CGM for recording of hypoglycemic events occurring in the 
ambulatory setting. 
For each episode, patients recorded hypoglycemia symptoms/signs, the lowest SMBG 
reading during the episode, actions taken to treat or prevent the episode, requirement 
for assistance, and whether the episode was postprandial. Study drug injections were 
also recorded, and adherence was additionally monitored via accounting of returned 
study drug vials. 


Page 4 of 4 
 
Outcomes Measurement 
Primary and secondary endpoints were based on participant responses to MMTT in the 
CRU, while exploratory endpoints were based on events captured via eDiary, SMBG, 
and blinded CGM in the outpatient setting. The primary outcome was postprandial 
plasma glucose nadir during MMTT and the main secondary outcome was postprandial 
insulin peak during MMTT. Exploratory outcomes captured by SMBG and eDiary were 
pre-specified with definitions updated post-hoc according to current international 
consensus guidelines on the reporting of hypoglycemia in clinical trials, as follows: Level 
1 hypoglycemia: SMBG<70 mg/dL; Level 2 hypoglycemia: SMBG<54 mg/dL; Level 3 
hypoglycemia: a severe event characterized by altered mental and/or physical 
functioning that requires assistance from another person for recovery.  
Exploratory outcomes captured by CGM were prespecified with definitions revised post-
hoc in accordance with current guidance36 and included percent time above or below 
extreme glycemic thresholds (<54 mg/dL; >250 mg/dL) and number of events <54 
mg/dL. Percent time <54 mg/dL and number of events <54 mg/dL were also defined 
temporally by fasting (12am-8am) vs. prandial/post-prandial (8am-12am) periods; the 
latter more broadly representing the hours during which meal-induced hypoglycemia 
may occur and accounting for the mean 1-2-hour delay from mealtime to glucose nadir 
observed in patients with PBH. The pharmacokinetic profile for each dosing regimen 
was evaluated on an exploratory basis. Safety assessments included adverse events, 
clinical laboratory results, and physical examination findings. 
 
Statistical Analysis Plan 
A sample size of 12 completed patients was selected to provide more than 90% power 
to detect an increase in glucose nadir of at least 15.0 mg/dL assuming a standard 
deviation of 14.0 mg/dL at a significance level (α) of 0.05 using a two-sided paired t-test. 
The primary efficacy endpoint was calculated and examined in a mixed-effect model, 
including treatment, treatment sequence, and treatment period as fixed effect, and 
subject-within sequence as random effect. The Least Squares (LS) mean, standard 
error (SE), 95% confidence interval (CI), and p-value were derived from the mixed-effect 
model for each active treatment. No multiplicity adjustment was planned, and the 
primary endpoint was evaluated through the nominal p-values. Placebo-corrected 
secondary and exploratory endpoint data were analyzed in the same manner as the 
primary endpoint, with the exception of pharmacokinetic data, which were summarized 
descriptively.