Conditions: Diabetes Mellitus, Type 1
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 110
Healthy volunteers: yes

Brief summary:
The purpose of this study is to test if a specific research medication could increase the response to low blood glucose in people with type 1 diabetes. The response of the body to low blood sugar will be measured in healthy people as a reference point.

Detailed description:
This is a placebo-controlled, double-blinded, within-subject, cross-over phase 2a study. In randomized order, (Latin square, randomly assigned to placebo-active and active-placebo periods) and in a double-blinded manner, the participants with T1D received 14 days of daily dosing with MBX-2982 (or placebo), taken at the same time each day after breakfast. The last dose of treatment/placebo was given when the glucose tracer infusion for the euglycemic/hypoglycemic-glucose clamp started. Participants with T1D underwent two euglycemic-hypoglycemic clamps (induction of controlled hypoglycemia by an insulin infusion), using a within-subject cross-over design, with the two clamps separated by approximately four weeks, that is, two weeks of drug washout followed by two weeks of treatment with the alternative therapy. Glucagon, hepatic glucose production and other counter-regulatory hormonal responses were assessed during hypoglycemia. After completion of the first clamp study, participants did not receive any study medication for two weeks (washout phase) and then begin 14 days of the other arm (placebo or MBX-2982) in a double-blinded manner, followed by a repeat euglycemic-hypoglycemic clamp study. During treatment on each arm and during wash out phase, a blinded CGM was used to assess daily and nocturnal patterns of glycemia. On the day preceding a clamp study, while admitted to the research unit, a standardized meal test was used to assess fasting and postprandial glucagon, GLP-1 and GIP secretion. A healthy normal volunteer cohort with no diabetes was enrolled in the study for 14 days for comparison of normal responses to insulin induced hypoglycemia.

Arms:
arm 1: Participants with type 1 diabetes (T1D) will be randomized to either study medication or placebo group. In this arm, participants will receive a pill that contains the study medication (MBX-2982). This will be followed by a wash-out period and a cross over to the second study period in which they will receive a pill that does not contain the medication (placebo). arm 2: This group will not receive any medication. It will be studied to establish the norm of the measurement that will be performed to obtain the study outcomes. arm 3: Participants with type 1 diabetes (T1D) will be randomized to either study medication or placebo group. In this arm, participants will receive a pill that does not contain the medication (placebo). This will be followed by a wash-out period and a cross over to the second study period in which they will receive a pill that contains the study medication (MBX-2982).

Interventions: intervention 1: Placebo intervention 2: Study Medication (MBX-2982) intervention 3: No medication for this group
Intervention descriptions: intervention 1: Each group will receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo) intervention 2: Each group will receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo) intervention 3: This group will be studied to establish the norm of the measurement that will be performed to obtain the study outcomes.

Protocol document:
Prot_SAP_004.pdf: 
 
 
 
 
A randomized, placebo-controlled, double-blinded cross-over study of the 
pharmacologic action of a GPR119 agonist on glucagon counter-regulation 
during insulin-induced hypoglycemia in Type 1 diabetes mellitus. 
Short title: GPR119 agonist for hypoglycemia in T1D  
Protocol Number: IRBNet #1552172 
National Clinical Trial (NCT) Identified Number:  NCT04432090 
Principal Investigator: Richard E. Pratley, MD 
Senior Investigator and Diabetes program lead 
Translational Research Institute – Advent Health 
301 E. Princeton Street 
Orlando, Florida, 32804 
Phone 407-303-2519 
email: Richard.Pratley.MD@AdventHealth.com 
IND Sponsor: AdventHealth 
IND # 151908 
 
 
Funded by: The Helmsley Charitable Trust 
Version Number:  v.10.0 
21Nov2022


  
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
Site Principal Investigator Statement ....................................................................................................................... 2 
Abbreviations ............................................................................................................................................................... 3 
1 
PROTOCOL SUMMARY ............................................................................................................................... 6 
1.1 
Synopsis ................................................................................................................................................ 6 
1.2 
Schema ............................................................................................................................................... 10 
1.3 
Schedule of Activities (SoA) ............................................................................................................. 11 
2 
INTRODUCTION .......................................................................................................................................... 12 
2.1 
Study Rationale .................................................................................................................................. 12 
2.2 
Background......................................................................................................................................... 14 
2.2.1 
Physical, Chemical and Pharmaceutical Properties ................................................. 14 
2.2.2 
Repeat Dose Pharmacokinetics................................................................................... 15 
2.2.3 
Pharmacologic Profile ................................................................................................... 15 
2.2.4 
Toxicology Profile ........................................................................................................... 16 
2.2.5 
Safety Pharmacology .................................................................................................... 17 
2.2.6 
Human Experience ........................................................................................................ 17 
2.2.7 
Human Safety and Tolerability Profile ......................................................................... 19 
2.2.8 
Summary of Non-clinical and Clinical Investigations with MBX-2982 .................... 20 
2.2.9 
Overall Safety Conclusions .......................................................................................... 20 
2.3 
Risk/Benefit Assessment .................................................................................................................. 20 
2.3.1 
Known Potential Risks ................................................................................................... 20 
2.3.2 
Known Potential Benefits .............................................................................................. 22 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 22 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 24 
4 
STUDY DESIGN ........................................................................................................................................... 25 
4.1 
Overall Design .................................................................................................................................... 25 
4.2 
Scientific Rationale for Study Design.............................................................................................. 26 
4.3 
Justification for Dose ......................................................................................................................... 26 
4.4 
End of Study Definition ..................................................................................................................... 27 
5 
STUDY POPULATION ................................................................................................................................ 28 
5.1 
Inclusion Criteria ................................................................................................................................ 28 
5.2 
Exclusion Criteria ............................................................................................................................... 28 
5.3 
Screen Failures .................................................................................................................................. 30 
5.4 
Strategies for Recruitment and Retention ...................................................................................... 30 
5.4.1 
Subject recruitment ........................................................................................................ 30 
5.4.2 
Vulnerable populations .................................................................................................. 30 
5.4.3 
Subject stipends or payments ...................................................................................... 31 
6 
STUDY INTERVENTION ............................................................................................................................ 31 
6.1 
Study Intervention(s) Administration ............................................................................................... 31 
6.1.1 
Study Intervention Description ..................................................................................... 31 
6.1.2 
MBX-2982 ....................................................................................................................... 32 
6.1.3 
Placebo 32 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 33 
6.2.1 
Acquisition and accountability ...................................................................................... 33 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 33 
6.4 
Study Intervention Compliance ........................................................................................................ 33 


  
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6.5 
Concomitant Therapy ........................................................................................................................ 33 
6.5.1 
Rescue Medicine ............................................................................................................ 34 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 34 
7.1 
Discontinuation of Study Intervention ............................................................................................. 34 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 34 
7.2.1 
Investigator Withdrawal of Subjects ............................................................................ 34 
7.2.2 
Subject Request for Withdrawal from Study .............................................................. 34 
7.2.3 
Data Collection and Follow-up for Withdrawn Subjects ........................................... 34 
7.3 
Lost to Follow-Up ............................................................................................................................... 35 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 35 
8.1 
Schedule of Events............................................................................................................................ 35 
8.1.1 
Visit 1- Screening Visit/ Day -35 up to -7 (outpatient, 2-3 hours) ............................ 36 
8.1.2 
Visit 2 – Baseline visit/ Day -7±2 (T1DM cohort) or 8 days before V5 (healthy 
cohort) (outpatient, 1 hour): 36 
8.1.3 
Visit 3 – randomization visit/ Day 0±2 (outpatient, 1 hour) ...................................... 37 
8.1.4 
Visit 4 – follow up visit/ Day 7±2 (outpatient, 1-1.5 hours) ....................................... 37 
8.1.5 
Visit 5 – Period 1/ Day 13-14+5 (T1DM cohort) (inpatient, 2 days) or within 28 
days after screening (Healthy cohort) ............................................................................................................ 37 
8.1.6 
Weeks 5 Days 21±2 (phone call, 15 to 30 min) ......................................................... 39 
8.1.7 
Visit 6 – Drug start for period 2/ Day 28±2 (outpatient, 1 hour) .............................. 39 
8.1.8 
Visit 7 – follow up visit/ Day 35±2 (outpatient, 1-1.5 hours): .................................... 40 
8.1.9 
Visit 8 – Period 2/ Day 41-42+5 (inpatient, 2 days): ................................................. 40 
8.1.10 
Visit 9 EOT – Safety visit/ Day 49±2 (outpatient, 1-1.5 hours): ............................... 41 
8.2 
Efficacy Assessments ....................................................................................................................... 41 
9 
Safety and Other Assessments .................................................................................................................. 44 
9.1 
Adverse Events and Serious Adverse Events ............................................................................... 45 
9.1.1 
Definition of Adverse Events (AE) ............................................................................... 45 
9.1.2 
Definition of Serious Adverse Events (SAE) .............................................................. 46 
9.1.3 
Classification of an Adverse Event .............................................................................. 46 
9.1.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 47 
9.1.5 
Reporting Events to Participants ................................................................................. 47 
9.1.6 
Events of Special Interest ............................................................................................. 47 
9.1.7 
Reporting of Pregnancy ................................................................................................ 48 
9.2 
Unanticipated Problems .................................................................................................................... 48 
9.2.1 
Definition of Unanticipated Problems (UP) ................................................................. 48 
9.2.2 
Unanticipated Problem Reporting ................................................................................ 48 
9.2.3 
Reporting Unanticipated Problems to Participants ................................................... 49 
10 
STATISTICAL CONSIDERATIONS .......................................................................................................... 49 
10.1 
Statistical Hypotheses ....................................................................................................................... 49 
10.2 
Sample Size Determination .............................................................................................................. 50 
10.3 
Randomization ................................................................................................................................... 50 
10.4 
Blinding ................................................................................................................................................ 51 
10.4.1 
Institutional Review board ............................................................................................. 51 
10.4.2 
Data and Safety Monitoring Board (DSMB) or Equivalent ....................................... 51 
10.4.3 
Monitoring Plan............................................................................................................... 51 
10.4.4 
Quality Assurance and Quality Control ....................................................................... 51 


  
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10.5 
Materials of Human Origin:  Collection, Preparation, Handling and Shipping .......................... 52 
10.6 
Data Handling and Record Keeping ............................................................................................... 53 
10.6.1 
Data Collection and Management Responsibilities................................................... 53 
10.6.2 
Study Records Retention .............................................................................................. 54 
10.6.3 
Protocol Deviations ........................................................................................................ 54 
10.6.4 
Publication and Data Sharing Policy ........................................................................... 54 
10.6.5 
Conflict of Interest Policy .............................................................................................. 55 
10.7 
Additional Considerations ................................................................................................................. 55 
11 
Protocol Amendment History ...................................................................................................................... 56 
12 
REFERENCES ............................................................................................................................................. 61 
 


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STATEMENT OF COMPLIANCE 
 
This trial will be conducted in compliance with the International Council for Harmonisation (ICH) E6(R2) 
guideline for Good Clinical Practice (GCP), and the applicable regulatory requirements from the United 
States Code of Federal Regulations (CFR), including 45 CFR 46 (Human Subjects Protection); 21 CFR 312 
(Investigational New Drug); 21 CFR 50 (Informed Consent), and 21 CFR 56 (Institutional Review Board 
[IRB]). 
 
All individuals who are responsible for the conduct, management, or oversight of this study have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the protocol 
and the consent form must be obtained before any participant is enrolled. Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented to the study. In 
addition, all changes to the consent form will be IRB-approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a previously 
approved consent form. 
 
 


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SITE PRINCIPAL INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and the package insert/product label, and I agree that 
the protocol contains all necessary details for my staff and me to conduct this study as described. I will 
personally oversee the conduct of this study as outlined herein and will make a reasonable effort to 
complete the study within the time designated. I agree to make all reasonable efforts to adhere to the 
attached protocol. 
I will provide all study personnel under my supervision with copies of the protocol and access to all 
information provided by the sponsor or the sponsor’s representative. I will discuss this material with study 
personnel to ensure that they are fully informed about the efficacy and safety parameters and the conduct 
of the study in general. I am aware that, before beginning this study, the Institutional Review Board (IRB), 
or equivalent oversite entity must approve this protocol in the clinical facility where it will be conducted. 
I agree to obtain informed consent from participants, as required by the IRB of record and according to 
government regulations and ICH guidelines. I further agree to ensure the study is conducted in accordance 
with the provisions as stated and will comply with the prevailing local laws and customs. 
 
 
 
 
 
Principal Investigator Name (Print) 
Principal Investigator Signature 
Date 
 
 


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ABBREVIATIONS 
 
↑  
Increased  
↓  
Decreased  
A/G ratio 
Albumin Globulin Ratio 
AE  
Adverse event  
AGAP 
Anion Gap 
ALT 
Alanine Aminotransferase 
ANOVA  
Analysis of variance  
Anti GAD Ab 
Antibodies to Glutamic Acid Decarboxylase 
Anti IA-2 Ab 
Antibodies to Thyrosinephosphatase IA-2 
Anti ZnT8 Ab 
Antibodies to Zinc Transporter 8 
APA  
Action potential amplitude  
APD  
Action potential duration  
API  
Active pharmaceutical ingredient  
AST 
Aspartate Aminotransferase 
AUC  
Area under the time-plasma concentration curve  
AUC0-24h  
The area under the concentration-time curve from 0 to 24 h  
BUN 
Blood Urea Nitrogen 
cAMP  
Cyclic Adenosine Monophosphate  
CAP  
Cellulose acetate phthalate  
CGM 
Continuous Glucose Monitoring 
CHO  
Chinese hamster ovary  
CKD-EPI 
Chronic Kidney Disease – Epidemiology Collaboration 
Cmax  
Maximum plasma concentration  
CMC  
Carboxymethylcellulose  
CYP  
Cytochrome P450 isozyme  
DIA  
Diastolic arterial pressure  
DMSO  
Dimethylsulfoxide  
DPP-4  
Dipeptidyl peptidase-4  
EC50  
Concentration that produced 50% of the maximum possible response  
ECG  
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
FBG 
Fasting blood glucose 
FDA  
Food and Drug Administration  
FPG  
Fasting plasma glucose  
FT3  
Free thyroxine  
FT4  
Free triiodothyronine  
GH 
Growth Hormone 
GIP  
Gastric inhibitory peptide  
GLP  
Good laboratory practice  
GLP-1  
Glucagon-like peptide-1  
GPR  
G-protein coupled receptor  
Gαs  
Trimeric G protein α  
h  
Hour  
HCD  
20% Hydroxycyclodextrin/Water  


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HCl 
Hydrochloride 
HDL 
High Density Lipoprotein 
HEENT 
Head, Eye, Ear, Nose and Throat exam 
HEK-293  
Human embryonic kidney cells  
hERG  
Human ether-a-go-go-related gene  
HFD 
High- fat diet 
HGP 
Hepatic glucose production 
HIV 
Human immunodeficiency virus 
HOMA-B 
Homeostasis model assessment of beta cell function 
HOMA-IR 
Homeostasis model assessment of insulin resistance 
HR  
Heart rate  
Hz  
Hertz  
IB 
Investigator’s Brochure 
IC50  
Concentration that causes 50% inhibition  
ICH  
International Conference on Harmonisation  
IFG  
Impaired fasting glucose  
IKr  
Cardiac delayed rectifier repolarizing current  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV  
Intravenous  
kg  
Kilogram  
LC-MS/MS  
Liquid chromatography coupled with tandem mass spectrometry  
LDL 
Low Density Lipoprotein 
LLOQ  
Low limit of quantitation  
MAD  
Multiple ascending dose  
MAP  
Mean arterial pressure  
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
mg  
Milligram  
mL  
Milliliter  
MMTT  
Mixed meal tolerance test  
mRNA  
messenger Ribonucleic Acid  
NA  
Not applicable  
NADPH  
Reduced nicotinamide adenine dinucleotide phosphate  
ng  
Nanogram  
NOAEL  
No observed adverse effect level  
NOEL  
No observed effect level  
OGTT  
Oral glucose tolerance test  
PD  
Pharmacodynamics  
PEG400  
Polyethylene glycol 400  
PK  
Pharmacokinetics  
POC 
Point of care 
PoP 
Proof of Pharmacology 
PP  
Pulse pressure  
PR  
Measurement from beginning of P wave to beginning of QRS complex  


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QBS 
Qualified Bilingual Staff 
QRS  
Measurement of depolarization of the ventricles; from beginning of Q to end of S 
wave  
QT  
Measurement from beginning of QRS complex to the end of the T Wave  
QTc  
QT interval corrected by heart rate  
RH  
Relative humidity  
RMP  
Resting membrane potential  
RR  
Measurement from one R wave to the following R wave  
S9  
Metabolic activation with rat hepatic A9 microsomal fraction  
SAE  
Serious adverse event  
SD  
Sprague Dawley  
SDD  
Spray Dried Dispersion  
SYS  
Systolic arterial pressure  
t½  
Half-life  
T1DM 
Type 1 Diabetes Mellitus 
T2DM 
Type 2 Diabetes Mellitus 
tmax  
Time at which maximum plasma concentration occurs  
TPGS  
D-alpha-tocopheryl polyethylene glycol 1000 succinate  
TSH  
Thyroid stimulating hormone  
VLDL 
Very Low Density Lipoprotein 
Vmax  
Maximum rate of depolarization  
Vss  
Volume of distribution at steady state  
X  
Fold (e.g. 10X = 10-fold)  
ZDF  
Zucker diabetic fatty rat  
μg  
Microgram  
μM  
Micromolar  
 
 
 


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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
A randomized, placebo-controlled, double-blinded cross-over study of the 
pharmacologic action of a GPR119 agonist on glucagon counter-regulation 
during insulin-induced hypoglycemia in Type 1 diabetes mellitus. 
 
Study Description: 
 
This is a placebo-controlled, double-blinded, within-subject, cross-over 
Phase 2a study to test the hypothesis that short term (14-day) 
administration of MBX-2982, a G-protein coupled receptor-119 (GPR119) 
small molecule agonist, will significantly increase the glucagon counter-
regulatory response to hypoglycemia in individuals with Type 1 Diabetes 
Mellitus (T1DM).  
 
Objectives: 
 
 
Primary objective: 
• 
To compare (relative to placebo treatment) the effect of MBX-2982, a 
GPR119 agonist, on glucagon counter-regulatory responses to insulin-
induced hypoglycemia in subjects with T1DM. 
 
 
Secondary objectives: 
• 
To determine whether MBX-2982, through its effect upon glucagon 
counter-regulation, increases hepatic glucose production (HGP) during 
insulin-induced hypoglycemia and during recovery to euglycemia in 
subjects with T1D relative to placebo treatment.  
• 
To determine whether MBX-2982 reduces time of recovery from 
hypoglycemia to euglycemia in T1DM relative to placebo treatment. 
• 
To determine whether there is any effect of MBX-2982 upon other key 
counter-regulatory hormones in T1D relative to placebo treatment. 
• 
To compare the glucagon counter-regulatory response in healthy (non-
diabetic) volunteers during insulin-induced hypoglycemia to that of 
subjects with T1DM treated with MBX-2982 and placebo. 
• 
To compare time to recovery to euglycemia from insulin-induced 
hypoglycemia in healthy (non-diabetic) volunteers to that of subjects 
with T1DM treated with MBX-2982 and placebo. 
• 
To compare the hepatic glucose production response to insulin-induced 
hypoglycemia in healthy (non-diabetic) volunteers to that of subjects 
with T1DM treated with MBX-2982 and placebo. 
 
 
Exploratory objectives: 
• 
To evaluate the effects of MBX-2982 upon fasting and postprandial 
glucagon, GLP-1 and GIP concentrations in subjects with T1DM relative 
to placebo treatment. 
• 
To evaluate the effects of MBX-2982 on patterns of glycemia 
determined by continuous glucose monitoring in subjects with T1DM 
relative to placebo.  
• 
To evaluate the pharmacokinetic profile of MBX-2982 in subjects with 
T1DM. 


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Endpoints: 
 
Primary Endpoint: 
• 
The glucagon response to hypoglycemia defined as: 
• 
Maximal glucagon concentration during hypoglycemia 
• 
Total area under the curve (AUC) for glucagon during hypoglycemia.  
• 
Incremental AUC for glucagon during hypoglycemia (above baseline 
levels during euglycemia). 
Measured in subjects with T1D treated with MBX-2982 relative to placebo. 
 
Secondary and Exploratory Endpoints:  
• 
The glucagon response to hypoglycemia defined as: 
• 
Maximal glucagon concentration during hypoglycemia 
• 
Total area under the curve (AUC) for glucagon during hypoglycemia.  
• 
Incremental AUC for glucagon during hypoglycemia (above baseline 
levels during euglycemia). 
Measured in subjects with T1D treated with MBX-2982 or placebo relative 
to healthy controls. 
 
• 
HGP during insulin-induced hypoglycemia 
• 
HGP during recovery from insulin-induced hypoglycemia to euglycemia 
• 
Time of recovery from hypoglycemia (time to reach 85 mg/dL) 
• 
Plasma levels of counter regulatory hormones during hypoglycemia 
including epinephrine, cortisol, GH. 
• 
Fasting and post-prandial levels of glucagon, GLP-1 and GIP.  
 
All measured in subjects with T1D treated with MBX-2982 relative to 
placebo and relative to healthy controls. 
 
• 
Continuous glucose monitoring (CGM) indices of glycemic control 
including hypoglycemia (percent of time < 70 mg/dL, < 54 mg/dL), 
hypoglycemic events, mean glucose, percent of time 70-180 mg/dL, 
percent of time > 180 mg/dL, percent of time > 250 mg/dL, glycemic 
variability. 
• 
MBX-2982 plasma levels  
 
Measured in subjects with T1D treated with MBX-2982 relative to placebo. 
 
Study Population: 
 
The study will recruit 20 participants with T1DM fulfilling the following 
criteria:  
• 
Age 20-60 years 
• 
Diagnosis of T1DM according to American Diabetes Association (ADA) 
criteria continuously requiring insulin for survival  
• 
Diabetes diagnosis performed more than 5 years before enrollment  
• 
Fasting C-peptide levels < 0.7 ng/mL with a concurrent plasma glucose 
concentration > 90 mg/dL (Labs may need to be repeated if FBG < 90) 


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• 
For female participants: agrees not to become pregnant during the 
study and for at least 2 weeks after the last dose of the study 
medication.  
• 
For male participants: agrees not to donate sperm and to avoid getting 
a woman pregnant during the study and for at least 2 weeks after the 
last dose of the study medication. 
 
A cohort of 9 healthy volunteers will also be recruited, fulfilling the 
following criteria: 
• 
Age 20 -60 years 
• 
General good health 
• 
Creatinine clearance >80 mL/min based on CKD-EPI equation 
• 
Fasting blood glucose (FBG) >70 mg/dL and <100 mg/dL 
• 
No history of diabetes 
• 
For female participants: agrees not to become pregnant during the 
study 
 
T1DM subjects must be generally healthy, without clinical evidence of 
impaired adrenal, pituitary, or thyroid function, and without evidence of 
symptomatic autonomic neuropathy. The subjects should not have: 
 
1.  
Evidence of moderate or severe end-organ diabetic complications of 
retinopathy, nephropathy or neuropathy; proliferative retinopathy. 
Non-proliferative retinopathy will be allowed as is microalbuminuria 
but subjects must have a GFR > 60 mL/min/m2 by CKD-EPI.   
2.  
Evidence by history, ECG or exam of clinically significant 
cardiovascular disease. Subjects must have a QTcF <450 ms for 
males and < 470 ms for females.  
3.  
Body mass index outside the range of 18.5 – 30 kg/m2 for females 
and 20-30 kg/m2 for males. Weight must have been stable (±3 kg) 
for at least the preceding 3 months. 
4.  
Subjects can have stable hyperlipidemia and hypertension treated 
with no more than one lipid lowering medication or two 
antihypertensive medications. For each medication the dose should 
be stable for the past 3 months. Beta-adrenergic blocking agents 
will not be allowed during the study. 
5.  
Hypoglycemia unawareness, as assessed by GOLD score at  
screening (1, 2). For this study, subjects with severe hypoglycemic 
episodes associated with seizure or coma within three months of 
screening or diabetic ketoacidosis within six months of screening 
will be excluded. 
6.  
Predictive low blood glucose suspend mode on an insulin pump, or   
             a hybrid closed loop algorithm for insulin delivery 
7.          Hba1c >9% 
8.          One or more DKA episodes in the past 3 months 
9.          Insulin dose less than 0.3 U/kg or on a low carbohydrate diet 
 
 
 
 


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Phase: 
2a 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
 
The study will be conducted at the AdventHealth Translational Research 
Institute (TRI) in Orlando, Florida, USA and ProSciento, Chula Vista, 
California, USA. Assays will be performed at the TRI, ProSciento 
laboratories, Scripps Mercy Hospital Laboratory, LabCorp and at Covance 
Laboratory Inc. (pharmacokinetic measures). 
 
Description of Study 
Intervention: 
 
Overview of the study design:  
• 
In randomized order, (Latin square, randomly assigned to placebo-
active and active-placebo periods) and in a double-blinded manner, 
T1DM subjects will receive 14 days of daily dosing with a MBX-2982 (or 
placebo), taken at the same time each day after breakfast, except on 
Day 14 and Day 42. The last dose of treatment/placebo will be given in 
the morning (before the tracer) before the euglycemic/ hypoglycemic 
glucose clamp is started. T1DM subjects will undergo two Euglycemic - 
hypoglycemic clamps (induction of controlled hypoglycemia by an 
insulin infusion), using a within-subject cross-over design, with the two 
clamps separated by approximately four weeks, that is, two weeks of 
drug washout followed by two weeks of treatment with the alternative 
therapy.  
• 
After completion of the clamp, participants will not receive any study 
medication for two weeks (washout phase) and will then begin 14 days 
of the other arm medication (placebo or MBX-2982) in a double-
blinded manner, followed by a repeat Euglycemic -hypoglycemic clamp 
study.  During the study blinded CGM will be used to assess daily and 
nocturnal patterns of glycemia.   
• 
On the day preceding a clamp study, while admitted to the research 
unit, a standardized meal test will be used to assess fasting and 
postprandial glucagon, GLP-1 and GIP secretion. 
 
Regarding the clamp procedures, there will be an initial euglycemic run-in 
phase of the clamp (~85 mg/dL), followed by induction and maintenance of 
hypoglycemia (target 50 mg/dL), and then a phase of recovery from 
hypoglycemia. Throughout, glucagon, other counter-regulatory hormones, 
and hepatic glucose production will be measured. Healthy, non-diabetic 
control subjects will be studied on a single occasion and will not receive pre-
treatment medication or placebo; they are being studied to establish 
“normal physiological responses” for comparison to drug and placebo 
treated responses in T1DM. 
Study Duration: 
The study will last 12 months. 
Participant Duration: 
Each T1DM participant will be enrolled for 84±2 days and each healthy 
participant will be enrolled for up to 28 days. 
 
 


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1.2 
SCHEMA 
 
 
 
 
 
 


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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
*On Visit 5 – these study activities are not completed by the Healthy cohort. See for further details in section 8.1 Schedule of events.  
** Healthy volunteers will wear the CGM for the 10 days preceding and including the clamps. 
 
 
Visits 
SV1 
V2 
V3 
V4 
V5 
Week 4 
V6 
V7 
V8 
V9 
Days 
-35 up to -7 
-7 
0 
7 
13-14 
21 
28 
35 
41-42 
49 
Windows 
 
±2 
±2 
±2 
+5 
±2 
±2 
±2 
+5 
±2 
Cohort completing visit 
T1DM 
Healthy 
T1DM 
Healthy 
T1DM 
only 
T1DM 
only 
T1DM 
Healthy 
T1DM 
only 
T1DM 
only 
T1DM 
only 
T1DM 
only 
T1DM 
only 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Medical History/Prior Medications 
X 
 
 
 
 
 
 
 
 
 
Anthropometry 
X 
 
 
 
X 
 
X 
 
X 
X 
Vital signs 
X 
 
 
 
X 
 
X 
 
X 
X 
ECG 
X 
 
 
X 
X 
 
 
X 
X 
 
Screening labs (CBC, CMP, HbA1c, 
lipid panel, C-peptide, islet 
autoAb, hepatitis/HIV, βHCG) 
X 
 
 
 
 
 
 
 
 
 
CBC, CMP 
 
 
 
 
 
 
 
 
 
X 
TSH, FT4 
X 
 
 
 
X 
 
 
 
X 
 
Follow up labs (CBC, CMP, HbA1c, 
lipid panel, thyroid function) 
 
 
 
 
X 
 
 
 
X 
 
Archive blood 
 
 
X 
 
X 
 
 
 
X 
 
Drug screening 
X 
 
 
 
 
 
 
 
 
 
GPR119 agonist plasma level 
 
 
 
 
X* 
 
 
 
X 
 
Urine POC Pregnancy test 
 
 
X 
 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
Archive urine 
 
 
X 
 
X 
 
 
 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
CGM training and placement 
 
X 
 
 
 
 
 
 
 
 
CGM wear time for T1DM 
 
X** 
CGM data review 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Glucose and insulin log review 
 
 
X 
X 
X* 
X 
X 
X 
X 
 
Study medication log review 
 
 
 
X 
X* 
 
 
X 
X 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Drug distribution 
 
 
X 
 
 
 
X 
 
 
 
Adherence to study drug 
 
 
 
 
X* 
 
 
 
X 
 
CRU admission 
 
 
 
 
X 
 
 
 
X 
 
Physical exam with fundoscopy 
X 
 
 
 
X 
 
X 
 
X 
X 
Standard mixed meal challenge 
 
 
 
 
X 
 
 
 
X 
 
Overnight IV insulin 
 
 
 
 
X* 
 
 
 
X 
 
Euglycemic-hypoglycemic clamp 
 
 
 
 
X 
 
 
 
X 
 


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2 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
GPR119 is a X-linked, class A (rhodopsin-like) Gαs receptor expressed on enteroendocrine cells 
and in pancreatic islets for which lysophospholipids and other lipid metabolites have been identified as 
endogenous ligands. Activation of GPR119 stimulates GLP-1 and GIP secretion from enteroendocrine cells 
and insulin secretion by β-cells in a hyperglycemia-dependent manner (3-5). More recently it has been 
reported that agonism of GPR119 augments the glucagon counter-regulatory response of α-cells to 
hypoglycemia (6), also in a glucose dependent manner as it did not stimulate glucagon secretion at 
euglycemia or hyperglycemia. Of relevance, recently reported single cell transcriptional analyses reveal 
that GPR119 is more highly expressed in islet α-cells than on β-cells (7). These emerging novel insights 
into GPR119 biology (and pharmacology) could fundamentally shift perceptions about the therapeutic 
potential of this target. Though the effects of GPR119 small molecule agonists on glucose-dependent 
insulin secretion and incretin secretion have been demonstrated preclinically and clinically, the effect to 
bolster the glucagon counter-regulatory response to hypoglycemia has only been demonstrated in 
rodents and has not yet been tested clinically. 
 
A spike of increased glucagon secretion as plasma glucose levels descend to hypoglycemic 
thresholds (approximately 60-65 mg/dl) is considered a crucial counter-regulatory response. Yet, a 
severely impaired glucagon secretion in the face of insulin-induced hypoglycemia is commonly found in 
individuals with T1DM and is widespread by the time patients have had the disease for more than 5 years 
(8-10). This impairment in glucagon counter-regulation raises risk for hypoglycemia and its severity in 
T1DM. Though the attainment of tight glycemic control in T1DM has been demonstrated to lessen the risk 
of end-organ diabetic complications and of cardiovascular events, intensified glycemic control is 
commonly associated with an increased risk of hypoglycemic events (11). There is considerable morbidity 
caused by hypoglycemia in T1DM and nocturnal hypoglycemia is of a special concern as is hypoglycemia 
occurring in patients with “hypoglycemia unawareness”. More broadly, fear of hypoglycemia is regarded 
as a major barrier to patients achieving tight glycemic control and thereby improving diabetes outcomes 
(12). Similar concerns about hypoglycemia (and impaired glucagon counter-regulation) apply to many 
patients with type 2 diabetes (T2DM) who are reliant upon exogenous insulin and have severely depleted 
β-cell function (12, 13), however, at this juncture our re-evaluation of the therapeutic potential of GPR119 
agonism to enhance hypoglycemic counter-regulation will focus upon T1DM. 
 
The failure of glucagon counter-regulation in T1DM was initially reported by Gerich and colleagues 
nearly 50 years ago (8) and has since been confirmed repeatedly. Extensive clinical research through use 
of an insulin-infusion hypoglycemic clamp has been conducted on hypoglycemic counter-regulation in 
healthy individuals, those with T1DM and those with T2DM (10, 14, 15); we propose to use this procedure 
in the current study. An adaptation of the hypoglycemic clamp (from humans to rodents) was used to 
demonstrate the effect of various GPR119 agonists on glucagon secretion during hypoglycemia in rodents 
(6). 
 
There are no currently approved therapeutics to address the defect in glucagon secretion during 
severe hypoglycemia, apart from the administration of exogenous glucagon which is used as an 
emergency treatment of severe hypoglycemia. Rectifying impaired glucagon secretion could lessen the 
frequency and severity of hypoglycemia seen in T1DM. Several years ago, a salutary effect to bolster 
glucagon secretion was reported using a somatostatin receptor antagonist in a rat model of T1DM (16, 


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17), however clinical translation of this effect has not been reported.  As earlier cited, recent research at 
Merck Research Laboratories and in collaboration with investigators at Yale University, reported that in 
rodents, structurally diverse small molecule GPR119 agonists significantly increased glucagon counter-
regulatory response to hypoglycemia, including in a STZ diabetic rat model of severely impaired glucagon 
counter-regulation (6). The goal of this proof of pharmacology (PoP) study is to test the clinical translation 
of this pharmacologic effect, from rodents to humans, and more specifically to those with T1DM. 
 
In considering how a GPR119 agonist might be used by patients with T1DM, we envision that 
GPR119 agonist administration would not be used as an emergency treatment (as is the case for glucagon 
injection or its nasal inhalation), but instead could be taken daily as an adjunct to insulin therapy as 
prophylaxis to reduce the frequency and severity of hypoglycemia. Ultimately, pivotal clinical trials will be 
needed using a GPR119 agonist to test whether this adjunctive approach to insulin therapy reduces 
hypoglycemic events, especially severe episodes. The proof of pharmacology study outlined in this 
proposal would serve as a segue in support of undertaking the larger and longer duration clinical trials 
that measure hypoglycemic events. In this context, we also propose in the current study to collect 
continuous glucose monitoring (CGM) to assess whether GPR119 agonist treatment reduces the time 
spent with glucose values < 70 mg/dl, and < 54 mg/dl; these CGM data could help inform the design of a 
subsequent proof of concept clinical trial. 
 
Initial interest in the GPR119 pathway was as a novel target for treating type 2 diabetes (T2DM), 
leveraging its effects on glucose-dependent insulin secretion and incretin secretion and thereby on 
glycemic control; the effect on glucagon was at that time not yet appreciated. Medicinal chemistry efforts 
led to the creation of numerous small-molecule GPR119 agonists, a number of which entered clinical trials. 
Unfortunately, only a modest effect in reducing hyperglycemia was observed in T2DM (17, 18) and this 
effect was not competitive with existing oral therapies. Consequently, further development of GPR119 
agonists as treatment for T2DM was mostly halted. It is noteworthy that GPR119 agonists have been 
generally well-tolerated and found to be safe in the various short-term clinical studies, several of which 
were of 4 weeks duration. Also, it is noteworthy that GPR119 agonist effects on glucose-dependent insulin 
secretion and incretin secretion were demonstrated to translate from rodents to humans. However, the 
effect to mitigate hypoglycemia, and specifically, to augment glucagon counter-regulation was not 
examined in prior trials. In addition to direct effects on α-cell glucagon secretion, GPR119 agonism 
increases secretion of GIP which has been shown to further enhance the glucagon response to 
hypoglycemia (19, 20). 
 
We propose to evaluate the effects of MBX-2982, a GPR119 agonist, on glucagon counter-
regulatory responses during hypoglycemia in a placebo-controlled, randomized, cross-over design clinical 
trial in subjects with T1DM. To our knowledge, GPR119 agonists have not been previously given to subjects 
with T1DM. While our primary goal will be to examine an effect on glucagon counter-regulation in T1DM, 
we also propose to examine any effects on fasting and postprandial glucagon, GLP-1 and GIP. 
 
Success in a proof of pharmacology study with a GPR119 agonist, such as the one that we are 
proposing, would demonstrate to the biomedical community that the GPR119 agonists may have 
therapeutic value to mitigate hypoglycemia in T1DM. Thus, a successful outcome would set the stage for 
subsequent clinical trials of longer duration dosing of a GPR119 agonist (adjunctive to insulin) to assess its 
efficacy to reduce hypoglycemic events and impact upon daily patterns of glucose (e.g. time below 70 
mg/dl and effect on glycemic variation) as measured by CGM.  
Also, if the findings from the current proposal are favorable, further uses of the hypoglycemic 
clamp might be envisioned. For example, might GPR119 agonism alter the glycemic threshold at which 


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glucagon counter-regulation is triggered? Use of a so-called “stepwise” hypoglycemic clamp platform to 
delineate glycemic threshold could be undertaken. This would provide additional insights into 
mechanisms by which GPR119 agonism might reduce risk of hypoglycemia.  Another example is to conduct 
studies in insulin-treated T2DM who have impaired glucagon counter-regulation and vulnerability to 
hypoglycemia. 
The capacity of GPR119 agonism to augment the glucagon counter-regulatory response to 
hypoglycemia in individuals with T1DM is the focus of this research protocol, a placebo-controlled proof 
of pharmacology study. 
 
2.2 
BACKGROUND  
 
MBX–2982 is an agonist of the G-protein coupled receptor 119 (GPR119) that was initially studied as a 
novel therapeutic agent for the treatment of T2DM, evaluating its dual mechanisms of direct and incretin-
mediated effects on glucose-dependent insulin secretion. As previously described in the Introduction, 
GPR-119 is an X-linked, class A (rhodopsin-like) Gαs receptor expressed on entero-endocrine cells and in 
pancreatic islets, for which lysophospholipids and other lipid metabolites are endogenous ligands. 
Activation of GPR-119 stimulates GLP-1 and GIP secretion from enteroendocrine cells and insulin secretion 
by β-cells in a hyperglycemic-dependent manner (3-5). Clinical studies have demonstrated translation of 
these actions from preclinical models into humans, including those with T2DM (See section on Human 
Experience). Recently it has been reported that agonism of GPR119 augments the glucagon counter-
regulatory response of pancreatic islet alpha-cells (α-cells) (6) to hypoglycemia and does so in a glucose 
dependent manner as it did not stimulate glucagon secretion during hyperglycemia or euglycemia. In 
addition, recently reported single cell transcription analysis revealed that GPR-119 is more highly 
expressed in islet α-cells than on β-cells (7). These emerging and novel insights into GPR119 biology and 
its effects on pharmacodynamics could fundamentally shift the therapeutic potential of this receptor, re-
focusing upon glucagon mediated hypoglycemic counter-regulation. Multiple and structurally diverse 
GPR-119 receptor agonists have demonstrated effects to bolster the glucagon counter regulatory 
response to hypoglycemia in rodents, but this pharmacology has not been tested clinically. 
2.2.1 PHYSICAL, CHEMICAL AND PHARMACEUTICAL PROPERTIES 
MBX-2982 was synthesized and screened as a GPR119 agonist. It was found to be capable of activation of 
endogenous GPR119 in a cell line overexpressing the receptor.  MBX-2982 also increased incretin 
hormone levels in animals which may contribute to its glucose lowering effects in a hyperglycemic state. 
MBX-2982 is 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine. It 
has a molecular formula of C22H24N8OS, and a molecular weight of 448.55 Daltons. MBX-2982 will be 
used as the HCl salt MBX-2982 in this study. 
2.2.1.1 SALT FORMULATION PHARMACOKINETIC PROFILE  
An HCl salt formulation of MBX-2982 (MBX-2982A) has been identified. Similar to the spray dried 
dispersion (SDD) formulation, MBX-2982A has increased aqueous solubility relative the MBX-2982 
microcrystalline free base formulation. This enhancement of solubility by the SDD and the HCl salt 
formulation, relative to the microcrystalline free base formulation, is thought to provide supersaturated 
drug levels for increased absorption in the intestinal tract. 
 
The pharmacokinetics of MBX-2982A have been assessed following single oral dosing of suspensions to 
rats and dogs. Direct comparisons of the oral exposure of the MBX-2982A and SDD formulations were 


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made in order to select the range of MBX-2982A doses for the clinic. Single oral doses of MBX-2982A 
suspension at 200 mg/kg in male rats were rapidly absorbed with a mean plasma Cmax value that was 
80% of that for the SDD formulation at the same dose level. The mean plasma AUC values ranged from 
57% (AUC0-48h) to 87% (AUC0-24h) compared to equivalent doses of the SDD suspension. 
 
A cross-over study comparing SDD and MBX-2982A suspensions as single oral doses was conducted in 
male Beagle dogs at 200 mg/kg. Relative to the SDD suspension, MBX-2982A suspensions achieved 67% 
of the Cmax and 56% (AUC0-24h) to 89% (AUC0-∞) exposure parameters. Thus, the single dose oral 
exposure of the MBX-2982A is comparable to the SDD material in both species at 200 mg/kg. 
2.2.1.2 SINGLE DOSE PHARMACOKINETICS 
MBX-2982 was absorbed with oral bioavailability of 36% and 39% in mice and rat following single oral 
doses of 5 and 10 mg/kg, respectively. Absorption appeared to be limited in rats and dogs at the higher 
doses used in the single dose pharmacokinetic and multiple dose pharmacokinetic and toxicology studies. 
No sex differences were noted in dogs; however, the toxicokinetic data from the 4-week repeat oral dose 
study in the rats indicated that exposures in female rats were approximately 2- to 3-fold higher than in 
male rats. Following single dose IV administration, the half-life (t1/2) ranged from 2.4 to 3.1 hours, and 
clearance from 120-156 mL/h/kg for mice and rats, respectively. 
2.2.2 REPEAT DOSE PHARMACOKINETICS 
In repeat dose pharmacokinetic studies in rats, dogs and monkeys, MBX-2982 exhibited non-dose 
proportional, non-linear pharmacokinetics. Systemic exposure to MBX-2982, as measured by Cmax and 
AUC, increased with increasing dose, although the increase appeared to be less than proportional to dose 
in both rats and dogs, suggesting limitation of absorption at higher doses. No marked accumulation of 
MBX-2982 was observed in dog plasma after repeated oral dosing, and no gender differences were noted. 
Exposure in rats was 3-fold higher in females than in males. Minimal accumulation was observed after 
multiple doses in rats. 
2.2.3 PHARMACOLOGIC PROFILE 
MBX-2982 is a GPR119 agonist that binds and modulates the GαS activity of the GPR on pancreatic β-cells 
and enteroendocrine cells. As earlier noted, the original intent in developing GPR119 agonists was to 
exploit its potential to induce glucose-dependent insulin secretion for the treatment of T2DM; the 
pharmacology studies described below are pertinent toward this objective. Studies have demonstrated 
that MBX-2982 effectively reduces plasma glucose excursion during an Oral Glucose Tolerance Test 
(OGTT) in normal mice and rats. Several lines of evidence support a model in rodents in which MBX- 2982 
exerts its actions directly at the pancreas (insulin secretion from β-cells) and in the GI tract (incretin 
secretion from enteroendocrine cells). The pancreatic effects of MBX-2982 were demonstrated by its 
enhancement of glucose-dependent insulin secretion from isolated rat and human pancreatic islets and 
by its dose-dependent stimulation of insulin secretion and glucose utilization in a rat hyperglycemic clamp 
model. Intestinal effects were documented by enteroendocrine-derived increases in active GLP-1 and 
total GIP in normal mice. This effect was enhanced when MBX-2982 was given in combination with the 
DPP-4 inhibitor sitagliptin, when compared to sitagliptin alone. As expected, the increases in incretins 
were accompanied by increases in insulin and by decreases in glucose excursion in response to an oral 
glucose challenge. These latter effects could presumably be due to the combined effects of incretins on 
their receptors and agonism of the GPR119 receptor. 
 


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From a therapeutic perspective, a follow-up study in mice showed that MBX-2982 and sitagliptin are 
additive in lowering the glucose excursion during an OGTT. These combined studies suggest that there 
may be dual or multiple mechanisms responsible for the glucose-lowering effects of MBX-2982, including 
but not limited to direct insulin secretion by islet cells and the stimulation of incretin secretion from 
enteroendocrine cells. Furthermore, the ability of MBX-2982 to lower glucose may be enhanced by a DPP-
4 inhibitor and supports the role of an incretin signal in the mechanism of action of MBX-2982. Female 
leptin-deficient Zucker diabetic fatty (ZDF) rats are obese and insulin-resistant but develop diabetes 
mellitus only if fed a high-fat diet (HFD). In this pre-diabetic model, daily MBX-2982 for five weeks delayed 
the onset of post-prandial hyperglycemia and prevented the development of hyperinsulinemia and 
subsequent decline in insulin levels. It also blunted the increase in fasting glucose levels that generally 
occurs after a period of HFD, in conjunction with increasing fasting insulin levels. These effects translated 
to an increase in HOMA-B and a decrease in HOMA-IR in MBX-2982 treated animals on HFD, suggesting 
improved β-cell function and insulin sensitivity, respectively. There was no observed increase in pancreatic 
insulin content or changes in islet cell architecture. 
2.2.4 TOXICOLOGY PROFILE 
The results from in vivo animal toxicity and toxicokinetic studies indicate that MBX-2982 has a very low 
order of toxicity, with a no-observed-adverse-effect level (NOAEL) at doses up to 2000 mg/kg in single-
dose studies and 1000 mg/kg in repeat-dose studies (top doses studied). The single and repeat dose 
toxicity studies described below were performed with the microcrystalline free base formulation. 
2.2.4.1 ACUTE TOXICITY 
Single dose toxicity at doses of 250, 750 and 2000 mg/kg MBX-2982 was evaluated after oral 
administration in mice and rats. No test article-related mortality or clinical observations were noted within 
the 14-day observation period. In rats, slight increases (up to 1.6-fold) in cholesterol levels were noted in 
female rats orally administered MBX-2982; these increases were not considered adverse and were not 
observed in mice. Histopathologic examination of tissues from mice and rats administered 2000 mg/kg 
indicated no test article-related changes. The NOAEL in mice and rats following a single oral dose is >2000 
mg/kg. 
2.2.4.2 REPEAT DOSE TOXICITY 
In repeat dose toxicity studies of 1-month duration in both rats and dogs, there were no apparent effects 
of microcrystalline form of MBX-2982 up to doses of 1000 mg/kg/day (NOAEL > 1000 mg/kg/day). 
Specifically, there were no toxicologically meaningful changes in body weight, food consumption, 
necropsy parameters, histopathologic parameters, or laboratory measurements in either species. The 
maximum dose of 1000 mg/kg/day was based on the single dose and multiple dose pharmacokinetic and 
toxicokinetic data which demonstrated that at dosages above 300 mg/kg in rats and dogs, the total 
amount absorbed did not increase markedly with increasing dose, suggesting limitation of absorption at 
higher doses. 
 
Additional repeat dose toxicity studies of 1-month duration in both rats and dogs were conducted with 
the SDD formulation to explore higher exposures. Despite achieving higher exposure than with the 
microcrystalline form of MBX-2982 in both species, no treatment related organ toxicity was identified. 
The only noted adverse effect for either study was decreased body weight gain that was observed in male 
rats at the top dose investigated (230 mg/kg/day) that was associated with an AUC0-24h of 698 μg*h/mL. 
The NOAELs were 75 mg/kg/day in male rats and 115 mg/kg/day, the top dose evaluated in female rats. 


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These represent approximate 1.8-fold and 2.4-fold increases in the respective previous NOAEL exposures 
(AUC0-24h) from the microcrystalline free base formulation. In dogs, the NOAEL was the top dose 
evaluated, 400 mg/kg/day of the SDD formulation, in both males and females. The associated plasma 
exposures were increased 3.1-fold and 3.3-fold, respectively, over the microcrystalline free base 
formulation NOAEL exposures. While not considered adverse, there was increased emesis and non-
formed feces observed in the MBX-2982 treated dogs. 
2.2.5 SAFETY PHARMACOLOGY 
During safety pharmacology studies with the microcrystalline free base formulation, no neurobehavioral 
effects were observed in male rats treated with MBX-2982. No changes in QT interval were observed in 
an oral safety pharmacology study designed to assess cardiovascular effects in conscious telemeterized 
dogs or in a general toxicology study conducted in dogs. During the conscious telemeterized dog study, 
minimal hemodynamic changes, considered physiologically insignificant, were observed at the highest 
dosages (300 and 1000 mg/kg).  
 
To further enable human studies with the anticipated improvements in exposure due to the SDD 
formulation of MBX-2982, an additional oral safety pharmacology study was conducted with the SDD 
formulation to assess cardiovascular effects in conscious telemeterized dogs with greater exposure to 
MBX-2982. No test article-related changes in electrophysiology parameters, including QT interval, were 
observed in this second study at the top dose (100 mg/kg), which was associated with a Cmax of 13.2 
μg/mL. This represents an approximate 5.1-fold increase over the previous no effect Cmax achieved at 
1000 mg/kg with the microcrystalline free base formulation in the first dog cardiovascular safety study. 
Except for minor and transient higher heart rates compared to control (but not to baseline), there were 
no hemodynamic changes in the oral safety pharmacology study with the SDD formulation. 
 
In vitro assays were performed to evaluate the effects of MBX-2982 on cardiac ion channel and action 
potential durations (APD). In the first assay, effects of MBX-2982 concentrations on the IKr (cardiac 
delayed rectifier repolarizing current) channel were assessed. In this study, the IKr channel was inhibited 
by MBX-2982 in a concentration-dependent manner with a 50% inhibitory concentration (IC50) of 1.16 
μM (0.52 μg/mL). In the APD assay, MBX-2982 produced no effect on the action potential at a normal 
stimulation rate. At the highest concentration, 20 μM (9.0 μg/mL), a slight but statistically significant 
APD90 prolongation occurred under stimulation rates corresponding to bradycardia and tachycardia. As 
noted above, no in vivo cardiac effects or QT prolongation were observed in the telemetrized dog studies 
or during the 4-week repeat dose dog study. MBX-2982 was not genotoxic in any of the systems evaluated 
2.2.6 HUMAN EXPERIENCE 
 
Phase 1 and Phase 2 Studies in Patients 
In early human studies, as earlier noted, undertaken with the original intent of exploring a potential for 
treating T2DM, MBX-2982 consistently lowered fasting plasma glucose (FPG) and glucose excursion 
following a mixed meal tolerance test (MMTT) and an oral glucose tolerance test (OGTT). During a graded 
glucose infusion, MBX-2982 attenuated hyperglycemia and enhanced glucose-sensitive insulin secretion. 
Across the three completed Phase 1 studies, MBX-2982 had variable effects on other biomarkers such as 
GLP-1 and glucagon during an MMTT or OGTT. Four Phase l studies and a 28-day Phase 2 human study 
have been completed and there has been no safety, pharmacokinetic (PK) or tolerability concerns with 
MBX–2982 dosing. A Phase 2 study evaluated sitagliptin as a comparator to MBX-2982. These data 


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suggested that there may be additional benefit on glucose homeostasis if MBX-2982 is combined with 
sitagliptin. 
 
MBX-2982 was studied in 3 formulations in the clinic. A microcrystalline free base formulation (MBX-
2982), a spray dried dispersion (MBX-2982 SDD) formulation and an HCl salt formulation (MBX-2982A). 
The HCl salt, which had an exposure of 54,600 ng*ml/hr., was deemed the formulation best suited to take 
forward in development. Administration of MBX-2982 HCl salt formulation in single and multiple doses of 
100 mg and 300 mg capsules have been safe and well tolerated. 
 
 
 
 
 
 
0
6
1 2
1 8
2 4
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
3 0 0  m g  (N  =  1 1 )
1 0 0  m g  (N  =  1 0 )
T im e  (h rs )
C o n c e n tra tio n  (n g /m L )
Table 1 and Figure 1: Data from the first-in-human study (Protocol M2982-10712)  
Micronized free base formulation 


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2.2.6.1 MBX-2982 COMPLETED CLINICAL STUDIES 
 
Table 2: Human studies 
2.2.7 HUMAN SAFETY AND TOLERABILITY PROFILE 
Overall, there were good non-clinical and clinical safety and tolerability profiles with wide safety margins 
against 6-month toxicity studies. PK of the salt formulation was found to be excellent and exposure 
increased in a dose related manner. There was a significant increase in exposure with food relative to 
fasting therefore dosing in this study will be in the fed condition. 
2.2.7.1 SAFETY EVALUATIONS 
In both Phase 1 and Phase 2 studies with MBX-2982 there were no AE or SAE trends, and most AEs were 
mild and few possibly related drug AEs and 1 related. One subject did withdraw consent due to AEs. There 
were no group or individual adverse treatment effects in either safety labs or ECGs. Unblinded individual 
ECG data did not show an imbalance of QTc prolongation and no patient met severe QTc threshold. In the 
Phase 2a study there was no dose-limiting safety or toxicity up to 300 mg for 28 days. 
2.2.7.2 ANALYSIS OF ADVERSE EVENTS 
 
There were no significant differences between MBX-2982 and placebo in the number of subjects with AEs 
overall or the number of subjects with AEs that were judged to be possibly or probably related to study 
drug. Two subjects in the 300 mg cohort experienced symptoms consistent with possible hypoglycemia, 
although in one case the blood glucose was normal and in the other case the blood glucose value was 
mildly decreased towards the end of the OGTT but no different than the mildly low value observed at the 
baseline pre-dosing OGTT. This suggested the possibility of a delayed insulin response to a glucose load, 
as is well described in this population. Nevertheless, these events were captured as AEs. 
 
Constipation was the most common possibly treatment-related AE overall (7 subjects [16%]). The 
percentage of subjects experiencing constipation in the MBX-2982 treated groups (6 subjects [18%]) was 
Phase 
Protocol 
Number 
Description 
Formulation(s) Studied 
Number on  
MBX-2982 
1 
M2982-10712 
Single ascending dose 
study 
Micronized free base 
10, 30, 100, 300, 600, 1000 mg 
48 
1 
M2982-10813 
Multiple ascending dose 
study – 4 days – in IFG 
patients 
Micronized free base 
100 and 300 mg 
23 
1 
M2982-10918 
5-day repeat dose PK 
study in IFG or IGT 
SDD 
25, 100, 300, 600 mg 
33 
1 
M2982-11021 
Single dose PK in fed and 
fasted subjects 
SDD 300 mg 
HCl salt 50, 200, 600 mg 
32 
2 
M2982-20920 
4-week study in T2D 
patients 
SDD: 25, 100, 300 mg 
Sitagliptin: 100 mg 
68 


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only modestly greater than the percentage in the placebo treated group (1 subject [9%]) and the incidence 
was generally not dose-dependent. An overview of AEs and the incidence of the most frequently occurring 
treatment-related AEs, by treatment, can be found in the Investigator’s Brochure (IB). 
 
No life-threatening AEs, serious AEs, or deaths were reported. One subject in the 300 mg MBX-2982 SDD 
group withdrew due to AEs. The majority of AEs reported were mild. There were no severe AEs (See the 
Investigator Brochure [IB] for detailed information). 
2.2.7.3 LISTING OF DEATHS, OTHER SERIOUS ADVERSE EVENTS, AND OTHER SIGNIFICANT 
ADVERSE EVENTS 
No life-threatening AEs, SAEs, or deaths were reported (see IB for detailed information). 
2.2.8 SUMMARY OF NON-CLINICAL AND CLINICAL INVESTIGATIONS WITH MBX-2982 
Non-clinical and clinical studies showed that MBX-2982 has desirable effects on blood glucose levels. 
Nonclinical studies and clinical studies to date including safety pharmacology studies and repeat dose 
toxicokinetic studies, failed to show any significant safety or toxicological concerns. 
Please see the IB for additional details of the nonclinical studies conducted with MBX-2982. 
2.2.9 OVERALL SAFETY CONCLUSIONS 
MBX-2982 dosed daily was generally safe and well tolerated. No clinically significant changes or findings 
were noted in clinical laboratory evaluations, vital sign measurements, physical examinations, or 12-lead 
ECGs for any of the subjects studied or treatment groups. 
 
A total of six subjects (4 at 100 mg and 2 at 300 mg) experienced mild, subclinical increases in TSH (< 10 
μIU/mL) without changes in FT4 or FT3 in one study. The changes in TSH in this study were not observed 
in the subsequent Phase 1c study which produced significantly higher drug exposures. Based upon the 
absence of significant changes in FT4 or FT3, as well as the absence of a thyroid signal in 4-week animal 
toxicology studies, these findings are not felt to be clinically or toxicologically meaningful and may 
represent a spurious measurement. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
For potential risks please refer to the IB. Some of these potential risks are due to taking the 
investigational drug MBX-2982, and some may be due to the underlying disease or being on placebo. 
Although no significant safety concerns have arisen from the animal or human studies with MBX-2982 to 
date, the compound remains in the early phases of human testing and therefore carries the risk associated 
with a compound with limited human experience. 
2.3.1.1 RISKS ASSOCIATED WITH THE STUDY PROCEDURES 
 
Intravenous lines/blood draws (lab samples) – there is a risk of pain, vasovagal syncope, hematomas, 
and/or infection at IV insertion/blood draw site (low risk of serious AEs).   
 


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CGM placement 
There is a low risk for developing a local skin infection at the site of the sensor needle placement. Itchiness, 
redness, bleeding, and bruising at the insertion site may occur, as well as local tape allergies. 
 
Standardized meal test 
Participants may experience increase of their blood glucose.  
 
Insulin infusion and hypoglycemic clamp 
The administration of insulin intravenously during the euglycemic-hypoglycemic clamp may lead to a 
greater degree of hypoglycemia than expected. Hypoglycemia could be associated with adrenergic and 
neuroglycopenic symptoms, that could rarely cause seizure. The stable isotope of glucose infused during 
the euglycemic-hypoglycemic clamp carries no additional risks. Intravenous infusion of glucose may cause 
venous irritation (phlebitis) or less commonly infiltration of the surrounding tissues, both which may cause 
discomfort. 
2.3.1.2 POTENTIAL RISKS ASSOCIATED WITH THE INVESTIGATIONAL MEDICATION 
 
Human Safety and Tolerability Profile 
Overall, there were good non-clinical and clinical safety and tolerability profiles with wide safety margins 
against 6-month toxicity studies. The PK of the salt formulation was found to be excellent and exposure 
increased in a dose related manner. There was a significant increase in exposure with food relative to 
fasting therefore dosing in this study will be given in the fed condition. 
 
Analysis of Adverse Events 
There were no significant differences between MBX-2982 and placebo in the number of subjects with AEs 
overall or the number of subjects with AEs that were judged to be possibly or probably related to study 
drug. Two subjects in the 300 mg cohort experienced symptoms consistent with possible hypoglycemia, 
although in one case the blood glucose was normal and in the other case the blood glucose value was 
mildly decreased towards the end of the OGTT but no different than the mildly low value observed at the 
baseline pre-dosing OGTT. This suggested the possibility of a delayed insulin response to a glucose load, 
as is well described in the T2DM population. Nevertheless, these events were captured as AEs. 
Constipation was the most common possibly treatment-related AE overall (7 subjects [16%]). The 
percentage of subjects experiencing constipation in the MBX-2982 treated groups (6 subjects [18%]) was 
only modestly greater than the percentage in the placebo treated group (1 subject [9%]) and the incidence 
was generally not dose-dependent.  An overview of AEs and the incidence of the most frequently 
occurring treatment-related AEs, by treatment, can be found in the IB. 
No life-threatening AEs, serious AEs, or deaths were reported. One subject in the 300 mg MBX-2982 SDD 
group withdrew due to AEs. The majority of AEs reported were mild. There were no severe AEs. (See the 
IB for detailed information) 
 
Listing of Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
No life-threatening AEs, SAEs, or deaths were reported (see IB for detailed information). 
 
Unknown safety areas 
To date, no in vivo human or animal drug interaction studies have been performed with MBX-2982. Based 
on in vitro data and the anticipated maximum human concentrations, no significant drug-drug interactions 
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Based upon safety and tolerability monitoring from the 4 phase 1 and 1 phase 2 studies completed to 
date, there are no apparent adverse central nervous system effects of MBX-2982 in humans. No 
neurobehavioral effects were observed in rats. 
 
MBX-2982 was not genotoxic in any of the systems evaluated, but no data are available regarding animal 
or human carcinogenicity. No specific animal or human studies have been performed to determine the 
reproductive and developmental toxicity of MBX-2982. In human studies to date, there have been no 
reported cases of pregnancy in subjects receiving MBX-2982 or in partners of subjects receiving MBX-
2982. There is no information about the effect of MBX-2982 on sperm or its production in the body, nor 
is there information about effects on the development of the fetus. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
The study being proposed is a placebo-controlled, double-blind, cross-over study design to test 
the hypothesis that short term (14 day +/- 2 days drug administration) of GPR119 will significantly increase 
the glucagon counter-regulatory response to hypoglycemia in subjects with T1DM. 
Participation in this study will not result in any direct benefits to participants, however 
participation in the screening may identify previously unrecognized medical conditions, which may 
provide a general health risk assessment. Subjects will also receive some general medical information, 
including laboratory testing and medical examination. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
2.3.3.1 MITIGATION OF RISKS ASSOCIATED WITH THE STUDY PROCEDURES  
 
Intravenous lines/blood draws (lab samples) 
All venipuncture will be conducted by qualified staff using aseptic techniques. 
 
Standardized meal test 
Suggestion for appropriate insulin dosing will be provided to correct abnormal glucose excursion. 
 
CGM placement 
The site of CGM insertion will be periodically monitored and strategies to prevent local skin reaction will 
be suggested such as, but not only, site rotation, liquid adhesive or additional tape. 
 
Insulin infusion and hypoglycemic clamp 
During the clamp studies, a qualified team member (either MD/PA/ARNP and RN) will be present at 
bedside to mitigate any risks of hyper- and hypoglycemia. Hypoglycemia will be closely monitored, kept 
within the planned range and severe effects will be rapidly corrected with intravenous glucose. At the end 
of each visit, the participant will receive guidance for glucose monitoring, food intake, and insulin dosing 
as needed. 
2.3.3.2 MITIGATION OF POTENTIAL RISKS ASSOCIATED WITH THE INVESTIGATIONAL DRUG 
 
The drug was well tolerated and had a very low order of toxicity at the proposed concentration in previous 
human studies and at higher concentrations in animal models.  


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It is important that women of childbearing potential receiving MBX-2982 in early investigational 
development do not become pregnant for at least 2 weeks after the last dose. As a precaution, women of 
childbearing potential receiving MBX-2982 should use at least one medically accepted method of 
contraception with >99% effectiveness when used consistently and correctly. As the induction potential 
of MBX-2982 on CYP enzymes is not clear. Given that the effectiveness of hormonal contraceptives can 
be reduced by CYP enzyme inducers, we recommend that study subjects who are women of childbearing 
potential use a barrier method during the study to prevent unintended pregnancy. In addition, it is 
important that partners of male subjects receiving MBX-2982 should not become pregnant during the 
study. As a precaution, male subjects receiving MBX-2982 should use dual method of contraceptive use: 
medically accepted contraception (e.g., condoms w/spermicide), or their partner should also use a 
medically accepted form of contraception along with condoms during this period.  
 
Although the studies in humans did not show clinically relevant ECG alterations, in vitro studies showed 
potential for QT prolongation. For this reason, ECGs will be performed on Visits 4, 5, 7, 8 during 
investigational medication treatment, in addition to the screening Visit 1. At visits 5 and 8, the ECG will be 
performed during the meal test at the time of predicted drug concentration peak 180 min after taking the 
medication. The QTcF will be manually calculated for each ECG.  
 
Elevated TSH levels were reported in one of the human studies but not confirmed in others. TSH and FT4 
have been added to the safety measures at visit 5 and visit 8 during study treatment. 
 
 
MBX-2982 could potentially affect plasma glucose levels, causing either a reduction via incretin 
stimulation or an increase via glucagon stimulation. The participants will be instructed to check their blood 
glucose with a glucometer before meals and at bedtime. The participants will be instructed on signs and 
symptoms of hyper- or hypo-glycemia, and on appropriate treatment. To prevent the risk of DKA caused 
by a decrease of insulin due to incretin reduction of blood glucose and glucagon potentiation, subjects 
requiring less than 0.3 U/Kg/day of insulin, on a low carb diet or with an episode of DKA in the past three 
months will not be enrolled.  Written instruction on sick day management and on management of unusual 
symptoms associated with alcohol intake, strenuous or prolonged activity will be provided. Urine ketone 
checks will be recommended when blood glucose is >250 mg/dl and whenever the participant is not 
feeling well. If small to moderate amounts of ketones are measured (small to moderate in the urine or 
blood β-hydroxybutyrate 0.6-1.5 mmol/L) the participants will be instructed to contact the research team, 
administer rapid-acting insulin, consume 15-30g of carbohydrate, hydrate with 300-500 ml of fluid hourly, 
check self-monitored blood glucose frequently and ketones every 3-4 hours. If trace ketones are present 
on more than 3 separate days in a 7-day period, the participant will be instructed to contact the study 
team, measure fasting ketone daily and hold the study medication. 
 
Further mitigation of glucose excursions will be facilitated through the weekly review of the CGM patterns 
and adjustment of insulin doses. As much as possible, the basal insulin dose will be maintained at baseline 
levels to prevent DKA 
 
Due to the unknown profile in elderly and children, these categories of participants will not be enrolled. 
Since no specific studies have been performed in patients with renal dysfunction or renal failure, only 
subjects with a glomerular filtration rate >60 ml/min will be enrolled. 
 


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3 
OBJECTIVES AND ENDPOINTS 
 
Primary Objectives and Endpoints 
Objective 
Endpoint 
To compare (relative to placebo treatment) the 
effect of MBX-2982, a GPR119 agonist, on 
glucagon counter-regulatory responses to 
insulin-induced hypoglycemia in subjects with 
T1DM. 
Maximal glucagon concentration during 
hypoglycemia. 
Total area under the curve (AUC) for glucagon 
during hypoglycemia. 
Incremental AUC for glucagon during hypoglycemia 
(above baseline levels during euglycemia)  
 
Secondary Objectives and Endpoints 
Objectives 
Endpoint 
To determine whether MBX-2982, through its 
effect 
upon 
glucagon 
counter-regulation, 
increases hepatic glucose production (HGP) 
during insulin-induced hypoglycemia and during 
recovery to euglycemia in subjects with T1D 
relative to placebo treatment.  
  
 
HGP during insulin-induced hypoglycemia. 
HGP during recovery from insulin-induced 
hypoglycemia to euglycemia. 
To determine whether MBX-2982 reduces time 
of recovery from hypoglycemia to euglycemia in 
T1DM relative to placebo treatment  
Time of recovery from hypoglycemia (time to reach 
85 mg/dL). 
To determine whether there is any effect of 
MBX-2982 upon other key counter-regulatory 
hormones in T1D relative to placebo treatment  
Plasma levels of counter regulatory hormones 
during hypoglycemia including epinephrine, 
cortisol, GH. 
To compare the glucagon counter-regulatory 
response in healthy (non-diabetic) volunteers 
during insulin-induced hypoglycemia to that of 
subjects with T1DM treated with MBX-2982 and 
placebo. 
Total area under the curve (AUC) for glucagon 
during hypoglycemia  
Incremental AUC for glucagon during hypoglycemia 
(above baseline levels during euglycemia)  
Plasma levels of counter regulatory hormones 
during hypoglycemia including epinephrine, 
cortisol, GH. 
To compare time to recovery to euglycemia 
from insulin-induced hypoglycemia in healthy 
(non-diabetic) volunteers to that of subjects 
with T1DM treated with MBX-2982 and placebo 
Time of recovery from hypoglycemia. 
To compare the hepatic glucose production 
response to insulin-induced hypoglycemia in 
healthy (non-diabetic) volunteers to that of 
subjects with T1DM treated with MBX-2982 and 
placebo  
HGP during insulin-induced hypoglycemia. 
HGP during recovery from insulin-induced 
hypoglycemia to euglycemia. 
 


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Exploratory Objectives and Endpoints 
Objective 
Endpoint 
To evaluate the effects of MBX-2982 upon 
fasting and postprandial glucagon, GLP-1 and 
GIP concentrations in subjects with T1D relative 
to placebo treatment. 
Fasting and post-prandial levels of glucagon, GLP-1 
and GIP  
To evaluate the effects of MBX-2982 on patterns 
of glycemia determined by continuous glucose 
monitoring in subjects with T1DM relative to 
placebo.  
 
Continuous glucose monitoring (CGM) indices of 
glycemic control including hypoglycemia (percent of 
time < 70 mg/dL, < 54 mg/dL), hypoglycemic events, 
mean glucose, percent of time 70-180 mg/dL, 
percent of time > 180 mg/dL, percent of time > 250 
mg/dL, glycemic variability 
To evaluate the pharmacokinetic profile of 
MBX-2982 in subjects with T1DM. 
MBX-2982 plasma levels. 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
This research will be carried out as a placebo-controlled, double-blinded, within-subject, cross-over phase 
2a study. 
Overview of the study design:  
• 
In randomized order, (Latin square, randomly assigned to placebo-active and active-placebo periods) 
and in a double-blinded manner, the T1DM subjects will receive 14 days of daily dosing with MBX-
2982 (or placebo), taken at the same time each day after breakfast. The last dose of 
treatment/placebo will be given when the glucose tracer infusion for the euglycemic/hypoglycemic-
glucose clamp is started.   
• 
T1DM subjects will undergo two euglycemic-hypoglycemic clamps (induction of controlled 
hypoglycemia by an insulin infusion), using a within-subject cross-over design, with the two clamps 
separated by approximately four weeks, that is, two weeks of drug washout followed by two weeks 
of treatment with the alternative therapy.  
• 
After completion of the first clamp study, participants will not receive any study medication for two 
weeks (washout phase) and then begin 14 days of the other arm (placebo or MBX-2982) in a double-
blinded manner, followed by a repeat euglycemic-hypoglycemic clamp study. During treatment on 
each arm and during wash out phase, a blinded CGM will be used to assess daily and nocturnal 
patterns of glycemia. 
• 
On the day preceding a clamp study, while admitted to the research unit, a standardized meal test 
will be used to assess fasting and postprandial glucagon, GLP-1 and GIP secretion. 
 
Overview of the hypoglycemic clamp: Regarding the procedures of the clamp, there will be an initial 
euglycemic run-in phase of the clamp, (~85 mg/dL), followed by induction and maintenance of 
hypoglycemia (target 50 mg/dL), and then a phase of recovery from hypoglycemia. Throughout, glucagon, 
other counter-regulatory hormones, and hepatic glucose production will be measured. Healthy, non-
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medication or placebo; they will be studied to establish “normal physiological responses” for comparison 
to drug and placebo treated responses in T1DM. 
 
 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The study design and procedures were chosen to assess the effect of 14 days of treatment on glucagon 
response to insulin-induced hypoglycemia. The study design allows an ample wash out time to minimize 
the risk of carry-over effects before crossing over the two groups. 
 
A hypoglycemic clamp has been chosen to evaluate the response to hypoglycemia during treatment.  
It is acknowledged by the field that a hypoglycemic clamp does not fully recapitulate all aspects of clinical 
episodes of hypoglycemia occurring under conditions of daily life (such as effects of stress, physical 
activity, altered food intake or variation in insulin dose and its subcutaneous absorption). However, it is a 
controlled, reproducible platform enabling delineation of the counter-regulatory hormonal response and 
lends itself as particularly suitable for paired, within-subject evaluations as we propose to do in evaluating 
the pharmacology of a GPR119 agonist on glucagon counter-regulation. 
 
While our primary goal will be to examine an effect on glucagon counter-regulation in T1DM, we also 
propose to examine any effects on fasting and postprandial glucagon, as well as upon incretin secretion 
(GLP-1 and GIP). We acknowledge that it is improbable much effect upon hyperglycemia will be observed 
in T1DM, given the severity of the deficiency in insulin secretion in T1DM, and given that the effect in 
T2DM was only modest. Yet, the testing is important for several reasons. Firstly, if a GPR119 agonist were 
to elevate glucagon in T1DM under fasting and postprandial conditions, this would be quite unfavorable 
and thus important to know early in its evaluation. Increases in incretin secretion in T1DM (as have been 
observed with DPP-4 inhibitors) could also be potentially favorable, perhaps especially for increased GIP 
which can mitigate risk of hypoglycemia by bolstering glucagon counter-regulation to hypoglycemia; this 
might be most relevant to mitigation of risk for postprandial episodes hypoglycemia in T1DM. 
 
4.3 
JUSTIFICATION FOR DOSE 
 
The dose proposed for this study is 600 mg of MBX-2982 as the HCl salt formulation. Though the dose-
response relationship for MBX-2982 and stimulation of insulin and incretin secretion has been described, 
euglycemic 
insulin infusion
•25 mU/min-m2
•60 minutes duration
hypoglycemia 
induction and 
maintenance
•25 mU/min-m2
•60 minutes duration
halt insulin and 
observe 
recovery from 
hypoglycemia
•measure time to recovery from 
hypoglycemia to euglycemia


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it is uncertain whether this pertains equally to a stimulatory effect on glucagon counter-regulation during 
hypoglycemia. In consideration that the current proposal will be the first study of potential clinical 
translation of this effect previously observed in rodent and the safety of the medication, a dose that 
achieves high exposure of MBX-2982 was chosen to ensure a high level of GPR119 target engagement. If 
positive findings are obtained, consideration will be given to a supplemental study to delineate if doses 
lower (and higher) than 600 mg daily achieve similar or accentuated stimulatory effect on glucagon 
counter-regulation during hypoglycemia. 
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the study 
including the end of trial visit seven days after the last dose of the study medication as shown in the 
Schedule of Activities (SoA). 
 
4.5 
STUDY SITE(S)/LOCATION(S) AND NUMBER OF SUBJECTS 
 
The study will be conducted at two centers with AdventHealth Orlando, Translational Research Institute 
serving as the principal site. The participating centers are as follows:  
 
• 
AdventHealth Translational Research Institute (TRI) in Orlando, Florida 
• 
ProSciento, Chula Vista, California 
 
Estimated number of subjects at both sites combined: 20 T1DM and 9 Healthy 
Estimated number of subjects at AdventHealth TRI site: 15 T1DM and 4 Healthy 
Estimated number of subjects at ProSciento site: 5 T1DM and 5 Healthy 
 
4.6 
MULTI-SITE RESEARCH LOGISTICS/COMMUNICATION PLAN 
 
AdventHealth Orlando Translational Research Institute will be the coordinating center and Dr. Richard 
Pratley will be the lead investigator for this study. As this is a multi-site study, the following processes 
will be put in place with all the participating centers: 
• 
All sites will have the most current version of the protocol and consent document 
• 
All required approvals will be obtained at each site (including approval by the site’s IRB of record). 
• 
All modifications will be communicated to sites and approved (including approval by the site’s IRB 
of record) before the modification is implemented. 
• 
All engaged participating sites will safeguard data as required by local information security 
policies. 
• 
All local site investigators conduct the study appropriately. 
• 
All non-compliance with the study protocol or applicable requirements will be reported in 
accordance with local policy. 
 


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Emails, Teams Meetings, and telephone calls will be used to communicate with all participating sites to 
address any study-related issues and to inform the sites on closure of the study. Interim analysis will not 
be performed. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
Type 1 diabetes cohort 
1. 
Age 20-60 years 
2. 
Diagnosis of T1DM according to American Diabetes Association (ADA) criteria continuously 
requiring insulin for survival 
3. 
Diabetes diagnosis performed more than 5 years before enrollment 
4. 
Fasting C-peptide levels < 0.7 ng/mL with a concurrent plasma glucose concentration > 90 
mg/dL (Labs may need to be repeated if the Plasma glucose is < 90 mg/dL) 
5. 
For female participants: must be > 6 months post-partum and not lactating and agrees not 
to become pregnant during the study and for at least 2 weeks after the last dose of the 
study medication. For male participants: agrees not to donate sperm or not to get a woman 
pregnant during the study and for at least 2 weeks after the last dose of the study 
medication. 
 
Healthy subject cohort 
1. 
Age 20-60 years 
2. 
General good health 
3. 
Creatinine clearance >80 mL/min based on CKD-EPI equation 
4. 
Fasting blood glucose (FBG) >70 mg/dL and <100 mg/dL 
5. 
No history of diabetes 
6. 
For female participants: must be > 6 months post-partum and not lactating and agrees not 
to become pregnant during the study 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. BMI >35 kg/m2 and <18.5 kg/m2 for females and BMI >35 kg/m2 and <20 kg/m2 for males.  
2. Increase or decrease body weight greater than 3kg in the 3 months before enrollment.  
3. Evidence by history, ECG or exams of clinically significant cardiovascular disease (unstable angina, 
myocardial infarction or coronary revascularization within 6 months, clinically significant 
abnormalities on ECG, presence of cardiac pacemaker, implanted cardiac defibrillator) 
4. Evidence of autonomic neuropathy 
5. Liver disease (AST or ALT >2.5 times the upper limit of normal) 
6. Kidney disease (creatinine >1.6 mg/dl or estimated GFR <60 ml/min).  
7. Dyslipidemia, including triglycerides >500 mg/dl, LDL >200 mg/dl or unstable hyperlipidemia. 
Treatment with a single lipid lowering agents is allowed if stable within the previous 3 months.  
8. Anemia (hemoglobin <12 g/dl in men, <11 g/dl in women)  


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9. Thyroid dysfunction (suppressed TSH, elevated TSH <10 µIU/ml if symptomatic or elevated TSH 
>10 µIU/ml if asymptomatic)  
10. Uncontrolled hypertension (BP >160 mmHg systolic or >100 mmHg diastolic) or treatment with 
more than 2 antihypertensive medications. 
11. Current use of beta-adrenergic blocking agents or their use was stopped less than one month 
before recruitment 
12. History of cancer within the last 5 years (skin cancers, with the exception of melanoma, may be 
acceptable)   
13. History of organ transplant 
14. History of HIV, active Hepatitis B or C, or Tuberculosis 
15. Pregnancy, lactation or 6 months postpartum from the scheduled date of screening lab collection 
16. Females of childbearing potential (any female except those with tubal ligation, hysterectomy, or 
absence of menses >2 years) unwilling to use an approved method of contraception (one 
medically accepted method of contraception with ≥99% effectiveness when used consistently and 
correctly). Male participants: he or he and his partner unwilling to use an approved method of 
contraception with ≥99% effectiveness when used consistently and correctly  
17. History of Major Depression in the last 5 years 
18. History of an eating disorder 
19. History of bariatric surgery 
20. History of drug or alcohol abuse (> 3 drinks per day) within the last 5 years 
21. Self-report of marijuana use ≥3 days/week in any form 
22. Psychiatric disease prohibiting adherence to study protocol  
23. Current use of oral or injectable anti-hyperglycemic agents: metformin, sulfonylureas, DPP IV 
inhibitors, SGLT-2 inhibitors, thiazolidinediones, acarbose, GLP-1 analogs  
24. Initiation or change in hormone replacement therapy within the past 3 months (including, but not 
limited to thyroid hormone or estrogen replacement therapy). Hormone based contraception is 
acceptable. 
25. Use of any medications known to influence glucose, fat and/or energy metabolism (e.g., growth 
hormone therapy, glucocorticoids [steroids], prescribed medications for weight loss, etc.). 
Patients on medications with acute effects on glucose metabolism used for other indications 
(certain antidepressants, ADHD and antiepileptic medications) may be enrolled if they have been 
on chronic, stable doses (≥6 months) 
26. Uncontrolled seizure disorder 
27. Current night shift worker 
28. Presence of any condition that, in the opinion of the Investigator, compromises participant safety 
or data integrity or the participant’s ability to complete study visits 
29. Unwilling and/or unable to follow and comply with scheduled visits and protocol requirements 
Additional exclusion Criteria for the type 1 diabetes cohort 
1. 
HbA1c >9% 
2. 
Insulin dose less than 0.3 U/kg or low carbohydrate diet  
3. 
History of T2DM or any form of diabetes other than T1DM 
4. 
Hypoglycemia unawareness as assessed using the GOLD score 
5. 
Using a predictive low blood glucose suspend mode on an insulin pump or a hybrid closed 
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management of blood glucose and willing to participate, the algorithm will be stopped at 
enrollment. 
6. 
Two or more episodes of severe hypoglycemia (Hypoglycemia requiring help from a third 
party) per month in the past six months 
7. 
One or more DKA episodes in the past 3 months 
8. 
QTcF >450 msec for males and >470 msec for females 
9. 
Using non-insulin agents to control blood glucose levels 
10. 
History or evidence of moderate or severe end-organ diabetic complications of retinopathy, 
nephropathy or neuropathy. Proliferative diabetic retinopathy. Non-proliferative retinopathy 
and microalbuminuria will be allowed. 
Additional exclusion Criteria for the healthy cohort 
1. Insulin treatment 
 
5.3 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
modifiable factor may be rescreened. Rescreened participants will be assigned a new study number. 
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
5.4.1 SUBJECT RECRUITMENT 
 
Recruitment methods utilized may include, but will not be limited to, the following: recruitment from 
within the AdventHealth TRI or ProSciento patient population, electronic medical records and database 
searches (including third party recruitment vendors); advertising in multiple media such as print ads, 
flyers, brochures, posters; radio ads; television spots; and internet/social media advertising. All 
advertising materials will be submitted to the AdventHealth Orlando IRB or ProSciento’s IRB of record for 
review prior to using or publishing them. Recruitment efforts will follow AdventHealth Orlando or 
ProSciento recruitment SOPs for research. 
Advertising material, phone screening script and worksheet will be approved by the IRB before use.  
5.4.2 VULNERABLE POPULATIONS 
 
Cognitively Impaired Adults: N/A 
Children: N/A 
Pregnant Women: N/A 
Neonates of non-viable or uncertain viability: N/A 
Prisoners: N/A 
Students: N/A 


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Employees: AdventHealth Employees:  Recruitment efforts will follow AdventHealth recruitment Standard 
Operating Procedures (SOPs) for research. AdventHealth employees will not be individually targeted nor 
excluded from study participation based on employment. AdventHealth employees who engage the 
AdventHealth Translational Research Institute asking to participate in the study will be processed per 
standard consent procedures for participants. In addition, during the consent process, the study staff will 
review standard consent language stating that an employee’s participation or lack of participation in the 
study will not affect their employment status or relationship with AdventHealth. 
5.4.3 SUBJECT STIPENDS OR PAYMENTS 
After the participant’s completion of all study visits, a total amount for the study will be $3075.00 
(T1DM group) and $1100.00 (Heathy group). A payment Card will be processed with the Dollar amount 
per visits completed as indicated in the table below. Payments may take up to 3 business days to be 
processed, once requested. In the event the participant is unable to complete all study visits the 
payment will be prorated. Participants who agree to take part in this study will be paid for completed 
study visits according to the following schedule: 
Visit 
Type 1 Diabetes 
Amount 
Heathy participant 
Amount 
Screening  
$150 
$150 
Visit 2 – Baseline 
$150 
$150 
Visit 3 - Randomization 
$150 
 
Visit 4 
$150 
 
Visit 5 
$1000 
$800 
Payment # 1 (after Visit 5) 
$1600 
$1100 
Week 4 Visit 
$25 
 
Visit 6 
$150 
 
Visit 7  
$150 
 
Visit 8  
$1000 
 
Visit 9 - ETO 
$150 
 
Payment # 2 (after Visit 9) 
$1475 
 
Total Amount 
$3075 
$1100 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Study drug is defined as the investigational drug(s), and placebo intended to be administered to a study 
participant according to the study protocol. 
The intervention will be done by administering MBX-2982, a G-protein coupled receptor-119 (GPR119) 
agonist and placebo. The study is investigator initiated and AdventHealth will be the holder of the IND. 


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6.1.2 MBX-2982 
6.1.2.1 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
MBX-2982 HCl capsules and matching placebo are provided by Cymabay. The investigational drug product 
has been produced as a formulation in capsules that are white in color. Each capsule contains 150 mg 
active drug. 
Study drug will be packaged and labeled in a masked manner and in compliance with regulatory 
requirements. 
6.1.2.2 PRODUCT STORAGE AND STABILITY 
 
MBX-2982 will be stored at 25ºC with excursions from 15-30°C permitted. Temperatures will be 
monitored daily. 
6.1.2.3 PREPARATION AND DRUG DISPENSING 
 
After randomization, a quantity of study drug sufficient for 14+5 days will be dispensed by authorized 
pharmacy personnel for the participant with T1DM at Visit 3 (Day 0).  
At Visit 6 (Day 28), subjects with T1DM will receive study medication, the opposite treatment arm, in a 
double-blinded manner. 
6.1.2.4 DOSING AND ADMINISTRATION 
Study drug will be supplied as 150 mg capsules. Participants will receive a 600 mg daily dose (4 capsules) 
to be taken daily after the morning meal. All study drug doses will be oral self-administrations. 
6.1.2.5  
RATIONALE FOR SELECTION OF DOSE 
 
The rationale for the proposed dose is described above with the scope of ensuring a high level of GPR119 
target engagement (see section 4.3). 
 
6.1.3 PLACEBO 
6.1.3.1 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Placebo will be provided in a similar appearance as the study drug and be packaged and labeled in a 
masked manner in compliance with regulatory requirements. Inactive capsule ingredients are starch, 
lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, sodium lauryl sulfate, stearic 
acid and gelatin. 
6.1.3.2 PRODUCT STORAGE AND STABILITY 
 
Placebo should be stored at room temperature (15°C - 30°C). 


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6.1.3.3 PREPARATION AND DRUG DISPENSING 
 
After randomization, a quantity of study drug sufficient for 14+5 days will be dispensed by qualified 
pharmacy personnel for the participant with T1DM at Visit 3 (Day 0). 
At Visit 6 (Day 28), subjects with T1DM will receive study medication, the opposite treatment arm, in a 
double-blinded manner. 
6.1.3.4 DOSING AND ADMINISTRATION 
All placebo doses will be oral self-administrations. Participant will receive 4 capsules to be taken daily 
after the morning meal. 
6.1.3.5  
RATIONALE FOR SELECTION OF DOSE 
 
N/A 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
All study drugs will be received, stored and dispensed according to regulatory requirements and will be 
used only on subjects and be used only by authorized investigators. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Individuals with T1DM will be randomized in a blinded manner in a 1:1 ratio to receive either placebo or 
MBX-2982 as the treatment for Period 1. Randomization will be conducted by a statistician. This 
information will only be released as the patients are enrolled. A master list of the patient names and 
intervention group will be stored in a limited access, confidential file. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Use of study drug will be monitored at Visit 5 (Day 14) and Visit 8 (Day 42).  Adherence to study drug as 
provided will be assumed unless reported otherwise. 
 
6.5 
CONCOMITANT THERAPY 
 
Medication use will be permitted if not conflicting with the exclusion criteria. Concomitant prescription 
medications, over-the-counter medications and supplements will be reported in the Case Report Form 
(CRF). 
Use of beta-adrenergic blocking agents and hypoglycemic agents other than insulin is not permitted. Their 
use will be assessed at enrollment. 
 
 


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6.5.1 RESCUE MEDICINE 
 
No experiments have been performed to determine a specific antidote to MBX-2982. General supportive 
measures should be taken as appropriate. 
Glucagon can be used as a rescue medication for severe hypoglycemia. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
The study will be stopped if one of the events leading to participant discontinuation occurs in more than 
15% (n=3) of the planned number of 20 enrolled participants with Type 1 diabetes. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
7.2.1 INVESTIGATOR WITHDRAWAL OF SUBJECTS 
The participation in this study may be stopped at any time by the study PI without the participant’s 
consent because: 
• 
The study Medical investigator thinks it necessary for subject’s health or safety; 
• 
Participant has not followed study instructions; 
• 
The AdventHealth Translational Research Institute has stopped the study; or 
• 
Administrative reasons require the participant’s withdrawal. 
 
A participant will be discontinued/withdrawn if the following occur during study treatment: 
• 
Any episode of Level 3 hypoglycemia according to the ADA classification  
• 
Any episode of Diabetes Ketoacidosis (DKA) defined by serum or urine ketones greater than the 
upper limit of normal range and serum bicarbonate <15 mmol/l or blood pH <7.3 without a 
satisfactory alternative cause for anion-gap acidosis 
• 
Persistent glycemia aberration defined as: 
o Hypoglycemia: ≥ 3 episodes per week of level 2 hypoglycemia (blood glucose ≤ 54 
mg/dL, [3.0 mmol/L]) not prevented by appropriate insulin dose adjustments. 
o Hyperglycemia: Level 2 fasting hyperglycemia (blood glucose ≥ 250 mg/dL [13.9 
mmol/L]) in 4/7 days not prevented by appropriate insulin dose adjustments 
• 
Increase in QTcF to >500 ms or >60 ms over baseline confirmed in at least two ECGs 
 
7.2.2 SUBJECT REQUEST FOR WITHDRAWAL FROM STUDY 
Participation in this study is voluntary. Participants may decide not to participate in this study or may 
withdraw from this study at any time without penalty or loss of benefits. If a participant leaves the study 
before the final regularly scheduled visit, she/he may be asked by the study doctor to make a final visit 
for some ‘end-of–study’ procedures. This is to make sure that there are no safety concerns. 
7.2.3 DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN SUBJECTS 


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Participants who request withdrawal or who are withdrawn by the PI from the study will have their data 
maintained in the research database up to the point of withdrawal. The available data will be included in 
subsequent analysis because a participant may have withdrawn due to possible drug side effects (if 
applicable) and keeping these participants in the analysis is essential for study validity. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for one scheduled visit and is 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant. These contact attempts will be documented in the 
participant’s study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
SCHEDULE OF EVENTS 
 
Each participant will be enrolled for up to 84±2 days. 
The intervention study will take up to 19 + 19 days. 
The total length of the study is expected to be 1 year. 
 
8.1.1 CONSENT PROCESS  
We attest that all study staff delegated the authority to obtain informed consent will follow The 
AdventHealth institutional SOP:  401.116  Informed Consent Process and Written Documentation of 
Informed Consent or ProSciento’s consent process. If applicable due to participant preferences or 
circumstances that would require the consent to be obtained at an earlier or same day via remote 
consent, the institute will follow the HRP-831 Investigator Guidance: Remote Informed Consent Process 
in Non-Exempt Research.  
8.1.1.1 SUBJECTS WHO ARE NOT YET ADULTS (INFANTS, CHILDREN, TEENAGERS) 
N/A 
8.1.1.2 COGNITIVELY IMPAIRED ADULTS 
N/A 
8.1.1.3 ADULTS UNABLE TO CONSENT 
N/A 


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8.1.1.4 DOCUMENTATION OF INFORMED CONSENT PROCESS 
Documentation of the informed consent process is required to establish that the subject was accurately 
and adequately informed and that no study-related procedures were initiated prior to obtaining 
informed consent.  A research team member will note in the source documentation the consent 
process, date consent was obtained and that consent was obtained prior to initiating any research 
procedures. 
8.1.1.5 WAIVER OF WRITTEN DOCUMENTATION OF CONSENT OR WAIVER OF CONSENT  
N/A  
8.1.1.6 NON-ENGLISH SPEAKING SUBJECTS 
The participant population is primarily English speaking.  In the unlikely event that a non-English 
speaking participant meets criteria for enrollment, a Qualified Medical Interpreter or Video Remote 
Interpretation will be utilized when there is a need of sight translation. A Qualified Bilingual Staff (QBS), 
or if not available, a Qualified Medical Interpreter or Video Remote Interpretation will be utilized if only 
interpreting for another staff member is required. We will use an Institutional approved short form 
(HRP-804 Investigator Guidance: Short-Form Consent Process in Research) when needed. The plan is not 
to translate the consent, study questionnaires or instructions. 
8.1.2 VISIT 1- SCREENING VISIT/ DAY -35 UP TO -7 (OUTPATIENT, 2-3 HOURS) 
Subjects will take part in a screening visit in the TRI or ProSciento. 
After the participant has read and signed the study informed consent and agreed to study participation, 
the following procedures will be completed for both healthy participants and participants with T1DM: 
• 
Assessment of medical history and demographics 
• 
Physical exam 
• 
Height and weight measurement 
• 
BMI calculation 
• 
Vital signs (Heart rate x 2, blood pressure x 2, respirations, temperature) 
• 
Con-med Assessment 
• 
ECG 
• 
Screening blood (fasting for at least 8 hours, water is permitted): CBC, CMP, HbA1c, thyroid 
function tests, lipid panel, C-peptide, islet autoantibody panel, hepatitis/HIV 
• 
Urinalysis and urine drug screening 
• 
Serum beta HCG for pregnancy in female subjects of childbearing potential (all women are 
considered to be of childbearing potential unless they have undergone a hysterectomy, tubal 
ligation, or have had an absence of menses for > 2 years) 
Inclusion and exclusion criteria will be verified. Recruited candidates meeting all enrollment 
criteria will be scheduled for visit 2.  
8.1.3 VISIT 2 – BASELINE VISIT/ DAY -7±2 (T1DM COHORT) OR 8±2 DAYS BEFORE V5 
(HEALTHY COHORT) (OUTPATIENT, 1 HOUR):  
The visit will be done at the TRI or ProSciento. 
 


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The following procedures will be completed for patients with T1DM and healthy volunteers:  
• 
CGM placement (Healthy volunteers will wear the CGM for the 10 days preceding and including 
the clamps). 
 
• 
Training on sensor insertion and use for continuous glucose monitoring (CGM). Sites provided 
CGM will be blinded and subjects with T1DM should continue their normal finger stick glucose  
and/or personal CGM monitoring. 
• 
AE/Con-med Assessment 
• 
Instruction on insulin dose adjustments, ketone testing and sick day management, 
hypoglycemia symptoms and treatment of participants with T1DM 
 
8.1.4 VISIT 3 – RANDOMIZATION VISIT/ DAY 0±2 (OUTPATIENT, 1 HOUR) 
The visit will be done at the TRI or ProSciento. 
 
The following procedures will be completed for participants with T1DM: 
• 
CGM management and data review 
• 
Review knowledge of insulin dose adjustments, ketone testing and sick day management, 
hypoglycemia symptoms and treatment 
• 
Fingerstick blood glucose/personal CGM data, and insulin log review 
• 
AE/Con-med Assessment 
• 
Urine pregnancy test 
• 
Blood draw for archive (fasting for at least 10 hours) 
• 
Urine for archive 
• 
Randomization 
• 
Drug distribution for Period 1 
 
8.1.5 VISIT 4 – FOLLOW UP VISIT/ DAY 7±2 (OUTPATIENT, 1-1.5 HOURS) 
The visit will be done at the TRI or ProSciento. 
 
The following procedures will be completed for participants with T1DM: 
• 
CGM management and data review 
• 
Review knowledge of insulin dose adjustments, ketone testing and sick day management, 
hypoglycemia symptoms and treatment 
• 
Fingerstick blood glucose/personal CGM data, insulin and study medication log review 
• 
AE/Con-med Assessment 
• 
ECG 
 
Data from the CGM will be analyzed. 
 
8.1.6 VISIT 5 – PERIOD 1/ DAY 13-14+5 (T1DM COHORT) (INPATIENT, 2 DAYS) OR WITHIN 
28 DAYS AFTER SCREENING (HEALTHY COHORT) 
The visit will be done at the TRI or ProSciento. 
The scheduled day of intervention is valid for participants with T1DM. 


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Healthy participants will undergo the same procedures of this visit any time between 7 and 28 days after 
screening 
Because moderate and severe episodes of hypoglycemia can have a transient effect of at least several 
days to dampen counter-regulatory responses to a subsequent episode of hypoglycemia (12, 15, 21) the 
clamp procedure may need to be re-scheduled so that a window of at least 5 days without moderate or 
severe episodes of hypoglycemia (blood glucose <55 mg/dl) precedes the clamp study (and supplemental 
study medication can be provided under such circumstances). Subjects will be admitted in the fasting 
state (10hours) to the Research Center in the morning the day prior to the clamp study (which will be 
conducted on the following morning).   
The following procedures will be completed in participants with T1DM and in healthy participants: 
• 
Physical exam 
• 
Height and weight measurement 
• 
BMI calculation 
• 
Vital signs (Heart rate x 2, blood pressure x 2, respirations, temperature) on each day of CRU staying 
• 
ECG during the meal test 
• 
AE/Con-med Assessment 
• 
Follow up labs (fasting for at least 10 hours, water is permitted): CBC, CMP, HbA1c, lipid panel, thyroid 
function. 
• 
Urine pregnancy test 
• 
Standard meal challenge with pre- and post-meal blood draw to measure glucose, glucagon, total GLP-
1, total GIP, and blood study medication levels (GRP119 PK)  
• 
Overnight IV infusion of regular insulin (T1DM participants only) 
• 
Euglycemic and hypoglycemic clamp 
• 
CGM management and data review 
• 
Fingerstick blood glucose/personal CGM data, ketone, insulin and study medication log review 
(T1DM participants only) 
• 
Adherence to study drug will be evaluated (T1DM participants only) 
• 
Blood for archive 
• 
Urine for archive 
 
On the morning of admission, subjects with T1DM will be instructed to withhold long-acting insulin 
injections, and not to eat breakfast (which will be served at the research center after admission). A T1DM 
subject will be asked to monitor blood glucose every four hours (or more frequently) and administer short-
acting insulin to control hyperglycemia. The study physician and nurse will help guide subjects in these 
dose selections. Subjects who are on insulin pump therapy will continue their usual basal rates and 
prandial dosing of insulin delivery since this will clear rapidly once discontinued. 
 
Upon admission to the Research Center, the participant will have an intravenous catheter inserted 
and afterwards will receive a standard mixed meal challenge of consistent composition and calorie 
amount on both admissions, preceded by a pre-prandial dose of insulin. The intervention drug will be 
taken 30 minutes, ±5 minutes window, after beginning the meal. At 30-minute intervals, preceding and 
during the meal, for the next 3.5 hours, blood samples will be obtained according to Table 2.  The key 
objective of this meal study is to examine fasting and prandial glucagon responses while on GPR119 
agonist treatment. After the mixed meal challenge, the IV catheter will be maintained. Subjects will 
receive a weight maintaining, controlled carbohydrate lunch and dinner on the unit. After dinner, research 
subjects will be kept NPO (other than water) and will remain fasting in the morning and until completion 
of the clamp study. 


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For T1DM subjects, a second catheter might be placed for an overnight infusion of low-dose 
regular insulin to control plasma glucose within a range of 80 to 120 mg/dl. A POC and/or CGM instrument 
will be used for bed-side glucose determinations. To monitor plasma glucose overnight, every 1 to 2 hours 
(more frequently if necessary). Blood glucose sampling/evaluation via CGM/POC will be done to inform 
adjustments of the insulin infusion rate using a previously established algorithm. No further subcutaneous 
insulin use, by injection or via pump delivery, will be used until subjects resume their usual therapy after 
the clamp study. The last medication dose will be taken before the beginning of the clamp. 
 
At the end of the clamp procedure, subjects will be served a meal and observed for two to three 
hours afterwards to monitor blood glucose and for adverse effects of the study. Subjects may receive a 
pre-prandial dose of short acting insulin and will receive instructions from the study physician on re-
starting their usual insulin regimen and any adjustment or changes for that day. Blood glucose levels will 
be monitored every 15-30 minutes until stable or in case of hypoglycemia symptoms. 
 
The study medications will be stopped. The ppt will be wearing a CGM during the wash out phase, 
additional supplies will be provided if needed. In the scenario the participant is not comfortable with 
placing new CGM at home a TRI site visit will be scheduled for a study staff member to assist with CGM 
insertion.   
 
The study stops here for healthy participants.  
8.1.7 WEEKS 4 DAYS 21±2 (OUTPATIENT, 15 TO 30 MIN) 
The visit will be done at the TRI or ProSciento.  
 
The following will be done: 
• 
Fingerstick blood glucose/personal CGM data and insulin log review 
• 
AE/Con-med Assessment 
• 
AE/Con-med Assessment 
 
During the first 14 days after discharge, subjects will not receive any study medication; this will be a “drug 
washout” phase. The research team member will be in contact with the subject to monitor for adverse 
effects.  
8.1.8 VISIT 6 – DRUG START FOR PERIOD 2/ DAY 28±2 (OUTPATIENT, 1 HOUR) 
The visit will be done at the TRI or ProSciento. 
 
The following procedures will be completed for participants with T1DM: 
• 
Physical exam 
• 
Height and weight measurement 
• 
BMI calculation 
• 
Vital signs (Heart rate x 2, blood pressure x 2, respirations, temperature)  
• 
CGM management and data review 
• 
Review knowledge of insulin dose adjustments, ketone testing and sick day management, 
hypoglycemia symptoms and treatment 
• 
Fingerstick blood glucose/personal CGM data, and insulin log review 
• 
AE/Con-med Assessment 


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• 
Urinary pregnancy test 
• 
Drug distribution for Period 2 
 
During the following 14 days, subjects with T1DM will receive study medication, the opposite treatment 
arm, in a double-blinded manner.  
8.1.9 VISIT 7 – FOLLOW UP VISIT/ DAY 35±2 (OUTPATIENT, 1-1.5 HOURS):  
The visit will be done at the TRI or ProSciento. 
 
The following procedures will be completed for participants with T1DM: 
• 
CGM management and data review 
• 
Review knowledge of insulin dose adjustments, ketone testing and sick day management, hypoglycemia 
symptoms and treatment 
• 
Fingerstick blood glucose/personal CGM data, insulin and study medication log review 
• 
ECG 
• 
AE/Con-med Assessment 
 
Data from the CGM will be analyzed primarily for the period commencing 7 days of dosing, and assuming 
steady-state drug concentrations that are within the desired therapeutic target range are achieved. 
8.1.10 VISIT 8 – PERIOD 2/ DAY 41-42+5 (INPATIENT, 2 DAYS):  
The visit will be done at the TRI or ProSciento. 
 
Because moderate and severe episodes of hypoglycemia can have a transient effect of at least several 
days to dampen counter-regulatory responses to a subsequent episode of hypoglycemia (12, 15, 21) the 
2nd clamp procedure may need to be re-scheduled so that a window of at least 5 days without moderate 
or severe episodes of hypoglycemia (blood glucose <55 mg/dl) precedes the clamp study (and 
supplemental study medication can be provided under such circumstances). 
 
Subjects will be admitted to the TRI or ProSciento in the morning, the day prior to the clamp study (which 
will be conducted on the following morning). 
 
The following procedures will be completed in participants with T1DM: 
• 
Physical exam 
• 
Height and weight measurement 
• 
BMI calculation 
• 
Vital signs (Heart rate x 2, blood pressure x 2, respirations, temperature) on each day of CRU staying 
• 
ECG during the meal test 
• 
AE/Con-med Assessment 
• 
Follow up labs (fasting for at least 10 hours, water is permitted): CBC, CMP, HbA1c, lipid panel, thyroid 
function. 
• 
Urine pregnancy test 
• 
Urine for archive 
• 
Standard meal challenge with pre- and post-meal blood draw to measure glucose, glucagon, total GLP-
1, total GIP, and blood study medication levels (GRP119 PK).  
• 
Overnight IV infusion of regular insulin 


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• 
Euglycemic and hypoglycemic clamp 
• 
CGM management and data review 
• 
Fingerstick blood glucose/personal CGM data, ketone, insulin and study medication log review 
• 
Adherence to study drug 
 
The study visit will be identical to those described for visit 5. 
 
At the end of the visit the TRI or ProSciento provided CGM will be removed. 
8.1.11 VISIT 9 EOT – SAFETY VISIT/ DAY 49±2 (OUTPATIENT, 1-1.5 HOURS):  
The visit will be done at the TRI or ProSciento. 
 
The following procedures will be completed for patients with T1DM:  
• 
Vital signs 
• 
Physical exam 
• 
Height and weight measurement 
• 
BMI calculation 
• 
AE/Con-med Assessment 
• 
Blood collection (fasting for at least 10 hours, water is permitted) for CBC, and CMP. 
 
8.2 
EFFICACY ASSESSMENTS  
 
Continuous Glucose Monitoring (CGM) 
Starting at Visit 2, participants with T1DM will wear a blinded continuous glucose monitor (CGM) for the 
duration of the study as a safety measure for glucose levels. 
Healthy volunteers will wear the CGM for the 10 days preceding and including the clamps. 
 
The CGM will be placed by a member of the study team (unless the participants is familiar and prefers to 
do it on their own), participants will be instructed on the use and removal of the device, as well as 
reinsertion of the device as needed. During CGM wear, participants will be instructed to perform standard 
fingerstick glucose measurements and/or continue with personal CGM to manage their blood glucose. 
Participants will be encouraged to document their blood glucose levels and insulin coverage on a home 
Glucose/Insulin log, for review by the medical study staff. The FDA-approved system (Dexcom) includes a 
sensor and transmitter. It measures interstitial fluid glucose levels in the range of 40 mg/dl to 400 mg/dl 
every 5 minutes. 
 
Standardized meal test 
Upon admission to the TRI or ProSciento, the participants will have an intravenous catheter inserted and 
afterwards will receive a standard mixed meal challenge of consistent composition and calorie amount on 
both admissions. The meal will comprise 25% of daily calorie requirement with a 48-50% Kcal from 
carbohydrate, 35% from fat and 15-17%% from proteins. The meal will be preceded by a pre-prandial dose 
of insulin calculated based on the participant insulin to carbohydrate ratio. 15 minutes prior to the start 
of the meal, a baseline sample will be drawn. From the start of meal, for the next 3.5 hours, at 30-minute 
intervals, blood samples will be obtained for glucose, glucagon, total GLP-1 and total GIP, and the study 
drug plasma levels (PK). The key objective of this meal study is to examine fasting and prandial glucagon 
responses while on GPR119 agonist treatment.  


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ECG will be performed during the meal test at the time of predicted drug concentration peak, 180 minutes, 
±5minutes window, after taking the medication. 
 
Euglycemic and hypoglycemic clamp procedures 
At approximately 6 a.m., a primed, continuous infusion of [6,6] di-deuterated glucose will be started to 
enable determination of hepatic glucose production (HGP) and systemic glucose utilization via the glucose 
isotope dilution method; at least 2.5 hours will be allowed for isotope equilibration. The principal target 
of glucagon action is the liver, and HGP more specifically, and assessing this parameter will give 
physiological context to any observed changes in glucagon secretion during induced hypoglycemia.  
At about 6 a.m. T1DM subjects will take the final dose of the study medication. A catheter will be placed 
in a vein on contralateral hand or arm and the arm warmed (via heating box or warming pad) to achieve 
“arterialization” of blood samples. Around 8:30am, shortly before the clamp insulin infusion start, the 
overnight insulin infusion will be discontinued. The euglycemic portion of the clamp will commence with 
insulin infusion at a constant rate of 25 mU/min∙m2. Blood / plasma glucose will be measured every 5 
minutes and allowed to decrease until it reaches a value of approximately 90 mg/dl, at which point a 20% 
dextrose (D20) spiked with [6,6] di-deuterated glucose will be given (glucose infusion rate; GINF), at an 
adjustable rate, in order to maintain blood glucose at approximately 85 mg/dl. At approximately 9:30 a.m. 
(or following at least 15 minutes of stable euglycemia, operationally defined as 85 ± 10 mg/dl, 3 sets of 
blood samples at 10 min intervals will be obtained for glucagon, insulin, catecholamines, cortisol, growth 
hormone, GLP-1 and GIP, and glucose enrichment.  
Subsequent to the 3rd baseline sample, the GINF will be stopped, the 25 mU/min-m2 insulin infusion will 
be continued, and the hypoglycemic portion of the clamp study will begin. Blood glucose will be allowed 
to decrease over ~30 min until values of 50 to 55mg/dl are observed and then will be maintained at this 
level for approximately 30 minutes by infusion of D20. Mild fluctuation of blood glucose values during the 
hypoglycemic portion of the clamp can be expected. As the blood glucose values approach the target level 
of hypoglycemia, an adjustable rate GINF infusion can be started at a low rate to prevent overshoot into 
more severe hypoglycemia and GINF adjusted as needed to maintain the target level of hypoglycemia. 
Blood sampling for glucose will occur every 5 minutes and at every 10 minutes for a panel of hormones 
and metabolite determinations (as described above). A questionnaire will be administered during the 
study to quantitate autonomic symptoms as the sum of scores ranging from 0 (none) to 5 (severe) for 
each of the following symptoms: anxiety, palpitations, sweating, tremor, hunger, and tingling.  
After 30 minutes of sustained hypoglycemia, the insulin infusion will be discontinued, and the recovery 
phase of the clamp will start. Including the time needed to reach hypoglycemia (induction), it is estimated 
that this hypoglycemic phase of the clamp will be approximately 60 minutes. The time to recover to 
euglycemia (operationally defined as a target blood glucose of 85+/- 5 mg/dL) will be ascertained. Once 
insulin infusion has been stopped, to prevent potential further decline in plasma glucose, GINF will initially 
be continued, at least until plasma glucose has risen above 70 mg/dl, at which point GINF will be rapidly 
tapered and discontinued over the next 10 minutes.  GINF will not be re-instituted unless plasma glucose 
declines again into the range of 50 mg/dl. In situations where blood glucose values decrease remain less 
than 50 mg/dl, at any time during the recovery phase, additional glucose will be given as a safety measure. 
Blood samples for glucagon, counter-regulatory hormones and glucose enrichment will be obtained every 
10 minutes for 30 minutes, then every 30 minutes during the recovery period. The recovery phase of the 
study will continue until one hour into recovery, at which point a meal will be provided, and blood glucose 
values monitored until euglycemic values are attained. 
Samples for PK studies will also be obtained. 
Efficacy laboratory measures 


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During the standardized meal test the following will be measured: 
Mixed Meal Tolerance (MMT) 
Time (min) -15 
-1 
30 
60 
90 
120 
150 
180 
210 
Glucose 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Glucagon 
x 
x 
x 
x 
x 
x 
x 
x 
 
GLP-1 
x 
x 
x 
x 
x 
x 
x 
x 
 
GIP 
x 
x 
x 
x 
x 
x 
x 
x 
 
GPR119PK 
 
x 
x 
x 
x 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
          
 
 
 
 
 
Table 2 
During the clamp studies, samples for blood / plasma glucose will be measured with an automated 
glucose analyzer and recorded on the study flow sheet, along with the rate of GINF at 5-minute intervals. 
All the other samples, per the flow sheet, will be collected, placed on ice at the time of collection and after 
centrifugation by study staff, aliquots will be frozen at -80° until analyses.  
    
 
 
 
 
 
 
 
 
 
 
Table 3 
    *Time 0 corresponds to the CLAMP insulin 25 infusion start 
 
Hyperinsulinemic euglycemic and hypoglycemic glucose clamp 
 
 
 
 
Baseline 
Prior to  
Insulin infusion 
 
Euglycemic phase  
 
Euglycemic 
Steady state 
(maintenance) 
Transition from 
Euglycemic to 
Hypoglycemic 
phase 
Hypoglycemic phase  
steady state 
(maintenance) 
Recovery 
phase 
Sample 
nomenclature 
Baseline 
Lab 
Draws 
-150 
-20 
-10 
0 
10 
20 
30 
40 
50 
E10 
min 
E20 
min 
E30 
min 
 
 
T15
min 
 
H10 
min  
H20
min 
H30 
min 
R30 
min 
R60 
min 
Time 
(min)* 
Prior to  
-150 
 
-150 
Start 
Glucose 
Test 
-20 
-10 
0 
10 
20 
30 
40 
50 
60 
70 
80 
 
100 
 
120 
130 
140 
170 
200 
Glucagon 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Insulin 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Glucose 
enrichment 
x 
 
x 
x 
x 
 
 
 
 
 
x 
x 
x 
 
 
 
x 
x 
x 
x 
x 
Catechola
mines 
 
 
x 
 
x 
 
 
x 
 
 
x 
x 
x 
 
 
 
x 
x 
x 
x 
x 
Cortisol 
 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
x 
x 
x 
x 
x 
Growth 
Hormone 
 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
x 
x 
x 
x 
x 
GLP-1, GIP 
 
 
x 
 
x 
 
 
x 
 
 
x 
x 
x 
 
 
 
x 
 
x 
x 
x 
GPR119 
PK 
x 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
x 
Exosome 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
x 
FFA 
 
 
x 
 
x 
 
 
x 
 
 
x 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
Archive 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
x 


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Glucagon and other hormone assays will be done using the paired samples from the two studies 
performed in each T1DM subject to reduce inter-assay variations. Because it has long been recognized 
that glucagon assays can be difficult, and can have relatively high levels of non-specific background, 
particular care will be made to select the most accurate available glucagon assay(s), and depending upon 
sample requirements, to run these in duplicate or triplicate.   
PK determinations of study drug concentrations will be done by the pharmaceutical partner. 
Additional plasma samples obtained during the clamp (baseline, end of euglycemic clamp, end of 
hypoglycemic phase, end of recovery) will be archived. 
9 
SAFETY AND OTHER ASSESSMENTS 
 
Medical History and Physical Exam 
A Health History will be obtained.  A standard physical examination will be performed by a study physician, 
physician assistant, or nurse practitioner. 
Physical exam will include general status, skin, HEENT (including fundoscopic examination), neck, 
cardiovascular, lungs, abdomen, upper and lower extremities, neurological, musculoskeletal and 
psychiatric systems. 
 
Anthropometric Measures 
Body weight (calibrated scale), height, will be obtained while in a gown, without shoes. BMI will be 
calculated.  
 
Screening Labs 
The laboratory assessments will be used to confirm study eligibility (inclusion/exclusion criteria), as well 
as overall health status: 
• 
complete blood count (CBC) white blood count, red blood count, Hemoglobin, Hematocrit, MCV, 
MCH, MCHC, RDW, Platelet Count, MPV, Neutrophils, Lymphocytes, Monocytes, Eosinophils, 
Basophils, Abs Neutrophil Count, Abs Lymphocyte Count, Abs Monocyte Count, Abs Eosinophil 
Count, Abs Basophil Count 
• 
comprehensive metabolic panel (CMP) (Anion Gap, Albumin, Globulin, A/G Ratio, Alkaline 
Phosphatase, ALT, AST, Bilirubin Total, BUN, Creatinine, eGFR by CKD-EPI, Calcium, Chloride, CO2, 
Creatinine, Glucose, Potassium, Sodium, Total Protein) 
• 
HbA1C 
• 
lipid panel (Total Cholesterol, HDL, LDL, Chol/HDL ratio, LDL/HDL Ratio, Non-HDL Cholesterol,    
                Triglycerides, VLDL, CHD Risk Assessment) 
• 
thyroid function test: thyroid stimulating hormone (TSH) and free T4 
• 
C-peptide (requires a blood glucose > 90mg/dL to be accurate) 
• 
islet autoantibody panel (anti GAD Ab, anti IA-2 Ab, Anti ZnT8 Ab) 
• 
Hepatitis B and Hepatitis C antibody tests [Hepatitis B Surface Antigen (HBsAg), Hepatitis B Surface 
Antibody (HBsAb), Hepatitis C Surface Anitbody  (HCsAB)] 
• 
HIV 1 &2 Ag/Ab Screening 
• 
urinalysis  
• 
Urine toxicology screening test (Amphetamine, Barbiturate, Benzodiazepine, Cocaine, 
Methadone, Opiate, THC, Tricyclics, Oxycodone 


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• 
Serum Beta HCG for pregnancy in female subjects of childbearing potential 
 
Screening labs can be repeated per PI discretion.  
 
Follow up labs 
• 
Complete blood count (CBC) white blood count, red blood count, Hemoglobin, Hematocrit, MCV, 
MCH, MCHC, RDW, Platelet Count, MPV, Neutrophils, Lymphocytes, Monocytes, Eosinophils, 
Basophils, Abs Neutrophil Count, Abs Lymphocyte Count, Abs Monocyte Count, Abs Eosinophil 
Count, Abs Basophil Count 
• 
Comprehensive metabolic panel (CMP) (Anion Gap, Albumin, Globulin, A/G Ratio, Alkaline 
Phosphatase, ALT, AST, Bilirubin Total, BUN, Creatinine, eGFR by CKD-EPI, Calcium, Chloride, CO2, 
Creatinine, Glucose, Potassium, Sodium, Total Protein) 
• 
HbA1C 
• 
lipid panel (Total Cholesterol, HDL, LDL, Chol/HDL ratio, LDL/HDL Ratio, Non-HDL Cholesterol,   
               Triglycerides, VLDL, CHD Risk Assessment) 
• 
Thyroid function test: thyroid stimulating hormone (TSH) and free T4• urine pregnancy test,  
               for female subjects of childbearing potential 
 
The total amount of blood required for the study will be about 547.1 ml during the whole study. 
 
Vital Sign Measurements 
Measurement of vital signs will include heart rate (HR), blood pressure (BP), respirations and temperature 
will be measured sitting for at least 5 min.   
 
Electrocardiograms (ECGs): ECG will be done at screening and during intervention periods at visits 4 and 
5, and visits 7 and 8. At visits 5 and 8, the ECG will be performed during the meal test at the time of 
predicted drug concentration peak 180 min after taking the medication. The QTcF will be manually 
calculated for each ECG. 
 
Fingerstick glucose and ketone measures 
Fingerstick glucose and/or monitoring of personal CGM will be encouraged to measure/monitor at home 
by the participant before meals and at bedtime. 
Participants will be instructed to check urinary ketones and in case of symptoms indicative of 
ketoacidosis or blood glucose >250 mg/dl. 
 
Counseling procedures and Insulin dose adjustments 
The participants will be instructed to check their blood glucose with a glucometer/personal CGM device 
before each meal and at bedtime. The participants may be instructed on insulin dose adjustments, 
ketone testing and sick day management, hypoglycemia symptoms and treatment. 
 
Assessment of adverse events. See below. 
9.1 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
9.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 


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9.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
 
9.1.3 CLASSIFICATION OF AN ADVERSE EVENT 
9.1.3.1 SEVERITY OF EVENT 
Adverse event severity will be graded as follows: 
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
9.1.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) will have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below. In a clinical trial, the study 
product must always be suspect. 
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (de-challenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory re-challenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (de-challenge). Re-challenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 


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can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
9.1.3.3 EXPECTEDNESS  
 
The PI and medical investigator will be responsible for determining whether an adverse event (AE) is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study intervention as 
reported in the IB. 
9.1.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits, and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training 
and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring 
after signing the informed consent must be documented appropriately regardless of relationship. All AEs 
will be followed to adequate resolution. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
A study team member will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 days after the last day of administration of the medication. At each study visit, 
a research team member   will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the initial acquisition of the information. 
 
9.1.5 REPORTING EVENTS TO PARTICIPANTS  
 
N/A 
 
9.1.6 EVENTS OF SPECIAL INTEREST  
 


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High and low glycemic events will be recorded by CGM and through the participant’s history and glucose 
log at each visit. Hypoglycemia will be defined and recorded according to the American Diabetes 
Association guidelines (Level 1 hypoglycemia is defined as a measurable glucose concentration <70 
mg/dL (3.9 mmol/L) but ≥54 mg/dL (3.0 mmol/L). Level 2 hypoglycemia (defined as a blood glucose 
concentration <54 mg/dL [3.0 mmol/L]) is the threshold at which neuroglycopenic symptoms begin to 
occur and requires immediate action to resolve the hypoglycemic event. Level 3 hypoglycemia is defined 
as a severe event characterized by altered mental and/or physical functioning that requires assistance 
from another person for recovery. Hypoglycemic events are among the endpoints measured to evaluate 
the effects of MBX-2982 on patterns of glycemia as described in section 3. 
9.1.7 REPORTING OF PREGNANCY  
 
Pregnancy in a study participant will be reported among adverse events and reported to the IRB and 
regulatory agencies. 
The study medication will be discontinued, and no additional study tests will be done, while continuing 
safety follow up. 
 
9.2 
UNANTICIPATED PROBLEMS 
 
9.2.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
9.2.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 


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• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported as described above (see SAE 
reporting). 
• 
Any other UP will be reported to the IRB within 10 days of the investigator becoming aware of 
the problem.  
• 
All UPs should be reported to appropriate institutional and regulatory officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), and the 
Office for Human Research Protections (OHRP) within 10 business days, of the IRB’s receipt of 
the report of the problem from the investigator per the guidelines per AH policy. 
 
The TRI has a standing committee that meets monthly to review all adverse events in our clinical trials 
and will additionally be charged with review of the study. ProSciento will report adverse events to TRI 
monthly. SAE/Unanticipated/Pregnancy events will be reported via email/call during working hours. 
After hours ProSciento will contact our on call line 407-303-7100 or Dr. Richard Pratley via cell.  
 
9.2.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
N/A 
 
10 STATISTICAL CONSIDERATIONS  
 
10.1 STATISTICAL HYPOTHESES 
 
For the primary endpoints, we hypothesize that the medication (14-day administration of MBX-2982) will 
increase the measured glucose counter-regulation to hypoglycemia expressed as the maximal glucagon 
concentration, AUC, and Incremental AUC (iAUC) for glucagon during hypoglycemia compared to placebo. 
For the secondary endpoints, we hypothesize that the medication: 
• 
will increase hepatic glucose production during insulin-induced hypoglycemia and during a 
subsequent recovery to euglycemia; 
• 
will reduce the time of recovery from hypoglycemia to euglycemia; 
• 
will increase other counter-regulatory hormones; 
• 
the above-mentioned effects will approach the counter-regulatory response in healthy (non-
diabetic) volunteers during insulin-induced hypoglycemia; 
Exploratory analysis will: 
• 
evaluate for any effects of a GPR119 agonist upon fasting and/or postprandial glucagon 
concentrations in T1DM, together with potential effects on fasting and postprandial, GLP-1 and 
GIP; 
• 
collect data patterns of glycemia of participants with T1DM while are receiving daily therapy with 
a GPR119 agonist (or placebo); 
• 
evaluate the pharmacokinetic profile of MBX-2982 in participants with T1DM. 
10.1.1.1 PRIMARY EFFICACY ENDPOINT(S):  


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• 
Maximal glucagon concentration during hypoglycemia 
• 
Total area under the curve (AUC) for glucagon during hypoglycemia  
• 
Incremental AUC for glucagon during hypoglycemia above baseline levels during euglycemia 
10.1.1.2 SECONDARY EFFICACY ENDPOINT(S): 
 
• 
HGP during insulin-induced hypoglycemia 
• 
HGP during recovery form insulin-induced hypoglycemia to euglycemia  
• 
Time of recovery from hypoglycemia (time to reach 85 mg/dL 
• 
Plasma levels of counter regulatory hormones during hypoglycemia: epinephrine, cortisol, GH 
 
10.1.1.3 EXPLORATORY ENDPOINT(S): 
 
• 
Levels of GLP-1, GIP in fasting and post-prandial conditions 
• 
Continuous glucose monitoring (CGM) indices of glycemic control including hypoglycemia 
(percent of time < 70 mg/dL, < 54 mg/dL), hypoglycemic events, mean glucose, percent of time 
70-180 mg/dL, percent of time > 180 mg/dL, percent of time > 250 mg/dL, glycemic variability. 
• 
MBX-2982 plasma levels 
 
10.2 SAMPLE SIZE DETERMINATION 
It is not precisely known how much of an improvement in glucagon counter-regulation is needed to be 
clinically significant for mitigating risk of hypoglycemia. Restoring glucagon counter-regulation to levels 
observed in people without diabetes would meet and quite likely exceed expectations, this may be too 
high a bar by which to judge success or failure in this initial short-term study. We estimate that a lower 
boundary of meaningful therapeutic effect would be at least a 30% increase in glucagon counter-
regulation and have used this criterion to estimate sample size for the current study. 
 
According to a published study that measured glucagon counter-regulation to hypoglycemia in T1DM (19), 
of the 28 T1DM subjects, the maximal glucagon concentration in placebo treated T1DM group during 
hypoglycemia was 23 pmol/l, while the standard deviation was 10.4 pmol/l. To apply these statistics in 
the current crossover design, 16 subjects are required to detect a 30% increase (6.9 pmol/l) in the GPR119 
agonist treated group compared to a placebo treated group, this will have an 0.8 power, assuming a 0.5 
correlation coefficient between two treatments within the same subjects, and a one-sided paired t-test 
at 0.05 significant level. Accounting for a potential (up-to) 25% dropout rate, 20 T1DM subjects are 
expected to be recruited to the current study.  A sample size of 9 Healthy subjects should be adequate to 
establish the normative (descriptive) data using the same assays and clamp procedures as being used for 
T1DM. 
10.3 RANDOMIZATION 
Randomization schedule based on the two-treatment, two-period, two-sequence cross-over design for 
20 patients will be generated by a biostatistician using SAS (9.4). The treatment assignments will be 
coded as A or B. This information will only be released as the patients are enrolled. The message 
communicating group assignment will be saved in the subject’s study file. 


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10.4 BLINDING 
The randomization schedule will be delivered to the pharmacist, who is the only unblinded person of the 
study. The TRI pharmacist will provide the randomization schedule to the ProSciento pharmacist. Then 
the pharmacist will determine the treatment assignments (placebo or GPR119) based on the treatment 
codes (A or B). The unblinded pharmacist will prepare the study drug, and then give to the designated 
staff member for administration. Allocation concealment, unexpected and/or severe adverse events will 
be reported to the AdventHealth Orlando IRB or ProSciento’s IRB of record.  
 
10.4.1 INSTITUTIONAL REVIEW BOARD 
Prior to study initiation the protocol and the informed consent documents will be reviewed and 
approved by the Institutional Review Board (IRB) of record. Any amendment to the protocol or consent 
materials must also be approved by the IRB before they are implemented.  
The study will be reviewed and overseen by the AdventHealth Orlando Institutional Review Board for 
the Translational Research Institute The study will be reviewed and overseen by ProSciento’s IRB of 
record for ProSciento. 
10.4.2 DATA AND SAFETY MONITORING BOARD (DSMB) OR EQUIVALENT 
Not required. 
10.4.3 MONITORING PLAN 
Clinical trial monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected.  Reported trial data are accurate, complete and verifiable.   
Clinical trial monitoring will be conducted by AdventHealth Office of Research Integrity monitoring 
team to ensure compliance with all applicable federal and state regulations, ICH GCP E6 (R2) standards 
and approved protocol.  This study will be monitored using a risk-based approached.  A monitoring plan 
will be created to ensure patient safety, data quality and integrity is ongoing throughout the life of the 
study.  The frequency and elements of monitoring will be outlined in the monitoring plan.  The monitor 
will ensure study is conducted, recorded and reported as required by federal regulations and IRB of 
record.  Monitoring will be conducted on-site and/or remote.  After completion of site monitoring, a 
report will be provided to PI and study team.  The PI and study team are required to review the report 
and work on significant findings or discrepancies to resolution.  If any findings are required to be 
reported to the IRB, the PI will be made aware and prompted to self-report.  All serious and continuing 
non-compliance is shared with the Research Oversight Committee who may require appropriate 
actions. 
 
10.4.4 QUALITY ASSURANCE AND QUALITY CONTROL 
 
We attest that all AdventHealth Translational Research Institute faculty and staff and ProSciento staff will 
be trained, and this training will be documented as described in AdventHealth Translational Research 
Institute Work Instruction 031.100.015 Documentation of Protocol Training and ProSciento.   
 


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We will implement regular, ongoing discussions between the PI and coordinator as per the AdventHealth 
Translational Research Institute SOP 030.000.002 Oversight of Research Studies at the Translational 
Research Institute. The coordinator will review source and communicate with all applicable study team 
members involved in the study on a regular basis regarding reportable new information, implementing 
amendments, study progress, and quality assurance/control. 
 
We will implement regular, ongoing discussions between the ProSciento PI and ProSciento coordinator. 
The ProSciento coordinator will review source and communicate with all applicable study team members 
involved in the study on a regular basis regarding reportable new information, implementing 
amendments, study progress, and quality assurance/control. 
 
The AdventHealth Translational Research Institute facilities and ProSciento have state of the art and  have 
within each building all required resources and staff to execute the study. The TRI has a Medical Oversight 
team, Medical Oversight Committee, as well as a Quality Committee to appropriately monitor and address 
adverse events. 
 
The AdventHealth Translational Research Institute and research team assigned to this protocol will meet 
prior to initiation to assure that the team members’ roles and the required timelines are clear. Protocol 
specific training will be carried out with the research team members designated in the Delegation of 
Authority Log. Re-training will occur at any time IRB reviewed and approved amendments or revisions to 
this protocol are made. Documentation of all training will be kept in the regulatory binder. 
 
10.5 MATERIALS OF HUMAN ORIGIN:  COLLECTION, PREPARATION, HANDLING AND 
SHIPPING 
The study will collect and archive biological specimens (blood, urine) from the study participants to 
achieve the study endpoints and for safety purposes. Any diagnostic testing will be performed at a CLIA 
accredited lab.  
Biospecimens collected for study-related endpoints, will be analyzed/tested:  both at AdventHealth 
Orlando and outside laboratories/institutions. Assays for pharmacokinetic endpoints on de-identified 
samples will be performed at Covance Laboratory Inc. 
Additionally, remaining biospecimens will be archived for any additional hypothesis-related 
experimentation or testing for this study, which cannot be predicted at the time the protocol is 
developed. Furthermore, if there are any left-over biospecimens after completing the endpoints 
described above, any left-over biospecimens may be archived for other research (not for this study), of 
any type (without limitation to disease, process, or research methods).  This other research can take 
place at AdventHealth Orlando or at outside institutions. 
Lastly, a predetermined amount of biospecimen samples will be collected specifically for archiving for 
future use, such as other research (not for this study), of any type (without limitation to disease, 
process, or research methods).  This other research can take place at AdventHealth Orlando or outside 
institutions. 


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The biospecimens collected for this study will be separated into biospecimen samples that will be used 
for the study and biospecimen samples that were collected to be archived for future use.  After study 
aims have been achieved and study related endpoints have been measured and analyzed, any remaining 
biospecimens will be stored at the TRI Biorepository and will also be considered as “archived 
biospecimens.”  Archived biospecimens will be used for any additional hypothesis-related 
experimentation or testing for the purposes of this study, consistent with the original aims, which 
cannot be predicted at the time the protocol is developed due to the evolving nature of scientific 
exploration.   
Additionally, archived biospecimen samples may be stored indefinitely for future research.  Archived 
biospecimens could be used for separate research by both AdventHealth Orlando scientists and 
scientists outside of AdventHealth Orlando.  This would be allowed for research of any type (without 
limitation to disease, process, or research methods) if it has scientific merit as determined by the TRI 
Scientific Review Committee.    For research outside of AdventHealth Orlando, a Material Transfer 
Agreement will be obtained, which will govern the transfer and chain of custody of the biospecimens 
outside of ADVENTHEALTH ORLANDO. Some of the endpoint testing will be conducted at outside 
laboratories/institutions.  To perform these analyses/testing/etc. and to interpret results, certain data 
elements will need to be shared along with the biospecimen samples.  Data Use Agreements (DUAs) will 
be obtained, which will identify the specific data elements to be shared and will govern the sharing of 
data related to this study.  Data will be de-identified, but a link/code is managed within an electronic 
research management system and maintained by the research team.  
Should archived biospecimens be needed for research outside of AdventHealth Orlando and certain data 
elements that are connected to the archived biospecimen samples are needed to conduct the research, 
then Data Use Agreement(s) will be obtained.  The Data Use Agreement(s) will identify the purpose for 
data sharing, the specific data elements to be shared, and will govern the sharing of data related to this 
study.  Data will be de-identified, but a link/code is managed within an electronic research management 
system and maintained by the research team. 
 
10.6 DATA HANDLING AND RECORD KEEPING  
 
10.6.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
The AdventHealth Translational Research Institute will act as the coordinating center throughout the 
study. Data collection will be performed via case report forms (CRF) at each site. Data from the CRFs will 
then be transferred into an electronic database. The AH-REDCap (Research Electronic Data Capture) will 
be used as the central location for data processing and management. All study activities will be conducted 
in coordination with the study PI/study coordinator and the clinical sites. Each site investigator is 
responsible for complete data ascertainment at their site and entry into the database. 
 
Data quality control will occur according to our SOPs on Data Entry, Quality Control Procedures and Query 
Management.  All data will be entered into an electronic data capture (EDC) system and checked against 
the paper source for accuracy by a second party (Data Entry SOP) and errors resolved through the Query 


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Management SOP.  Ten percent of the data points will be routinely checked at the beginning, middle, and 
close of a study for quality control (Quality Control SOP).  Finally, all critical endpoints (as determined by 
the PI or Sub-I) will be assessed using quality control analyses.  The data will be loaded into the clinical 
research database.  Data in the warehouse will also be routinely monitored over time. 
 
10.6.2 STUDY RECORDS RETENTION  
 
AdventHealth Translational Research Institute retention policy is maintained in the Records Management 
Policy. Electronic de-identified data will be kept indefinitely in our data warehouse. 
Per the institutional policy, investigator records must be kept for a minimum of 7 years after completion 
of discontinuation of the study, or for longer if required by applicable regulations. 
 
ProSciento will maintain records on site until after study closure. After study closure records will be stored 
in a secured offsite facility according to ProSciento’s policy. 
 
10.6.3 DATA SHARING 
Each site will have appropriate Data Use Agreements in place prior to sharing of any data.  
 
10.6.4 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol or International Conference on 
Harmonization Good Clinical Practice (ICH GCP) requirements. The noncompliance may be either on the 
part of the participant, the investigator, or the study site staff. As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the Sponsor to use continuous vigilance to identify and report deviations. All 
deviations must be addressed in study source documents. ProSciento will report all deviations to the IRB 
of Record per policy and to TRI. All deviations will be reported to AH ORI and regulatory team.   
 
10.6.5 PUBLICATION AND DATA SHARING POLICY 
 
Sharing of anonymized data with other organizations would be allowed, as defined in respective Data Use 
Agreements, for research of any type if the research has scientific merit as determined by the TRI Scientific 
Review Committee. 
 
Some of the endpoint testing will be conducted at outside laboratories/institutions. To perform these 
analyses/testing/etc. and to interpret results, certain data elements will need to be shared along with the 
biospecimen samples. Data Use Agreements will be obtained, which will identify the specific data 
elements to be shared and will govern the sharing of data related to this study. Data will be de-identified, 
but a link/code is managed within an electronic research management system and maintained by a study 
coordinator.  


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Should archived biospecimens be needed for research outside AdventHealth Orlando and certain data 
elements that are connected to the archived biospecimen samples are needed to conduct the research, 
then Data Use Agreement(s) will be obtained. The Data Use Agreement(s) will identify the purpose for 
data sharing, the specific data elements to be shared, and will govern the sharing of data related to this 
study. Data will be de-identified, but a link/code is managed within an electronic research management 
system and maintained by a study coordinator. 
 
TRI will publicly disclose data. Whenever possible, data dissemination will occur through presentation at 
major scientific conferences and/or publication in peer-reviewed journals, and will be complete, accurate, 
balanced, and timely. De-identified data will be made available to qualified investigators upon the 
completion of the study. 
The study will be published on the ClinicalTrials.gov website. 
 
10.6.6 CONFLICT OF INTEREST POLICY 
 
The study leadership and AdventHealth has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
10.7 ADDITIONAL CONSIDERATIONS 
N/A 
 


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11 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
V9.0 
29Sep2022 
Screening visit, pg. 36: definition of 
non-childbearing potential women 
updated. 
 
Table 3, pg. 42-43: The glucose 
tracer time would be the (-150) 
timepoint. The Baseline lab draw will 
be performed shortly before (-150) the 
glucose tracer timepoint. 
It was updated to align with 
exclusion # 16. 
 
 
 
V8.0 
08Aug2022 
Exclusion # 20:  marijuana use ≥3 
days/week in any form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion # 24 & 25: Allowing stable 
use 
of 
the 
antiepilectic 
drugs, 
however, uncontrolled seizure is 
exclusionary. 
 
Exclusion # 29: Added: “Unwilling 
and/or unable to follow and comply 
with scheduled visits and protocol 
requirements” 
Screening: Added “up to” 
"Evidence for whether cannabis 
use has beneficial or adverse 
effects in diabetes patients 
remains inconclusive." 
Furthermore, there is increasing 
use of cannabis recreationally, 
regardless of state laws, that is 
becoming more widely accepted 
socially. This increase has been 
seen broadly across different 
socio-economic and 
demographic groups. Given the 
numbers of diabetics, including 
younger type 1 diabetics, that 
are consuming cannabis, it is 
important to understand and 
observe the prevalence of 
marijuana use among this 
population and to capture data 
that may provoke new questions 
or suggest some mechanisms for 
its impact, whether beneficial or 
adverse, on glucose and 
metabolic regulation. 
 
 
 
 
To ensure ppts compliance with 
the protocol requirements and 
study visits 
Clarification regarding the 
screening window 
 


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Glucose Clamp: given the meal at the 
end of the clamp procedure not 
requiring the blood sugar to be at 85; 
due to some time points the ECG, IP, 
blood draws were happening at the 
same times, it was added a window 
 
ConMeds: When we originally wrote 
the protocol, we excluded ppts on 
drugs that could impact weight or 
metabolism. 
In completing 10 ppts with T1D 
and 2 HNV, we have come up 
with several small changes to 
our glucose clamp procedures to 
improve flow and data 
acquisition. 
 
We have had several ppts who 
have been on such medications 
for several years. In this case, 
we think it is highly unlikely 
that chronic use of these drugs 
would materially affect weight 
or metabolic responses. 
V7.0 
28Feb2022 
ConMeds: When we originally wrote 
the protocol, we excluded ppts on 
drugs that could impact weight or 
metabolism. 
 
 
 
 
Glucose Clamp procedure: given 
the meal at the end of the clamp 
procedure; shorten the timeframe of 
the required stable euglycemia to have 
15 min before starting euglycemic 
steady state blood collection and 
widen the range of 85 mg/dl (+/- 10) 
for their blood sugar level; T1D and 
healthy 
ppts 
euglycemia 
level 
changed to 70 mg/dl; in the recovery 
phase the blood glucose levels will be 
monitored every 15-30 minutes until 
stable 
 
Exclusion # 1: BMI >35 kg/m2 
We have had several ppts who 
have been on such medications 
for several years. In this case, 
we think it is highly unlikely 
that chronic use of these drugs 
would materially affect weight 
or metabolic responses. 
 
In completing 3 ppts with T1D 
and 2 HNV, we have come up 
with several small changes to 
our glucose clamp procedures to 
improve flow and data 
acquisition. 
 
 
 
 
 
 
 
 
Per NIH the T1DM population 
has a BMI significantly higher 
than the mean BMI general 
population 
V5.0 
19Jul2021 
Exclusion criteria # 4 (Labs may 
need to be repeated if FBG < 90) 
 
 
Section “Description and Study 
Interventions and Section 4.1  
The last dose of treatment/placebo 
will be given in the morning (before 
the tracer) before the euglycemic/ 
Clarifications to ensure that C-
peptide value is accurate, which 
requires a FBG > 90 
 
As the clamp timing is hard to 
predict, changed the verbiage 
and timing for more consistency 
and clearance.  
 
 


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hypoglycemic glucose clamp is 
started. 
 
Regarding the clamp procedures, 
there will be an initial euglycemic 
run-in phase of the clamp (~85 
mg/dL) –it was changed from 95 to 
85  
 
Section: Schedule of Events and 
section 4.1, 8.1.3:  
Added a line for total CGM wear time 
and foot note ** Healthy volunteers 
will wear the CGM for the 10 days 
preceding and including the clamps. 
 
Section 2.3.3.2 and Exclusion # 16 
Rewording/ clarifying methods of 
barrier methods 
 
Section 8.1.4  
Blood draw for archive – 
added (fasting for at least 
10 hours) 
 
Section 8.1.6 
Overnight Blood glucose parameters 
changed to 80-120 
 
CGM/POC (added POC) 
 
 
Statement added during wash out 
period for the CGM wear time  
 
Section 8.2 
Added: Around 8:30am, shortly 
before the clamp insulin infusion 
start, the overnight insulin infusion 
will be discontinued. 
 
 
 
Table 3:  
Nomenclature and times modified 
 
 
Oversight – to keep the protocol 
BG goals consistent 
 
 
 
 
Added for clarification about 
CGM wear times.  
 
 
 
 
 
Clarifications to reflect the 
acceptable methods of 
pregnancy prevention 
 
Clarifications that blood sample 
is fasting.  
 
 
 
Modified to keep the ppt at a 
more normal BG level.  
 
 
Added POC to allow flexibility 
if CGM reading not available 
 
Added for clarification 
 
 
Change the stop overnight 
insulin time to right before the 
start of clamp insulin time to 
reduce the time frame insulin Is 
turned off and the participant 
blood glucose could increase.   
 
Modifications made to 
distinguish the different clamp 
intervals and corresponding 
time frames/sample collections.  
V4.0 
01Apr2021 
Section 5.2 Exclusion: Additional 
exclusion Criteria for the type 1 
diabetes cohort 
This allows participants to 
continue to monitor and manage 
their Diabetes more efficient.  
 


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-Removed Exclusion criteria # 6: 
“Not willing/able to stop the use of 
their own CGM.” 
 
Section 8.1.3  
-Added “TRI provided” CGM 
-Added “and/or personal CMG” 
-Removed the statement “ If subjects 
normally wear their own CGM, that 
should be removed.” 
 
Section 8.1.4, 8.1.5, 8.1.6, 8.1.7, 
8.1.8, 8.1.9, and 8.1.10 
-Added “personal CGM data” 
 
Section 8.1.6 
-Added “(Type 1 diabetes only)” 
 
Section 8.1.10 
-Added “TRI provided” 
 
 
Section 8.2 
-Added 
“and/or 
continue 
with 
personal CGM” 
 
Section 9 
Fingerstick glucose and ketone 
measures 
-added “and/or monitoring of 
personal CGM will be encouraged to 
measure/monitor” at home by the 
participant before meals and at 
bedtime. 
 
Counseling procedures and Insulin 
dose adjustments 
-added “personal CGM device”  
 
 
 
 
Clarifications made for which 
CGM is being referred too. 
 
Removed to reflect Exclusion 
#6 removal.  
 
 
Clarifications made for which 
CGM is being referred too 
 
 
Clarifications made for which 
Cohort will undergo the 
procedure/test/task 
 
Clarifications made for which 
CGM is being referred too 
 
Clarification to incorporate 
CMG monitoring for Blood 
glucose checks and diabetes 
management. 
 
Clarification to incorporate 
CMG monitoring for Blood 
glucose checks and diabetes 
management. 
V3.0 
10Aug2020 
Description of Study Intervention: 
 
Schedule of Activities (SOA) 
 
Section 5.2 
Exclusion criteria 8 was split to 
Exclusion # 8 and Exclusion #9 for 
clarification.  
 
Section 6.2.1 
Clarifications on the days when 
not to take study medication 
 
Added which cohort will be 
completing the visit. 
 
 
 
 
 
 


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Sentence “will be used only on 
subjects and be used only by 
authorized investigators.” Was blue 
and changed to black ink. 
 
 
Section 8.1.1 
Added optional remote consent 
language 
 
 
Section 8.1.6 
Removed specific test and added 
reference to table.  
 
Section 8.2 
-Added partial sentence: “(unless the 
participants is familiar and prefers to 
do it on their own)” 
 
section Standardized meat test: 
Removed “exosome” test.  
 
Section: Euglycemic and 
hypoglycemic clamp procedures: 
   -Changed 3hrs to 2.5 hours 
 
   -removed 7:00 am 
 
-MMT (table 2) - Endpoint samples 
added and removed  
 
-Clamp (table 3) - Endpoint samples 
added and removed 
 
Section 9.0 
-Total blood volume increased from 
514ml to 547.1 ml 
- removed statement “suggestions 
will be provided to adjust the insulin 
treatment before and during the 
study. “ 
 
 
Added in the event remote 
consenting needs to be utilized. 
 
 
 
Added in the scenario the ppt 
would like to complete CGM 
insertion by themselves 
 
 
 
3 hrs are not needed, 2.5 is 
sufficient 
 
Allows more time flexibility 
 
 
 
 
 
 
 
 


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