A Phase 2, Single-Dose, Randomized, Open-Label, Active-Controlled, Crossover, Pharmacodynamic, and Pharmacokinetic Comparative Study of a Novel Pramlintide-Insulin Co-Formulation in Adults With Type 1 Diabetes Mellitus
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1, Insulin-dependent Diabetes Mellitus
Sponsor: Xeris Pharmaceuticals

EFFQUESTIONTITLE
 P 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2, Single-Dose, Randomized, Open-Label, Active-Controlled, Crossover, 
Pharmacodynamic, and Pharmacokinetic Comparative Study of a Novel 
Pramlintide-Insulin Co-Formulation in Adults with Type 1 Diabetes Mellitus 
 
Protocol Number: 
DPI-201 
Phase: 
2 
IND Number: 
142004 
Study Drug: 
Pramlintide-insulin injection (PRAM9) 
Sponsor: 
Xeris Pharmaceuticals, Inc. 
 
180 North LaSalle Street 
 
Suite 1600 
 
Chicago, IL 60601 
Medical Monitor: 
Khaled Junaidi, MD 
 
Date of Protocol: 
Version 1.0, 6/14/2019 
 
Version 2.0, 8/14/2019 
Version 3.0, 9/6/2019 
Version 4.0, 12/13/2019 
 
  
GCP Statement: 
This study is to be performed in full compliance with 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use (ICH) and all applicable local Good Clinical 
Practice (GCP) and regulations. All required study 
documentation will be archived as required by 
regulatory authorities. 
Confidentiality Statement: 
This document is confidential. It contains proprietary 
information of Xeris (the sponsor). Any viewing or 
disclosure of such information that is not authorized in 
writing by the sponsor is strictly prohibited. Such 
information may be used solely for the purpose of 
reviewing or performing this study. 
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Type 1 Diabetes 
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PROTOCOL SIGNATURE PAGE 
 
 
 
 
 
Please see esignatures on the last page 
 
 
 
Joy Geallis 
Senior Manager, Clinical Operations 
Xeris Pharmaceuticals, Inc.  
 
Date 
 
 
 
 
 
Please see esignatures on the last page 
 
 
 
Khaled Junaidi, MD 
Medical Director, Clinical Research 
Xeris Pharmaceuticals, Inc. 
 
Date 
 
 
 
 
 
Please see esignatures on the last page 
 
 
 
Nicole Close, PhD 
Head of Biostatistics and Clinical Data 
Management 
Xeris Pharmaceuticals, Inc. 
 
Date 
 
 
 
 
 
Please see esignatures on the last page 
 
 
 
Ed Drower, MS 
Director of Good Clinical Practices 
Xeris Pharmaceuticals, Inc. 
 
Date 
 
 
 
 
 
Please see esignatures on the last page 
 
 
 
Aziz Alam, MS 
Senior Director, Regulatory Affairs 
Xeris Pharmaceuticals, Inc. 
 
Date 
 
 
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SUMMARY OF REVISIONS 
Summary of Changes From Version 1.0 to Version 2.0 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Synopsis, 
6.1, 8.5 
Changed definition of hypoglycemia to 
blood glucose <70 mg/dL and instructions 
on rescue with IV dextrose concentration 
and administration. 
FDA Requested  
Synopsis, 
7.3 
Exclusionary Criteria for Hematocrit 
changed to <35.5% (female) and <38.3% 
(males) 
 
Exclusionary Criteria for Hemoglobin 
changed to  <11.5 g/dL (females) and 
<12.5 mg/dL (males). 
FDA Requested 
Reference 
Added reference of American Diabetes 
Association Guideline for Treatment of 
Hypoglycemia by IV glucose. 
Clarification 
Reference 
Joslin Diabetes Center and Beth Israel 
Deaconess Medical Center, Guideline for 
management of uncontrolled glucose in 
hospitalized adult. 
Clarification 
 
Summary of Changes From Version 2.0 to Version 3.0 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Title Page 
Publishing Reference Error 
Administrative 
 
Summary of Changes From Version 3.0 to Version 4.0 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
Synopsis 
 
No. of study centers increased to 4. 
Enrollment 
10.1 
Screening criteria allows for a single 
rescreening for laboratory and vital sign 
failures 
Clarification 
 
 
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INVESTIGATOR’S AGREEMENT 
 
 
I have received and read the protocol for Study DPI-201 and agree to conduct the study as 
outlined.  I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
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Type 1 Diabetes 
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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name, Title, & Address 
Email Address &  
Telephone Number 
Sponsor’s Study Leader & Primary 
Contact 
Joy Geallis 
Senior Manager, Clinical 
Operations 
Xeris Pharmaceuticals, Inc. 
180 North LaSalle Street 
Suite 1600 
Chicago, IL 60601 
JGeallis@xerispharma.com 
(312) 736-1234 (direct) 
(815)-546-9130(cell) 
Medical Monitor & 
24-Hour Emergency Contact 
Khaled Junaidi, MD  
Medical Director 
Xeris Pharmaceuticals, Inc. 
180 North LaSalle Street 
Suite 1600 
Chicago, IL 60601 
kjunaidi@xerispharma.com 
(312) 517-1461 (direct) 
(815) 593-2218 (cell) 
Reporting of Study Drug Concerns 
Xeris Medical Affairs 
 
safetyDPI201@xerispharma.com  
(630) 915-5885 
(815) 593-2218 
 
 
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1. 
SYNOPSIS 
Name of sponsor/company:  Xeris Pharmaceuticals, Inc. 
 
Name of investigational product:  Pramlintide-insulin injection (PRAM9)  
Name of active ingredient:  Pramlintide acetate and recombinant human insulin  
Study title 
A Phase 2, Single-Dose, Randomized, Open-Label, Active-Controlled, Crossover, 
Pharmacodynamic, and Pharmacokinetic Comparative Study of a Novel 
Pramlintide-Insulin Co-Formulation in Adults with Type 1 Diabetes Mellitus 
Protocol number 
DPI-201 
No. of study centers Up to 4 sites in the United States (US) 
Clinical phase  
Phase 2 
Study background 
Most people with diabetes are still unable to achieve glycemic targets with sole 
insulin therapy alone, particularly after mealtime. Physiologic restoration of the 
hormonal responses during meals, via pramlintide and insulin, has been 
demonstrated to reduce postprandial hyperglycemia and to improve blood glucose 
time in range.  
The synergy between insulin and pramlintide provides improved glucose control 
while reducing meal-time insulin requirements. Reduced insulin utilization may 
also reduce the effects associated with long-term insulin use such as weight gain 
and higher risks of hypoglycemia. 
A pramlintide-insulin co-formulation may help reduce the burden associated with 
co-administration (eg, reduce the number of injections per day). Additionally, co-
formulations of pramlintide and insulin may also improve treatment compliance 
and persistency.   
Study rationale 
People with diabetes may have a significant loss of pancreatic beta cell function. 
This leads to a deficiency of 2 hormones: insulin and amylin. The combined effect 
of insulin and amylin is to regulate and normalize blood sugar levels. 
Pramlintide is an injectable drug that closely resembles amylin. Many clinical 
studies that add pramlintide to insulin have demonstrated improved control of 
blood sugar. 
However, the benefits of these products used together also are associated with 
increased risk of pramlintide-associated nausea and vomiting; increased number of 
required injections; and tailoring of insulin and pramlintide doses. 
Xeris Pharmaceuticals has developed a novel, liquid-stable, co-formulation of 
pramlintide plus regular insulin (PRAM9) that can be delivered as a single, 
subcutaneous (SC) injection. The fixed dose combination product is expected to 
allow better management of patient glycemic conditions through improved 
compliance.   
Study objectives 
Primary objective 
 
Evaluate the pharmacodynamic (PD) properties of a single dose of PRAM9 
compared to single doses of regular insulin and regular insulin plus 
pramlintide (co-administered as separate injections) in adults with type 1 
diabetes mellitus (T1D)  
 
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Secondary objectives 
 
Evaluate the safety and pharmacokinetic (PK) profiles of a single dose of 
PRAM9 compared to single doses of regular insulin and regular insulin plus 
pramlintide (co-administered as separate injections) in adults with T1D 
Study endpoints 
Primary 
The PD effects upon plasma glucose levels will be compared between the 
treatments as defined by the following primary endpoint:  
 
Area under the curve area from administration to 180 minutes (AUC0-180) 
(mg/dL × minutes) for plasma glucose > 180 mg/dL 
Secondary 
Safety: 
 
Incidence of adverse events (AEs), serious adverse events (SAEs)  
 
Change from baseline in clinical safety laboratory evaluations 
(hematology and serum chemistry) 
 
Change in vital sign measurements (temperature, respiration, heart rate 
[HR], and blood pressure [BP])  
 
Change from baseline in body weight 
 
Local tolerability assessments (modified Draize Scale and injection site 
discomfort questionnaires) 
PK/PD: 
Key secondary endpoints include the following. The full list of secondary 
endpoints is provided in Section 13.3.2. 
 
Mean proportional time with plasma glucose > 180 mg/dL for 
0-180 minutes after study drug administration 
 
PK plasma levels (AUC0-90 min, AUC0-180 min, AUC0-360 min, Cmax, and Tmax) 
for both insulin and pramlintide 
 
 
Study design 
This is a randomized, open-label, active-controlled, single-dose, 3-treatment, 
3-period, 3-way crossover, comparative PD, and PK inpatient study in adults with 
T1D. 
Methodology 
The study comprises 5 visits:  Screening (Visit 1), Treatment Periods (Visits 2 − 
4), and Follow-Up (Visit 5). 
To determine eligibility, subjects will complete the Screening procedures (Visit 1) 
up to 28 days before the first treatment visit (Visit 2). Subjects will be instructed to 
eat normally and take their usual medications, but to refrain from alcohol for 
24 hours prior to checking in for treatment visits. 
Treatment periods 
For Treatment Period Visits 2 through 4, eligible subjects will be instructed to 
arrive for an overnight stay at the clinical research facility on the day prior to each 
treatment visit. At the clinic, subjects will be given a standardized dinner meal, and 
instructed to take their prescribed evening mealtime insulin regimen and basal 
insulin dose. The subjects will fast after midnight but will be allowed to drink 
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water ad libitum (ie, tap water, bottled water, distilled water, etc. [water without 
carbohydrates]) and take any prescribed medications. 
During each Treatment Period Visit (Visits 2, 3, and 4), eligible subjects will 
receive a single SC dose of PRAM9, regular insulin, or co-administered regular 
insulin plus pramlintide. On the morning of each treatment visit and prior to 
dosing, a fasting blood sample will be tested using a blood glucose meter (BGM) 
to confirm that blood glucose is in the range of 80 to 150 mg/dL.   
 
If the blood glucose is > 150 mg/dL after repeat test, then the investigator 
may treat with an intravenous (IV) bolus dose of regular insulin, per 
discretion, to bring the subject into the required blood glucose range. 
Before initiating study treatment, at least 40 minutes should have passed 
from the last dose of administered insulin and the subject’s glucose level 
should be within the range of 80 to 150 mg/dL. 
 
If the blood glucose is < 80 mg/dL after repeat test, then the investigator 
may treat with oral glucose tabs/solution or IV glucose, per discretion, to 
bring the subject into the required blood glucose range. Before initiating 
study treatment, at least 30 minutes should have passed from the last dose 
of administered glucose and the subject’s glucose level should be within 
the range of 80 to 150 mg/dL. 
 
If the subject’s blood glucose cannot be optimized to 80 to 150 mg/dL 
within 2 hours, then the visit should be rescheduled after a minimum 
24-hour wait, per investigator’s discretion.  
At Visit 2, once blood glucose is confirmed to be within the range of 80 to 
150 mg/dL, subjects will be randomized to their study drug treatment sequence.  
Sequence of Study Drug Administration 
Cohort 
Period 1 
Period 2 
Period 3 
1 
PRAM9 
Regular insulin 
Regular insulin 
+ pramlintide 
2 
Regular insulin 
Regular insulin 
+ pramlintide 
PRAM9 
3 
Regular insulin 
+ pramlintide 
PRAM9 
Regular insulin 
4 
PRAM9 
Regular insulin + 
pramlintide 
Regular insulin 
5 
Regular insulin 
PRAM9 
Regular insulin + 
pramlintide 
6 
Regular insulin + 
pramlintide 
Regular insulin 
PRAM9 
Insulin-to-carbohydrate calculations will be used to identify subject doses. All 
subjects will get flexible doses of insulin, pramlintide, and PRAM9. See 
Section 9.1 for complete information on study drug dosing. The dose of regular 
insulin will be calculated to correspond to a ratio of 9 µg of pramlintide for every 
1 unit of insulin. Additionally, the dose of regular insulin will be calculated from 
the subject’s insulin-to-carbohydrate (I:C) ratio to match a 75-gram carbohydrate 
challenge. Rule 450 will be used for carbohydrate counting and insulin dose 
calculation in this study (see Appendix 3). 
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Prior to study drug administration, a peripheral catheter for blood sampling will be 
placed into a vein ideally located within the antecubital fossa. The hand of the arm 
used for blood sampling will be kept warm by use of a heated hand box to increase 
blood flow and achieve “arterialized” samples. The subject will remain supine and 
kept warm and be allowed to drink only water (ad libitum).  
Once the catheter and hand box are in place, study drug(s) will be administered SC 
over 1 to 3 seconds to the abdomen (around the umbilicus). Co-administered 
regular insulin plus pramlintide injections should be administered to opposite sides 
of the abdomen (ie, left and right peri-umbilicus, opposite quadrants). Injection 
sites should be rotated to avoid injecting at a previously used site.  
To monitor for hypoglycemia, BGM will be performed in real time at each 
subject’s bedside at 10, 20, 30, 40, 50, 60, 90, 120, and 180 minutes post dosing at 
Visit 2 through 4. 
To evaluate drug PD (plasma glucose response) and PK (plasma 
insulin/pramlintide concentrations), blood samples are to be drawn at the time 
points described in the Schedule of Assessments (Table 2). 
Within 2 minutes after the 30 minutes post-dose blood draw, a standardized 
75-gram oral glucose challenge should be ingested (within 5 to 10 minutes) by the 
subject.  
After the last blood collection (at 360 minutes post-study drug administration), 
subjects are to be provided a regular meal and insulin (per investigators’ 
discretion).  
Injection sites will be evaluated by the investigator using the modified Draize scale 
(Appendix 1) and subjects will complete injection site discomfort questionnaires 
(Appendix 2).  
A subject may be discharged from the clinic, per investigator’s criteria, when the 
following has occurred: 
 
Subject has consumed their meal 
 
Subject has returned to their usual medication regimen, including insulin 
 
Subject’s capillary glucose concentration is confirmed to be > 100 mg/dL  
 
Subject is considered medically stable 
Any time during the visit if hypoglycemia occurs (ie, blood glucose < 70 mg/dL), 
the subject will be rescued with IV dextrose using the following formula to 
calculate the dose of dextrose: 
D50% mL = (100 minus BG) × 0.4 
Where D50% = the dose of IV dextrose, mL = the volume of dextrose, BG = 
the subject’s hypoglycemic blood glucose value 
 
The dose of dextrose should be administered slowly, over 2 to 5 minutes. 
If D50% is administered, then blood glucose will be remeasured by blood glucose 
meter at 10, 20, and 30 minutes following the end of administration of IV dextrose. 
Successful plasma glucose recovery should be confirmed (ie, glucose returns to 
≥ 70 mg/dL) and the subject medically stabilized. When the subject is medically 
stable, they can be discharged from the clinic (per criteria above). 
After a first washout period of 7 to 11 days, subjects will return to the clinic for 
Treatment Period 2 (Visit 3) and the treatment visit procedures will be repeated 
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with each subject crossed over to the next randomized study drug treatment 
sequence. Upon check-in and completion of morning activities, the subject will 
receive their second administration of study drug(s).  
After a second washout period of 7 to 11 days, subjects will return to the clinic for 
Treatment Period 3 (Visit 4) and the treatment visit procedures will be repeated 
with each subject crossed over to the last randomized study drug treatment 
sequence. Upon check-in and completion of morning activities, the subject will 
receive their third administration of study drug(s). 
During the Treatment Periods, subjects will undergo symptom-directed PEs, vital 
sign measurements, AE assessments, concomitant medication assessments, and 
pregnancy testing for females of childbearing potential.  
Follow-Up 
A Follow-up Visit (Visit 5) will be conducted 7 to 11 days after the subject’s last 
dose of study drug(s). Subjects will return to the clinic and undergo complete PE, 
vital sign measurements, weight measurements, sample collection for hematology 
and chemistry, AE assessments, concomitant medication assessments, and 
pregnancy testing for females of childbearing potential. 
Number of subjects 
 
Approximately 48 subjects may need to be screened in order to obtain 
18 randomized subjects (3 subjects per treatment sequence). 
Diagnosis and main 
entry criteria 
Inclusion criteria: 
Subjects must meet the following criteria to be included: 
1. Understands the study procedures, alternative treatment available, and risks 
involved with the study, and voluntarily agrees to participate by giving written 
informed consent 
2. Male or non-pregnant, non-lactating female diagnosed with T1D for at least 
24 months prior to Screening. 
3. Aged 18 to 64 years of age, inclusive 
4. On a stable insulin regimen for 21 days prior to Screening (no greater than 
± 20% variability in total daily dose)  
5. Have a plasma C-peptide level < 0.6 ng/mL at Screening  
6. Have an HbA1c < 10% at Screening 
7. Body mass index (BMI) in the range of ≥ 18 to ≤ 35 kg/m2 at Screening 
8. For women of childbearing potential, there is a requirement for a negative 
urine pregnancy test at Screening and for agreement to use contraception 
throughout the study and for 7 days after the last dose of study drug. 
Acceptable contraception includes birth control pill/patch/vaginal ring, Depo-
Provera® (medroxyprogesterone acetate), Norplant® System (levonorgestrel), 
an intra-uterine device (IUD), the double barrier method (the woman uses a 
diaphragm and spermicide and the man uses a condom), or abstinence. 
9. Fasting Serum Triglycerides concentration <200 mg/dL 
 
Exclusion criteria: 
Subjects meeting any of the following criteria are to be excluded. Laboratory 
criteria will be based on testing performed at the Screening Visit.  
1. Currently being treated with pramlintide or has discontinued pramlintide 
within 21 days of Screening 
2. Currently using an insulin pump 
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3. Has renal insufficiency (serum creatinine > 3.0 mg/dL) or end-stage renal 
disease requiring renal replacement therapy 
4. Has hepatic disease, including serum ALT or AST ≥ 3 times the upper limit of 
normal (ULN) 
5. Has hepatic synthetic insufficiency (serum albumin < 3.0 g/dL) 
6. Has a hematocrit value that is exclusionary, as shown below: 
a. Female <35.5% 
b. Male <38.3% 
7. Has a hemoglobin value that is exclusionary, as shown below: 
a. Female <11.5 g/dL 
b. Male <12.5 g/dL 
8. Has out-of-range systolic or diastolic BP readings at Screening (systolic 
BP < 90 or > 150 mm Hg or diastolic BP < 50 or > 100 mm Hg) 
9. Has clinically significant ECG abnormalities at Screening 
10. Has congestive heart failure, NYHA Class III or IV 
11. Has history of myocardial infarction, unstable angina, or revascularization 
within 6 months prior to Screening 
12. Has history of a cerebrovascular accident in 6 months prior to Screening with 
major neurological deficits 
13. Has active malignancy within 5 years prior to Screening (exception: basal cell 
or squamous cell skin cancers) 
14. Has had major surgical operation within 60 days prior to Screening or planned 
surgical operation during the study 
15. Has a seizure disorder (other than with suspected or documented 
hypoglycemia) 
16. Has a current bleeding disorder, treatment with anticoagulants, or platelet 
count < 50 ×109/L 
17. Has a history of allergies or significant hypersensitivity to pramlintide or any 
pramlintide-related products or to any of the excipients in the investigational 
formulation  
18. Has a history of positive test result for hepatitis B virus (HBV), hepatitis C 
virus (HCV), or human immunodeficiency virus (HIV)  
19. Has a concurrent illness not controlled by a stable therapeutic regimen 
20. Tests positive for drugs of abuse at Screening. Subjects testing positive for 
tetrahydrocannabinol (THC) at Screening or reporting active marijuana use 
will be allowed to participate in the study at the discretion of the investigator. 
21. Has active substance or alcohol abuse (> 21 drinks/week for males or 
> 14 drinks/week for females).  
22. Has participated in other studies involving administration of an investigational 
drug within 30 days or 5 half-lives prior to Screening (whichever is longer) or 
during participation in the current study. 
23. There is any reason the investigator deems exclusionary 
24. Has donated blood within 8 weeks prior to Screening.  
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Study drug, 
dosage, and 
administration 
PRAM9, a pramlintide-regular insulin co-formulation 
 
Dose:  See Sections 9.1.3and 9.1.4 for a full description of pramlintide dose 
adjustment. Route of administration: SC (in the abdomen, peri-umbilicus) 
Active Controls, 
dose, and route of 
administration 
Regular insulin:  Humulin® R (U-100) (regular insulin human injection)  
Dose:  See Section 9.1.2. 
Route of administration: SC (in the abdomen, peri-umbilicus) 
Regular Insulin plus pramlintide (co-administered as separate injections) 
Dose:  See Sections 9.1.3 and 9.1.4 for a full description and pramlintide dose 
adjustment. 
Route of administration: SC (in the abdomen, peri-umbilicus). The separate, co-
administered regular insulin and pramlintide injections should be given to 
opposites sides of the abdomen (ie, left and right peri-umbilicus, opposite 
quadrants). 
Duration of subject 
participation and 
duration of study 
Screening Phase of up to 4 weeks; Treatment Periods of up to 3 weeks; and 7 to 
11 days of follow-up. 
The estimated duration of subject participation is 8 weeks. 
Concomitant 
medications 
All medications taken within 28 days before the first study treatment visit (Day 1), 
including insulin, will be documented in the electronic case report form (eCRF). 
Any changes to a subject’s concomitant medication regimen after the first 
treatment on Day 1 will also be documented in the eCRF. 
Ideally, subjects should be on a stable regimen of all concomitant medications 
except insulin for at least 28 days prior to Screening, and they will be encouraged 
to avoid making changes (excepting insulin) to their concomitant medication 
regimen during participation in the study.  In addition, investigators are 
encouraged to avoid adding to or changing a participant’s medications during 
study participation unless deemed medically necessary. 
Diabetes Medication  
Subject diabetes medication will be recorded on the day of Screening:  
 
Total daily meal-time insulin 
o Type of insulin (regular insulin, lispro, or aspart) 
 
Basal insulin 
o Type of insulin (glargine, detemir, or degludac) 
 
Total daily dose of insulin 
 
Glucagon-like peptide-1 (GLP-1) analogue 
Safety assessments 
Safety assessments include reporting of AEs and SAEs, vital sign measurements, 
clinical safety laboratory evaluations, and reasons for treatment discontinuations 
due to toxicity. In addition, the investigator will use a modified Draize scale to 
evaluate the injection sites after each administration for signs of erythema and 
edema (Appendix 1) and subjects will complete questionnaires to assess injection 
site discomfort (Appendix 2). 
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To monitor for hypoglycemia, BGM will be performed in real time at each 
subject’s bedside at 10, 20, 30, 40, 50, 60, 90, 120, and 180 minutes post dosing at 
Visit 2 through 4. 
Safety assessments will be performed at specified time points. Vital sign 
measurements, including BP, HR, respiratory rate, and temperature will be taken 
after ≥ 5 minutes of seated rest.  
The AE reporting period for a subject enrolled in the study begins when the subject 
provides informed consent and is continued through the Follow-Up Visit. All AEs 
that occur in subjects during the AE reporting period must be recorded, regardless 
of the relationship of the AE to study drug. All AEs are to be followed until 
resolution or the subject is medically stable. 
Pharmacodynamics At Visits 2, 3, and 4, samples will be drawn to measure plasma glucose levels. 
Venous blood samples will be drawn 10 ± 2 minutes before and immediately prior 
to dosing (-2 to 0 minutes), and then 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240, 
300, and 360 minutes post-dosing (window allowance of ± 2 minutes). 
Plasma glucose levels will be used to calculate the following PD parameters: Cmax, 
Tmax, area over the curve (AOC), and AUC (see Section 13.3.2). 
Pharmacokinetics 
At Visits 2, 3, and 4, samples will be drawn to measure plasma insulin and 
pramlintide levels. Venous blood samples will be drawn 10 ± 2 minutes before and 
immediately prior to dosing (-2 to 0 minutes), and then 10, 20, 30, 40, 50, 60, 90, 
120, 150, 180, 240, 300, and 360 minutes post-dosing (window allowance of 
± 2 minutes). 
Insulin and pramlintide concentrations will be used to calculate the following PK 
parameters: Cmax, Tmax, AUC0-90, AUC0-180, and AUC0-360  
Statistical methods 
Complete details for the statistical analyses are included in a separate Statistical 
Analysis Plan (SAP).  
 
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Table 2: 
Schedule of Assessments 
Study Phase 
Screening 
Treatment Period 
Follow-Up 
Study Visit 
V1 
Period 1 
V2 
Period 2 
V3 
Period 3 
V4 
V5 
Study Day 
-28 to -1 
1 
 (V2+7-11  
days)14 
 (V3+7-11 
days)14 
 (V4+7-11 
days)14 
Informed consent 
X 
 
 
 
 
Medical history & demographics 
X 
 
 
 
 
Inclusion/exclusion review 
X 
 
 
 
 
Urine drug screen1 
X 
 
 
 
 
Physical exam & body weight 2 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
Vital sign measurements3 
X 
X 
X 
X 
X 
Hematology 
X 
 
 
 
X 
Clinical chemistry 
X 
 
 
 
X 
C-peptide & HbA1c 
X 
 
 
 
 
Urine pregnancy test 
X 
X 
X 
X 
X 
IV catheter placement  
 
X 
X 
X 
 
Clinic admission/discharge 4 
 
X 
X 
X 
 
Overnight fast from midnight  
 
X 
X 
X 
 
Blood glucose measurement (BGM)5 
 
X 
X 
X 
 
Randomization6 
 
X 
 
 
 
Study drug(s) injection(s)7 
 
X 
X 
X 
 
PK collection8  
 
X 
X 
X 
 
PD collection9 
 
X 
X 
X 
 
Draize scales10 
 
X 
X 
X 
 
Injection site discomfort11 
 
X 
X 
X 
 
Oral glucose administration12 
 
X 
X 
X 
 
Meal13 
 
X 
X 
X 
 
Review AEs 
 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
AE = adverse event; ECG = electrocardiogram; PD = pharmacodynamics; PK = pharmacokinetics; V = visit 
1) 
Urine Drug Screen:  To include cocaine, THC, opiates, amphetamines, methamphetamine, and phencyclidine. 
2) 
PE:  Full PE (excluding breast, pelvic, rectal, and genitourinary systems) to be performed at Screening and Follow-Up 
Visits; includes height at Screening. Symptom-directed PEs to be performed at Visits 2, 3, and 4. 
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3) 
Vital signs:  Temperature, respiration, HR and BP (after 5 minutes seated rest) to be performed at all visits. During 
injection visits, HR and BP measurements to be repeated 30 ± 5 minutes, 180 ± 5, and 360 ± 5 minutes post-dose.  
4) 
Admission and discharge:  Arrival for an overnight stay at the clinical research facility on the day prior to treatment 
visits. Subject to be discharged the next day after study procedures have been performed and after the following have 
occurred: 1) subject has consumed their meal; 2) subject has returned to their usual medication regimen [including 
insulin]; 3) capillary glucose concentration is confirmed to be > 100 mg/dL; and 4) subject is considered medically stable.  
5) 
Blood glucose measurement (BGM): BGM will be performed in real time at each subject’s bedside at 10, 20, 30, 40, 50, 
60, 90, 120, and 180 minutes post dosing at Visit 2 through 4.  Prior to dosing, a capillary blood sample will be tested to 
confirm that blood glucose is in the range of 80 to 150 mg/dL. If result is > 150 mg/dL after repeat test, the visit should be 
rescheduled after a minimum 24-hour wait. If the blood glucose is > 150 mg/dL after repeat test, then the investigator may 
treat with a bolus dose of IV regular insulin, per discretion, to bring the subject into the required blood glucose range. 
Before initiating study treatment, at least 40 minutes should have passed from the last dose of administered insulin, and 
the subject’s blood glucose level should be within the range of 80 to 150 mg/dL If the blood glucose is < 80 mg/dL after 
repeat test, then the investigator may treat with oral glucose tabs/solution or IV glucose, per discretion, to bring the 
subject into the required blood glucose range. Before initiating study treatment, at least 30 minutes should have passed 
from the last dose of administered glucose, and the subject’s blood glucose level should be within the range of 80 to 150 
mg/dL. If hypoglycemia occurs (ie, blood glucose <70 mg/dL), the subject will be rescued with IV dextrose, 
according to the formula shown in Section 8.5, Occurrence of Hypoglycemia.  
6) 
Drug sequence randomization:  To be performed just prior to first study drug injection at Period 1 (Visit 2).  
7) 
Study drug administration:  Glucose must be 80 to 150 mg/dL prior to administration of study drug(s). Injection sites 
should be rotated to avoid injecting at a previously used site. 
8) 
PK: Venous blood samples will be drawn 10 ± 2 minutes before and immediately prior to dosing (-2 to 0 minutes), and 
then 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240, 300, and 360 minutes post-dosing (window allowance of ± 2 minutes).  
9) 
PD: Venous blood samples will be drawn 10 ± 2 minutes before and immediately prior to dosing (-2 to 0 minutes), and 
then 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240, 300, and 360 minutes post-dosing (window allowance of ± 2 minutes).  
10) Draize scales:  To be performed by the investigator using the modified Draize scale at 30, 90, and 360 minutes 
(± 2 minutes) post-study drug injection (Appendix 1).  
11)  Injection site discomfort evaluation:  To be performed by the subject at 10 and 30 minutes (± 2 minutes) post-study 
drug injection. Subjects should complete injection site discomfort questions at 10 mins and then Question Q1c is to be 
answered at 360 mins post-study drug injection (Appendix 2). 
12) Oral glucose Within 2 minutes of the blood draw at 30 minutes post-dose, a standardized 75-gram oral glucose 
challenge (eg, 75 grams of glucose syrup and water) should be given to the subject. Subject should consume the solution 
within 5 to 10 minutes. 
13) Meal:  After the last blood collection (at 360 minutes post-study drug administration), subjects will be provided a regular 
meal and insulin (per investigator’s discretion) as per the site’s usual practice 
14) .Previous visit +7 to 11 days. 
 
 
 
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2. 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
SUMMARY OF REVISIONS .........................................................................................................3 
INVESTIGATOR’S AGREEMENT ...............................................................................................4 
1. 
SYNOPSIS ...................................................................................................................6 
2. 
TABLE OF CONTENTS ...........................................................................................16 
LIST OF TABLES .........................................................................................................................20 
3. 
LIST OF ABBREVIATIONS.....................................................................................21 
4. 
INTRODUCTION ......................................................................................................23 
4.1. 
Medical Need ..............................................................................................................23 
4.2. 
Xeris’ Pramlintide-Insulin Injection ...........................................................................23 
5. 
STUDY OBJECTIVES AND PURPOSE ..................................................................25 
5.1. 
Primary Objective .......................................................................................................25 
5.2. 
Secondary Objectives .................................................................................................25 
5.3. 
Study Endpoints ..........................................................................................................25 
6. 
INVESTIGATIONAL PLAN .....................................................................................26 
6.1. 
Overall Study Design ..................................................................................................26 
6.2. 
Treatment Assignment ................................................................................................29 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................30 
7.1. 
Number of Subjects ....................................................................................................30 
7.2. 
Subject Inclusion Criteria ...........................................................................................30 
7.3. 
Subject Exclusion Criteria ..........................................................................................30 
7.4. 
Subject Withdrawal Criteria .......................................................................................32 
7.5. 
Criteria for Study Termination ...................................................................................32 
8. 
TREATMENT OF SUBJECTS ..................................................................................33 
8.1. 
Concomitant Medications ...........................................................................................33 
8.2. 
Randomization ............................................................................................................33 
8.3. 
Treatment Compliance ................................................................................................33 
8.4. 
Subject Replacements .................................................................................................33 
8.5. 
Occurrence of Hypoglycemia .....................................................................................33 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................35 
9.1. 
Study Drugs and Doses ...............................................................................................35 
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9.1.1. 
PRAM9 .......................................................................................................................35 
9.1.2. 
Regular Insulin: Humulin® R (U-100) (regular insulin human injection) ..................35 
9.1.3. 
Regular Insulin Plus Pramlintide ................................................................................35 
9.1.4. 
Study Drug Doses .......................................................................................................35 
9.2. 
Study Drug Packaging and Labeling ..........................................................................36 
9.3. 
Administration of Study Drugs ...................................................................................36 
9.4. 
Study Drug Storage and Accountability .....................................................................36 
9.5. 
Study Drug Handling and Disposal ............................................................................37 
10. 
STUDY PROCEDURES ............................................................................................38 
10.1. 
Visit 1 – Screening ......................................................................................................38 
10.2. 
Visits 2, 3, and 4 .........................................................................................................39 
10.2.1. 
Clinic Arrival (Evening Before Dosing) .....................................................................39 
10.2.2. 
Day of Study Drug Administration.............................................................................39 
10.3. 
Visit 5 – Follow-Up ....................................................................................................40 
11. 
ASSESSMENTS.........................................................................................................42 
11.1. 
Pharmacodynamics .....................................................................................................42 
11.2. 
Pharmacokinetics ........................................................................................................42 
11.3. 
Safety Parameters .......................................................................................................42 
11.3.1. 
Vital Sign Measurements ............................................................................................42 
11.3.2. 
Physical Examination .................................................................................................42 
11.3.3. 
Electrocardiogram (12-Lead ECG) .............................................................................43 
11.3.4. 
Laboratory Assessments .............................................................................................43 
11.3.4.1. 
Drug Screen ................................................................................................................43 
11.3.4.2. 
Pregnancy Screen ........................................................................................................44 
11.3.5. 
Local Tolerability .......................................................................................................44 
12. 
SAFETY AND ADVERSE EVENT (AE) REPORTING..........................................45 
12.1. 
Definition of an Adverse Event ..................................................................................45 
12.1.1. 
Adverse Events of Special Interest .............................................................................45 
12.2. 
Reporting Adverse Events ..........................................................................................46 
12.3. 
Reporting Period .........................................................................................................46 
12.4. 
Serious Adverse Events ..............................................................................................46 
12.5. 
Severity Assessment ...................................................................................................47 
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12.6. 
Causality Assessment .................................................................................................47 
12.7. 
Withdrawal Due to Adverse Events ...........................................................................47 
12.8. 
Eliciting Adverse Event Information and Reporting ..................................................47 
12.9. 
Serious Adverse Event Reporting Requirements .......................................................47 
12.10. 
Nonserious Adverse Event Reporting Requirements .................................................48 
12.11. 
AE Reporting Requirements to Regulatory Authorities .............................................48 
12.12. 
Pregnancy ...................................................................................................................48 
12.13. 
Subject Monitoring .....................................................................................................50 
13. 
DATA ANALYSIS AND STATISTICAL METHODS ............................................51 
13.1. 
General Approach .......................................................................................................51 
13.1.1. 
Sample Size Calculation .............................................................................................51 
13.2. 
Primary Endpoint Analysis .........................................................................................51 
13.3. 
Secondary Endpoint Analysis .....................................................................................51 
13.3.1. 
Safety Endpoints .........................................................................................................51 
13.3.2. 
Pharmacodynamic and Pharmacokinetic Endpoints ...................................................52 
13.4. 
Adverse Events ...........................................................................................................52 
13.5. 
Laboratory Safety Assessments ..................................................................................53 
13.6. 
Physical Examination .................................................................................................53 
13.7. 
Vital Signs and Body Weight .....................................................................................53 
13.8. 
Electrocardiogram .......................................................................................................53 
13.9. 
Local Tolerability .......................................................................................................53 
13.10. 
Prior and Concomitant Medications ...........................................................................53 
13.11. 
Subgroup Analysis ......................................................................................................54 
13.12. 
Demographics and Baseline Characteristics ...............................................................54 
13.13. 
Subject Disposition .....................................................................................................54 
14. 
DATA HANDLING, RECORD KEEPING, MONITORING AND AUDITS ..........55 
14.1. 
Case Report Forms/Electronic Data Record ...............................................................55 
14.2. 
Record Retention ........................................................................................................55 
14.3. 
Monitoring ..................................................................................................................55 
14.4. 
Audits and Inspections ................................................................................................56 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................57 
16. 
ETHICAL CONSIDERATIONS................................................................................58 
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16.1. 
Conduct .......................................................................................................................58 
16.2. 
Institutional Review Board and Ethics Committee ....................................................58 
16.3. 
Subject Information and Consent ...............................................................................58 
16.4. 
Subject Recruitment ....................................................................................................59 
16.5. 
Reporting of Safety Issues and Serious Breaches of the Protocol ..............................59 
17. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY .................................................................................60 
17.1. 
Protocol Modifications and Deviations ......................................................................60 
17.2. 
Study Termination ......................................................................................................60 
18. 
LIST OF REFERENCES ............................................................................................61 
19. 
APPENDICES ............................................................................................................63 
 
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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................5 
Table 2: 
Schedule of Assessments ............................................................................................14 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................21 
Table 4: 
Sequence of Study Drug Administration ....................................................................27 
Table 5: 
Study Drugs Dosing ....................................................................................................36 
Table 6: 
Clinical and Safety Related Laboratory Tests ............................................................43 
Table 7: 
Adverse Event Severity Assessment ..........................................................................47 
 
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3. 
LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Table 3: 
Abbreviations and Specialist Terms  
Abbreviation Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AOC 
area over the curve 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-90 
area under the concentration-time curve from 0 to 90 minutes post-dosing 
AUC0-180 
area under the concentration-time curve from 0 to 180 minutes post-dosing 
AUC0-360 
area under the concentration-time curve from 0 to 360 minutes post-dosing 
BGM 
blood glucose measurement 
BMI 
body mass index 
BP 
blood pressure 
CLIA 
Clinical Laboratory Improvement Act 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CRO 
contract research organization 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GLP-1 
Glucagon-like peptide-1  
HbA1c 
glycated hemoglobin 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
IB 
Investigator’s Brochure 
I:C 
insulin-to-carbohydrate 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
ICH 
International Conference on Harmonisation 
IME 
important medical event 
IND 
Investigational New Drug 
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Abbreviation Definition 
IRB 
institutional review board 
IUD 
intra-uterine device 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numeric Rating Scale 
PD 
pharmacodynamics 
PE 
physical examination 
PK 
pharmacokinetic 
PT 
Preferred Term 
PRAM9 
Co-formulation of a fixed-ratio combination of 9 µg pramlintide per unit of regular 
insulin 
RBC 
red blood cells 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SD 
standard deviation 
SOC 
System Organ Class 
T1D 
Type 1 diabetes mellitus 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 
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4. 
INTRODUCTION 
4.1. 
Medical Need 
The response of insulin and amylin to food intake is absent in patients with type 1 diabetes 
(T1D) due to autoimmune β-cell destruction [Ludvik 1991, Koda 1992, Herrmann 2016].  
Insulin therapy is the primary treatment option for patients with T1D. 
Despite considerable advances in insulin chemistry, delivery, and pharmacology, only a small 
percentage of diabetic patients achieve near normal glycemic levels with insulin replacement 
alone [Klein 1996, Whitehouse 2002].  The increased risk of severe hypoglycemia and undesired 
weight gain that usually accompany glycemic improvements with insulin therapy represent 
major obstacles toward achieving satisfactory glycemic control [DCCT 1997, DCCT 1988, 
Purnell 1998].    
Pramlintide [AstraZeneca Pharmaceuticals, LP, 2016], a soluble, nonaggregating, equipotent 
synthetic analog of amylin, is approved by the FDA and used to treat T1D and T2D patients who 
are unable to obtain near-normoglycemia with insulin therapy.  In a study conducted in subjects 
with T1D with a mean HbA1c of 8.1 (mean age=41 years, mean duration of diabetes=20 years, 
mean body mass index (BMI)=28 kg/m2), pramlintide (SYMLIN®) or placebo was administered 
at major meals as an add on to insulin therapy at a dose of 15 µg and titrated upward at weekly 
intervals of 15 µg to maintenance doses of 30 µg or 60 µg.  The insulin dose was reduced by 
30% to 50% in order to minimize the risk of developing hypoglycemia.  Those who received 
pramlintide had a mean percent reduction of 7.1% in the mealtime insulin dose at 6 months post 
study drug administration initiation compared with 2.4% reduction in the placebo group 
[AstraZeneca Pharmaceuticals, LP, 2016]. 
Many clinical studies that add pramlintide to insulin have demonstrated improved control of 
blood sugar, lower hemoglobin A1c, and better patient satisfaction and well-being. However, the 
benefits of these products used together also are associated with increased risk of pramlintide-
associated nausea and vomiting ; increased number of required injections; and tailoring of insulin 
and pramlintide doses [AstraZeneca Pharmaceuticals, LP, 2016]. 
Although pramlintide does not cause hypoglycemia, when combined with insulin, the risk of 
severe hypoglycemia is increased.  In subjects with T1D, in 6-month controlled trials without 
insulin reduction at initiation, the incidence of severe hypoglycemia was 16.8% (0 to 3 months, 
n=716) in subjects receiving pramlintide and insulin, as compared with 10.8% (0 to 3 months, 
n=538) in subjects receiving placebo and insulin [AstraZeneca Pharmaceuticals, LP, 2016]. 
In addition to the risk of hypoglycemia, separated administrations of insulin and amylin at 
distinct times before meals, varying doses, and multiple injection sites are impediments to patient 
compliance that counter the known therapeutic benefits of pramlintide.  A fixed-ratio, single-
injection of a co-formulated insulin-pramlintide preparation would be desirable in mimicking 
physiological patterns [Riddle 2015, da Silva 2018].  
4.2. 
Xeris’ Pramlintide-Insulin Injection  
Xeris Pharmaceuticals has developed a liquid-stable, co-formulation of a fixed-ratio combination 
of 9 µg pramlintide per unit of regular insulin (PRAM9) that can be delivered as a single SC 
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injection.  The fixed-dose combination is designed to reduce the treatment burden associated 
with concomitant insulin and pramlintide therapy, ie, reduce the number of daily aggregate 
injections because the pramlintide would not require separate mealtime injections. 
In nonclinical studies, the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of 
pramlintide and Humulin® (or regular insulin) or Humalog® (lispro insulin) were studied in 
normal and streptozotocin-induced diabetic rats (STZ; mimicking T1D).  Treatments were given 
as separate injections of commercial products or as Xeris’ pramlintide-insulin combined dose 
single injection.  Consistent with pramlintide’s known pharmacological action, there was no 
glucose lowering with pramlintide alone for either the commercial or Xeris formulation.  
Additionally, glycemic profiles for pramlintide were similar to saline or Xeris vehicle 
administered by SC injection in rats.  Xeris’ pramlintide-insulin formulation showed a longer 
duration of glucose lowering compared to separate injections of commercial pramlintide 
(Symlin®) and insulin (Humulin®).   
This clinical study has been designed to compare the PD, PK, and safety of PRAM9 with regular 
insulin and regular insulin plus pramlintide (co-administered as separate injections) when 
injected subcutaneously (SC) in the abdomen of fasted adults with T1D.  A detailed description 
of, and rationale for the dosing regimen for this study is located in Section 9.1. 
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5. 
STUDY OBJECTIVES AND PURPOSE 
5.1. 
Primary Objective 
The primary objective of this study is to evaluate the PD properties of a single dose of PRAM9 
compared to single doses of regular insulin and regular insulin plus pramlintide (co-administered 
as separate injections) in adults with T1D. 
5.2. 
Secondary Objectives 
The secondary objectives of this study are to evaluate the safety and PK profiles of a single dose 
of PRAM9 compared to single doses of regular insulin and regular insulin plus pramlintide 
(co-administered as separate injections) in adults with T1D. 
5.3. 
Study Endpoints 
Primary 
The PD effects upon plasma glucose levels will be compared between the treatments as defined 
by the following primary endpoint:   
 Area under the curve area from administration to 180 min (AUC0-180) (mg/dL × 
minutes) for plasma glucose > 180 mg/dL 
Secondary 
See Section 13.3 for a complete listing of secondary endpoints to be analyzed in this study.  
Additionally, full description of secondary endpoints will be included in a separate Statistical 
Analysis Plan (SAP). 
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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a randomized, open-label, active-controlled, single-dose, 3-treatment, 3-period, 3-way 
crossover, comparative PD and PK inpatient study in adults with T1D.  The study comprises 
5 visits:  Screening (Visit 1), Treatment Periods (Visits 2 − 4), and Follow-Up (Visit 5). 
To determine eligibility, subjects will complete the Screening procedures (Visit 1) up to 28 days 
before the first treatment visit (Visit 2).  Subjects will be instructed to eat normally and take their 
usual medications, but to refrain from alcohol for 24 hours prior to checking in for treatment 
visits. 
Treatment Periods 
For Treatment Period Visits 2 through 4, eligible subjects will be instructed to arrive for an 
overnight stay at the clinical research facility on the day prior to each treatment visit.  At the 
clinic, subjects will be given a standardized dinner meal, and instructed to take their prescribed 
evening mealtime insulin regimen and basal insulin dose.  The subjects will fast after midnight 
but will be allowed to drink water ad libitum (ie, tap water, bottled water, distilled water, etc. 
[water without carbohydrates]) and take any prescribed medications. 
During each Treatment Period Visit, subjects will receive a single SC dose of PRAM9, regular 
insulin, or co-administered regular insulin plus pramlintide.  On the morning of each treatment 
visit and prior to dosing, a fasting blood sample will be tested using a blood glucose meter 
(BGM) to confirm that blood glucose is in the range of 80 to 150 mg/dL.   
 If the blood glucose is > 150 mg/dL after repeat test, then the investigator may treat 
with an intravenous (IV) bolus dose of  regular insulin, per discretion, to bring the 
subject into the required blood glucose range.  Before initiating study treatment, at 
least 40 minutes should have passed from the last dose of administered insulin and the 
subject’s glucose level should be within the range of 80 to 150 mg/dL. 
 If the blood glucose is < 80 mg/dL after repeat test, then the investigator may treat 
with oral glucose tabs/solution or IV glucose, per discretion, to bring the subject into 
the required blood glucose range.  Before initiating study treatment, at least 
30 minutes should have passed from the last dose of administered glucose and the 
subject’s glucose level should be within the range of 80 to 150 mg/dL. 
 If the subject’s blood glucose cannot be optimized to 80 to 150 mg/dL within 2 hours, 
then the visit should be rescheduled after a minimum 24-hour wait, per investigator’s 
discretion.   
At Visit 2, once blood glucose is confirmed to be within the range of 80 to 150 mg/dL, subjects 
will be randomized to their study drug treatment sequence. 
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Table 4: 
Sequence of Study Drug Administration 
Cohort Period 1 
Period 2 
Period 3 
1 
PRAM9 
Regular insulin 
Regular insulin 
+ pramlintide 
2 
Regular insulin 
Regular insulin 
+ pramlintide 
PRAM9 
3 
Regular insulin 
+ pramlintide 
PRAM9 
Regular insulin 
4 
PRAM9 
Regular insulin + 
pramlintide 
Regular insulin 
5 
Regular insulin 
PRAM9 
Regular insulin + 
pramlintide 
6 
Regular insulin + 
pramlintide 
Regular insulin 
PRAM9 
Insulin-to-carbohydrate calculations will be used to identify subject doses.  All subjects will get 
flexible doses of insulin, pramlintide, and PRAM9.  See Section 9.1 for complete information on 
study drug dosing.  The dose of regular insulin is calculated to correspond to a ratio of 9 µg of 
pramlintide for every 1 unit of insulin.  Additionally, the dose of regular insulin is calculated 
from the subject’s insulin-to-carbohydrate (I:C) ratio to match a 75-gram carbohydrate challenge.  
Rule 450 will be used for carbohydrate counting and insulin dose calculation in this study (see 
Appendix 3).   
Prior to dose administration, a peripheral catheter for blood sampling will be placed into a vein 
ideally located within the antecubital fossa.  The hand of the arm used for blood sampling will be 
kept warm by use of a heated hand box to increase blood flow and achieve “arterialized” 
samples.  The subject will remain supine and kept warm and be allowed to drink only water 
(ad libitum).   
Once the catheter and hand box are in place, study drug(s) will be administered SC over 1 to 
3 seconds to the abdomen (around the umbilicus).  Co-administered regular insulin plus 
pramlintide injections should be administered to opposite sides of the abdomen (ie, left and right 
peri-umbilicus, opposite quadrants).  Injection sites should be rotated to avoid injecting at a 
previously used site.  
To monitor for hypoglycemia, BGM will be performed in real time at each subject’s bedside at 
10, 20, 30, 40, 50, 60, 90, 120, and 180 minutes post dosing at Visit 2 through 4. BGM 
measurements from the cool hand are allowed. 
To evaluate drug PD (plasma glucose response), blood samples are to be drawn at 10 ± 2 minutes 
before and immediately (-2 to 0 minutes) prior to study drug injection.  After study drug 
injection, blood samples also will be collected at 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240, 
300, and 360 minutes post-dosing (window allowance of ± 2 minutes). After the 60-minute 
postdose time point, the subject’s hand must be reinserted into the heated box for at least 
10 minutes prior to the next blood collection. 
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To evaluate drug PK (plasma insulin/pramlintide concentrations), blood samples are to be drawn 
at 10 ± 2 minutes before and immediately (-2 to 0 minutes) prior to study drug injection.  After 
study drug injection, blood samples also will be collected at 10, 20, 30, 40, 50, 60, 90, 120, 150, 
180, 240, 300, and 360 minutes post-dosing (window allowance of ± 2 minutes). 
Within 2 minutes after the 30 minutes post-dose blood draw, a standardized 75-gram oral 
glucose challenge should be ingested (within 5 to 10 minutes) by the subject.  
After the last blood collection (at 360 minutes post-study drug administration), subjects are to be 
provided a regular meal and insulin (per investigators’ discretion).  
At 30, 90, and 360 minutes (± 2 minutes) post-dose, injection sites will be evaluated by the 
investigator using the modified Draize scale (Appendix 1).  Additionally, subjects will complete 
an injection site discomfort questionnaire at 10 and 30 minutes (± 2 minutes) post-dose 
(Appendix 2).   
A subject may be discharged from the clinic, per investigator’s criteria, when the following has 
occurred: 
 Subject has consumed their meal 
 Subject has returned to their usual medication regimen, including insulin 
 Subject’s capillary glucose concentration is confirmed to be > 100 mg/dL  
 Subject is considered medically stable 
Any time during the visit if hypoglycemia occurs (ie, blood glucose < 70 mg/dL), the subject 
will be rescued with IV dextrose using the following formula to calculate the dose of dextrose: 
D50% mL = (100 minus BG) × 0.4 
Where D50% = the dose of IV dextrose, mL = the volume of dextrose, BG = the subject’s 
hypoglycemic blood glucose value (ADA, 2008; Joslin Center, 2013) 
The dose of dextrose should be administered slowly, over 2 to 5 minutes. 
If D50% is administered, then blood glucose will be remeasured by blood glucose meter at 10, 
20, and 30 minutes following the end of administration of IV dextrose. 
Successful plasma glucose recovery should be confirmed (ie, glucose returns to ≥ 70 mg/dL) and 
the subject medically stabilized.  When the subject is medically stable, they can be discharged 
from the clinic (per criteria above).  
After a first washout period of 7 to 11 days, subjects will return to the clinic for Treatment 
Period 2 (Visit 3) and the treatment visit procedures will be repeated with each subject crossed 
over to the next randomized study drug treatment sequence.  Upon check-in and completion of 
morning activities, the subject will receive their second administration of study drug(s).  
After a second washout period of 7 to 11 days, subjects will return to the clinic for Treatment 
Period 3 (Visit 4) and the treatment visit procedures will be repeated with each subject crossed 
over to the last randomized study drug treatment sequence.  Upon check-in and completion of 
morning activities, the subject will receive their third administration of study drug(s). 
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During the Treatment Periods, subjects will undergo vital sign measurements; AE assessments; 
concomitant medication assessments; and pregnancy testing for females of childbearing potential 
as outlined in the Schedule of Assessments (Table 2).   
Follow-Up 
A Follow-Up Visit will be conducted 7 to 11 days after the subject’s last dose of study drugs(s).  
Subjects will return to the clinic and undergo a full PE, vital sign measurements, weight, AE 
assessments, concomitant medication assessments, sample collection for hematology, chemistry, 
C-peptide, and pregnancy testing for females of childbearing potential. 
6.2. 
Treatment Assignment 
Eligible subjects will receive single SC doses of PRAM9, regular insulin, and co-administered 
regular insulin plus pramlintide.  At Visit 2, subjects will be randomized to 1 of 6 study drug 
treatment sequences (3 subjects per treatment sequence).  See Table 4 for study drug 
administration sequences. 
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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Number of Subjects 
Approximately 48 subjects may be needed to screen in order to obtain 18 randomized subjects 
(3 subjects per treatment sequence). 
7.2. 
Subject Inclusion Criteria 
Subjects must meet the following criteria to be included: 
1. Understands the study procedures, alternative treatment available, and risks involved with 
the study, and voluntarily agrees to participate by giving written informed consent 
2. Male or non-pregnant, non-lactating female diagnosed with T1D for at least 24 months 
prior to Screening. 
3. Aged 18 to 64 years of age, inclusive 
4. On a stable insulin regimen for 21 days prior to Screening (no greater than ± 20% 
variability in total daily dose)  
5. Have a plasma C-peptide level < 0.6 ng/mL at Screening  
6. Have an HbA1c < 10% at Screening 
7. Body mass index (BMI) in the range of ≥ 18 to ≤ 35 kg/m2 at Screening 
8. For women of childbearing potential, there is a requirement for a negative urine 
pregnancy test at Screening and for agreement to use contraception throughout the study 
and for 7 days after the last dose of study drug.  Acceptable contraception includes birth 
control pill/patch/vaginal ring, Depo-Provera® (medroxyprogesterone acetate), 
Norplant® System (levonorgestrel), an intra-uterine device (IUD), the double barrier 
method (the woman uses a diaphragm and spermicide and the man uses a condom), or 
abstinence. 
9. Fasting Serum triglyceride concentration < 200 mg/dL 
7.3. 
Subject Exclusion Criteria 
Subjects meeting any of the following criteria are to be excluded.  Laboratory criteria will be 
based on testing performed at the Screening Visit.  
1. Currently being treated with pramlintide or has discontinued pramlintide within 21 days 
of Screening 
2. Currently using an insulin pump 
3. Has renal insufficiency (serum creatinine > 3.0 mg/dL) or end-stage renal disease 
requiring renal replacement therapy 
4. Has hepatic disease, including serum ALT or AST ≥ 3 times the upper limit of normal 
(ULN) 
5. Has hepatic synthetic insufficiency (serum albumin < 3.0 g/dL) 
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6. Has a hematocrit value that is exclusionary, as shown below: 
a.  Female <35.5% 
b. Male <38.3% 
7. Has a hemoglobin value that is exclusionary, as shown below: 
a. Female <11.5 g/dL 
b. Male <12.5 g/dL 
8. Has out-of-range systolic or diastolic BP readings at Screening (systolic BP < 90 or 
> 150 mm Hg or diastolic BP < 50 or > 100 mm Hg) 
9. Has clinically significant ECG abnormalities at Screening 
10. Has congestive heart failure, NYHA Class III or IV 
11. Has history of myocardial infarction, unstable angina, or revascularization within 
6 months prior to Screening 
12. Has history of a cerebrovascular accident in 6 months prior to Screening with major 
neurological deficits 
13. Has active malignancy within 5 years prior to Screening (exception: basal cell or 
squamous cell skin cancers) 
14. Has had major surgical operation within 60 days prior to Screening or planned surgical 
operation during the study 
15. Has a seizure disorder (other than with suspected or documented hypoglycemia) 
16. Has a current bleeding disorder, treatment with anticoagulants, or platelet count 
< 50 ×109/L 
17. Has a history of allergies or significant hypersensitivity to pramlintide or any 
pramlintide-related products or to any of the excipients in the investigational formulation  
18. Has a history of positive test result for hepatitis B virus (HBV), hepatitis C virus (HCV), 
or human immunodeficiency virus (HIV)  
19. Has a concurrent illness not controlled by a stable therapeutic regimen 
20. Tests positive for drugs of abuse at Screening.  Subjects testing positive for 
tetrahydrocannabinol (THC) at Screening or reporting active marijuana use will be 
allowed to participate in the study at the discretion of the investigator. 
21. Has active substance or alcohol abuse (> 21 drinks/week for males or > 14 drinks/week 
for females)  
22. Has participated in other studies involving administration of an investigational drug 
within 30 days or 5 half-lives prior to Screening (whichever is longer) or during 
participation in the current study 
23. There is any reason the investigator deems exclusionary 
24. Has donated blood within 8 weeks prior to Screening.  
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7.4. 
Subject Withdrawal Criteria 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, or 
administrative reasons.   
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject to determine the reason(s) why the subject failed to return for the scheduled visit, and to 
reschedule the missed visit.  This includes contacting subjects via email and telephone, including 
family members or emergency contacts.  If such efforts fail, a certified letter should be sent to 
the subject’s last known address requesting they contact study staff. 
In all circumstances, every effort should be made to document subject outcome, per the follow-
up.  Information regarding the reason for not completing the study will be recorded in the 
electronic case report form (eCRF).  The investigator should inquire about the reason for 
withdrawal, request that the subject return for a final visit, and follow-up with the subject 
regarding any unresolved AEs.  It will be documented whether each subject completed the study.   
If a decision by the investigator or sponsor is made to withdraw a subject, a final visit should be 
scheduled soon after the decision to withdraw is made.  The subject will be asked to return to site 
for the assessments listed in Section 10.3 (Follow-Up Visit).  
If the subject withdraws from the study and withdraws consent, no further evaluations should be 
performed, and no additional data should be collected.  The sponsor may retain and continue to 
use any data collected before such withdrawal of consent.   
7.5. 
Criteria for Study Termination 
The study may be prematurely terminated at any time because of a regulatory authority decision, 
change in opinion of the IRB or Xeris.   
Circumstances that may warrant premature study termination include, but are not limited, to the 
following: 
 Determination of unexpected, significant, or unacceptable risk to subjects 
 Failure to enter subjects at an acceptable rate 
 Insufficient adherence to the requirements of the protocol 
 Insufficient provision of complete and evaluable data 
 Plans to modify, suspend, or discontinue development of the study drug 
If the study is prematurely terminated or discontinued, Xeris will promptly notify the 
investigators and document the reason for study termination.  Specific procedures for termination 
will be arranged by the sponsor in coordination with the investigators.  After notification, the 
investigators must contact all participating subjects within 7 days.  All study materials must be 
collected and all eCRFs completed to the greatest extent possible, and all study materials must be 
returned to Xeris or its designee within 28 days of receiving notice of study termination from the 
sponsor. 
 
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8. 
TREATMENT OF SUBJECTS 
8.1. 
Concomitant Medications 
All subjects will be questioned about concomitant medications at each visit.  Medications taken 
within 28 days before Day 1, including insulin, will be documented in the eCRF.  Any changes 
to a subject’s concomitant medication regimen after the first treatment on Day 1 will also be 
documented in the eCRF. 
Ideally, subjects should be on a stable regimen of all concomitant medications except insulin for 
at least 28 days prior to Screening, and they will be encouraged to avoid making changes 
(excepting insulin) to their concomitant medication regimen during participation in the study.  In 
addition, investigators are encouraged to avoid adding to or changing a participant’s medications 
during study participation unless deemed medically necessary. 
Diabetes Medication  
Subject diabetes medication will be recorded on the day of screening:  
 Total daily meal-time insulin 
o Type of insulin (regular insulin, lispro, or aspart) 
 Basal insulin 
o Type of insulin (glargine, detemir, or degludac) 
 Total daily dose of insulin 
 Glucagon-like peptide-1 (GLP-1) analogue   
8.2. 
Randomization 
On the morning of Visit 2, subjects will be randomized into the appropriate treatment sequence 
order to receive each of the 3 study treatments (PRAM9, regular insulin, and co-administered 
regular insulin plus pramlintide).  The study statistician will create the randomization sequence 
using random permuted block methodology.    See Table 4 for study drug administration 
randomization sequence. 
8.3. 
Treatment Compliance 
Not applicable as study drug will be administered in an inpatient setting. 
8.4. 
Subject Replacements  
Subjects who are randomized but do not receive the first study drug will be replaced.  Up to 
3 subjects may be replaced. 
8.5. 
Occurrence of Hypoglycemia 
If hypoglycemia occurs (ie, blood glucose <70 mg/dL), the subject will be rescued with IV 
dextrose using the following formula to calculate the dose of dextrose: 
D50% mL = (100 minus BG) × 0.4 
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Where D50% = the dose of IV dextrose, mL = the volume of dextrose, BG = the subject’s 
hypoglycemic blood glucose value (ADA, 2008; Joslin Center, 2013) 
The dose of dextrose should be administered slowly, over 2 to 5 minutes. 
If D50% is administered, then blood glucose will be remeasured by blood glucose meter at 10, 
20, and 30 minutes following the end of administration of IV dextrose. 
Successful plasma glucose recovery should be confirmed (ie, glucose returns to ≥ 70 mg/dL) and 
the subject medically stabilized.  When the subject is medically stable, they can be discharged 
from the clinic.  A subject may be discharged from the clinic, per investigator’s criteria, when 
the following has occurred: 
 Subject has consumed their meal 
 Subject has returned to their usual medication regimen, including insulin 
 Subject’s capillary glucose concentration is confirmed to be > 100 mg/dL  
 Subject is considered medically stable  
Any occurrence of hypoglycemia must be recorded in the Adverse Event (AE) eCRF.   
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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drugs and Doses 
PRAM9, insulin, and pramlintide will be supplied by the sponsor. 
9.1.1. 
PRAM9  
PRAM9 is a stable, liquid, and ready-to-use co-formulation of pramlintide and regular insulin for 
SC injection. 
The pramlintide and insulin injection drug product is prepared as a sterile liquid for injection that 
is packaged as a 0.9 mg/mL pramlintide + 3.5 mg/mL insulin solution for injection in a 3-mL 
glass vial (2.5 mL fill volume). 
The dose of PRAM9 is to be based upon the subject’s historical mealtime insulin dose (based 
upon the subject’s historical carbohydrate: insulin ratio).  The historical insulin dose will be 
reduced by 50% to derive the new insulin dose.  The associated pramlintide dose will be related 
to the dosage of insulin (eg, 9 µg pramlintide per 1 U of insulin).   
PRAM9 is to be administered SC (in the abdomen, peri-umbilicus).  
9.1.2. 
Regular Insulin: Humulin® R (U-100) (regular insulin human injection)  
The dose of regular insulin is to be based upon the subject’s historical mealtime insulin dose 
(based upon the subject’s historical carbohydrate: insulin ratio).  Insulin is to be administered SC 
(in the abdomen, peri-umbilicus). 
Note:  The calculated insulin dose should be rounded to the closest whole unit.  For rounding, if 
the digit to the right of the decimal is ≤ 4, round down (example 4.3 units = 4 units).  If the digit 
to the right of the decimal is ≥ 5, round up (example 4.5 units = 5 units). 
9.1.3. 
Regular Insulin Plus Pramlintide  
Regular insulin plus pramlintide is to be co-administered as separate injections. 
The new insulin dose is to be based upon the subject’s historical mealtime insulin dose (based 
upon the subject’s historical carbohydrate: insulin ratio).  This historical dose will be reduced by 
50% to be the new insulin dose.  The associated pramlintide dose will be calculated from the new 
dosage of insulin (eg, 9 µg pramlintide per 1 U of insulin).  The dosage of pramlintide will then 
be adjusted to the nearest increment on the Symlin® pen (eg, nearest 15 µg increment). 
Regular insulin plus pramlintide is to be administered SC (in the abdomen, peri-umbilicus).  The 
separate, co-administered regular insulin and pramlintide injections should be given to opposite 
sides of the abdomen (ie, left and right peri-umbilicus, opposite quadrants). 
 
9.1.4. 
Study Drug Doses 
All subjects will get flexible doses of insulin, pramlintide, and PRAM9.  The dose of regular 
insulin is calculated to correspond to a ratio of 9 g of pramlintide for every 1 unit of insulin.  
Additionally, the dose of regular insulin is calculated from the subject’s insulin-to-carbohydrate 
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(I:C) ratio to match a 75-gram carbohydrate challenge.  Rule 450 will be used for carbohydrate 
counting and insulin dose calculation in this study (see Appendix 3).  Table 5 presents study drug 
doses for each study cohort. 
Table 5: 
Study Drugs Dosing 
Calculated Insulin 
Dose (U)a  
Based on Subject I:C 
Ratio 
Regular 
Insulin Arm 
Pramlintide + Regular Insulin  
Co-Administration Arm  
(Two Separate Injections) 
PRAM9  
Co-Formulation Acm 
(Single Injection)c 
Insulin Dose 
(U) 
Insulin Dose 
(U) 
Pramlintide Dose (µg) 
Modified for Symlin® 
Penb 
Insulin/Pramlintide Dose  
(U) 
2 
2 
1 
15 
1 
4 
4 
2 
15 
2 
6 
6 
3 
30 
3 
8 
8 
4 
30 
4 
10 
10 
5 
45 
5 
12 
12 
6 
60 
6 
14 
14 
7 
60 
7 
a:  The calculated insulin dose, if necessary, will be rounded to the closest whole unit (example 4.5 units = 5 units). 
b:  The dosage of pramlintide should be adjusted to the nearest increment on the Symlin® pen (eg, nearest 15-µg 
increment). 
c:  Each unit of PRAM9 contains 1 unit of insulin and 9 µg of pramlintide. 
9.2. 
Study Drug Packaging and Labeling 
PRAM9 will be labeled according to 21 CFR 312.6 investigational drug labeling regulatory 
requirements.  Study drug labels will include the protocol number, lot number, description of the 
study drug, dosing and storage instructions, name of Sponsor and manufacturer, and a statement 
that it is for clinical trial use only. 
9.3. 
Administration of Study Drugs 
Prior to administration, the intended injection sites should be cleansed with an alcohol swab and 
examined to ensure they have a normal appearance and are free from signs of inflammation or 
injury.  At Visits 3 and 4, injection sites should be rotated to avoid injecting at a previously used 
site.   
Study drug(s) will be administered SC to the abdomen (around the umbilicus).  When applicable, 
the regular insulin and pramlintide injections should be given to opposite sides of the abdomen 
(ie, left and right peri-umbilicus, opposite quadrants).  
Study drug(s) should be injected over 1 to 3 seconds.  Following injection, light pressure should 
be applied to the injection site, as the needle is withdrawn. 
9.4. 
Study Drug Storage and Accountability 
PRAM9 must be stored in a freezer (-20°C) and thawed only once on the day of use (avoid 
repeated freeze-thaw cycles).  On the morning of a dosing visit, the vial of PRAM9 should be 
placed at room temperature for 1 hour to thaw.  Prior to use, the vial should be inverted 25 times 
to mix.  If thawed and not used, then PRAM9 must be stored at a controlled temperature of 20°C 
to 25°C (68°F to 77°F) and discarded if not used within 30 days. 
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The investigator or an approved study staff will ensure that the study drug is stored in a secure 
area under recommended storage conditions and in accordance with applicable regulatory 
requirements. 
The site will maintain appropriate documentation of continuous storage conditions and these 
records will be monitored on an ongoing basis by the monitor.  Any deviations in the storage 
conditions must be documented (including minimum and maximum temperature excursion as 
well as estimate of total duration of storage outside the recommended storage conditions).  Such 
deviations must be communicated to the sponsor as soon as identified by the site with 
appropriate course of action taken regarding the future use of the study drugs upon consultation 
with Xeris Pharmaceuticals. 
The investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the investigational drug products and supplies.   
9.5. 
Study Drug Handling and Disposal 
Unused PRAM9 will be returned to Xeris at the end of the study. 
Unused regular insulin and pramlintide will be destroyed per site standard operating procedures 
(SOP). 
 
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10. 
STUDY PROCEDURES 
A schedule of procedures for this study is provided in the Schedule of Assessments (Table 2). 
10.1. 
Visit 1 – Screening  
Prior to completing any Screening activities, the investigator or study team member will obtain 
informed consent from each subject in accordance with the procedures described in Section 16.3.   
Subjects will complete a Screening Visit at least 1 day (to allow for receipt of blood test results), 
and no more than 28 days prior to the anticipated date of the first treatment visit (Treatment 
Period 1, Study Day 1).  The following evaluations will be completed during the Screening Visit: 
 Collection of medical history and demographic data 
 Assessment of inclusion/exclusion criteria by a study investigator 
 Urine drug screen. Note: At the investigator’s discretion, subjects with a positive 
result for drugs other than THC (which is allowed at the investigator’s discretion) will 
be allowed to participate if the subject reports use of a concomitant medication that 
explains the result (eg, positive urine test for opiates in a subject reporting use of 
cough syrup containing dextromethorphan).  
 Full PE (excluding breast, pelvic, rectal, and genitourinary exams); to include 
measurement of height and weight (no shoes, lightly clothed) 
 12-lead ECG (after the subject has completed a 5-minute supine or seated rest; ECG 
to be obtained before assessment of BP and HR, and prior to blood collections) 
 Assessment of vital signs, including temperature, respiration rate, HR, and BP, after a 
5-minute seated rest 
 Collection of venous blood for hematology, serum chemistry, and measurement of 
C-peptide and HbA1c (see Section 11.3.4 for complete listing of laboratory 
parameters)  
 Urine pregnancy test for women of childbearing potential and discussion about study 
requirements regarding contraception 
 Assessment of baseline concomitant medications, including diabetes medication: 
o Total daily meal-time insulin 
 Type of insulin (regular insulin, lispro, or aspart) 
o Basal insulin 
 Type of insulin (glargine, detemir, or degludac) 
o Total daily dose of insulin 
o GLP analogue  
Once laboratory results are obtained and a final determination of eligibility is made, subjects 
should be contacted to schedule the first treatment visit.  While immediate re-testing of 
laboratory results is not allowed, subjects failing to meet laboratory-based eligibility criteria may 
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be re-screened after a 30-day wait.  A single re-screening is permitted, and this re-screening is 
only permissible if the reason for the prior screen failure was for laboratory measurements or 
vital signs.  Blood for clinical laboratory tests can be redrawn after a 30-day wait; however, other 
Screening procedures do NOT need to be repeated.  Vital signs can be remeasured after a 24-
hour wait and other screening procedures do not need to be repeated if within the 28-day 
window. If the new clinical laboratory test results or vital signs meet eligibility, the subject may 
be dosed.  Otherwise, the subject is not eligible for dosing or further re-screening. 
10.2. 
Visits 2, 3, and 4  
10.2.1. 
Clinic Arrival (Evening Before Dosing) 
Subjects will be instructed to eat normal meals during the day but to refrain from alcohol (for 
24 hours prior to the visit), and to follow their usual insulin regimen prior to their evening clinic 
arrival.  Subjects will be instructed to arrive at the clinic on the day prior to the visit.  
At the clinic, subjects will be given a standardized dinner meal (per investigator’s discretion) and 
instructed to take their prescribed evening mealtime insulin regimen and basal insulin dose.  The 
subjects will fast after midnight but will be allowed to drink water ad libitum (ie, tap water, 
bottled water, distilled water, etc. [water without carbohydrates]) and take any prescribed non-
diabetic medications.  Blood glucose concentrations will be kept in the range of 80 to 150 mg/dL 
per investigator discretion, via IV glucose and/or IV insulin infusion.  
10.2.2. 
Day of Study Drug Administration 
The following procedures will be carried out on the day of dosing. 
 Symptom-directed PE 
 Assessment of vital signs.  Note:  HR and BP measurements are to be repeated 
30 ± 5 minutes, 180 ± 5, and 360 ± 5 minutes after study drug administration 
 Women of childbearing potential will undergo a urine pregnancy test, which must be 
negative before further participation is allowed 
 Prior to dosing, a capillary blood glucose measurement (BGM) will be tested to 
confirm that blood glucose is in the range of 80 to 150 mg/dL   
o If the blood glucose is > 150 mg/dL after repeat test, then the investigator may 
treat with a bolus dose of  IV regular insulin, per discretion, to bring the subject 
into the required blood glucose range.  Before initiating study treatment, at least 
40 minutes should have passed from the last dose of administered insulin and the 
subject’s glucose level should be within the range of 80 to 150 mg/dL. 
o If the blood glucose is < 80 mg/dL after repeat test, then the investigator may treat 
with oral glucose tabs/solution or IV glucose, per discretion, to bring the subject 
into the required blood glucose range.  Before initiating study treatment, at least 
30 minutes should have passed from the last dose of administered glucose and the 
subject’s glucose level should be within the range of 80 to 150 mg/dL. 
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o If the subject’s blood glucose cannot be optimized to 80 to 150 mg/dL within 
2 hours, then the visit should be rescheduled after a minimum 24-hour wait, per 
investigator’s discretion.  
 Randomization (at Visit 2 only) 
 Placement of peripheral catheter and hand placed in heated hand box  
 Study drug(s) administration (to be injected over 1 to 3 seconds) 
 PK sample collection at 10 ± 2 minutes before and immediately prior to dosing (-2 to 
0 minutes), and then 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240, 300, and 
360 minutes post-dosing (window allowance of ± 2 minutes) 
 PD sample collection at 10 ± 2 minutes before and immediately prior to dosing (-2 to 
0 minutes), and then 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240, 300, and 
360 minutes post-dosing (window allowance of ± 2 minutes) 
 Injection site assessment at 30, 90, and 360 minutes (± 2 minutes) post-dose using the 
modified Draize scale (Appendix 1)  
 Subject injection site discomfort questionnaire at 10 and 30 minutes (± 2 minutes) 
post-dose (Appendix 2). Question Q1c is to be answered at 360 mins post-study drug 
injection.  
 Within 2 minutes of the 30-minute post-dose blood draw, a standardized 75-gram oral 
glucose challenge (eg, 75 grams of glucose syrup and water) should be given to the 
subject and consumed within 5 to 10 minutes 
 After the last blood collection (at 360 minutes post-study drug administration), 
subjects are to be provided a regular meal and insulin (per investigators’ discretion) 
 AE assessment 
 Concomitant medications assessment  
A subject may be discharged from the clinic, per the investigator’s criteria, after the following 
has occurred: 
 Subject has consumed their meal 
 Subject has returned to their usual medication regimen, including insulin 
 Subject’s capillary glucose concentration is confirmed to be > 100 mg/dL  
 Subject is considered medically stable  
After a washout period of 7 to 11 days, subjects will return to the clinic for the next Treatment 
Period Visit and the treatment visit procedures will be repeated with each subject crossed over to 
the next randomized study drug treatment.   
10.3. 
Visit 5 – Follow-Up  
A Follow-Up Visit will be conducted 7 to 11 days following Visit 4 or if a subject is 
discontinued prematurely.  This visit will include the following assessments: 
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 Full PE (excluding breast, pelvic, rectal, and genitourinary exams); to include 
measurement of weight (no shoes, lightly clothed) 
 Assessment of vital signs after a 5-minute seated rest  
 Collection of venous blood for hematology and serum chemistry (see Section 11.3.4 
for complete listing of laboratory parameters)  
 Urine pregnancy test for women of childbearing potential 
 AE assessment 
 Concomitant medications assessment 
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11. 
ASSESSMENTS 
11.1. 
Pharmacodynamics 
At Visits 2, 3, and 4 (Treatment Periods), samples will be drawn to measure plasma glucose 
levels.  Venous blood samples will be drawn 10 ± 2 minutes before and immediately prior to 
dosing (-2 to 0 minutes), and then at 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240, 300, and 
360 minutes post-dosing (window allowance of ± 2 minutes).   
Over the course of the study, approximately 15 blood samples (approximately 3 mL each) will be 
collected for each subject, for an approximate total volume of 45 mL per subject. 
Plasma glucose levels will be used to calculate the following PD parameters: Cmax, Tmax, area 
over the curves (AOCs), and AUCs. 
Detailed instructions for sample collection and preparation will be provided in a separate 
laboratory manual. 
11.2. 
Pharmacokinetics 
At Visits 2, 3, and 4 (Treatment Periods), samples will be collected for determination of plasma 
insulin and pramlintide concentrations.  Venous blood samples will be drawn 10 ± 2 minutes 
before and immediately prior to dosing (-2 to 0 minutes), and then at 10, 20, 30, 40, 50, 60, 90, 
120, 150, 180, 240, 300, and 360 minutes post-dosing (window allowance of ± 2 minutes).   
Over the course of the study, approximately 15 blood samples (approximately 4 mL each) will be 
collected for each subject, for an approximate total volume of 60 mL per subject. 
Insulin and pramlintide concentrations will be used to calculate the following PK parameters: 
Cmax, Tmax, and AUC0-90, AUC0-180, AUC0-360. 
Detailed instructions for sample collection and preparation will be provided in a separate 
laboratory manual. 
11.3. 
Safety Parameters 
11.3.1. 
Vital Sign Measurements 
Vital signs, including measurements of temperature (ºC), respiration (breathes per minute), HR 
(beats per minute), and BP (mmHg) will be measured (after 5 minutes seated rest) at the times 
specified in the Schedule of Assessments.  Additional or changes to collection times, or 
collection using automated devices is permitted, as necessary, to ensure appropriate subject’s 
safety. 
Vital signs will be measured according to standard of practice of the site and recorded in the 
eCRF.  
11.3.2. 
Physical Examination 
Full PEs will be performed at Screening and Follow-Up Visits.  The PE will include a review of 
all body systems (excluding breast, pelvic, rectal, and genitourinary) and include measurements 
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of weight (in kg) and height (in cm; height to be measured only at Screening Visit).  Symptom-
directed PEs are to be performed at Visits 2, 3, and 4.   
Findings at Screening are to be recorded as medical history.  Any abnormal or clinically 
significant findings from the PE must be recorded in the AE eCRF.   
11.3.3. 
Electrocardiogram (12-Lead ECG) 
Single, supine 12-lead ECGs should be obtained at Screening per the site’s standard practice and 
before assessment of BP and HR, and prior to blood collections. 
11.3.4. 
Laboratory Assessments 
The tests outlined in Table 6 will be performed at the specified time points described in the 
Schedule of Assessments.   
Table 6: 
Clinical and Safety Related Laboratory Tests 
Hematology 
Chemistry 
Urine 
Laboratory 
Hematocrit 
Hemoglobin 
Platelet count 
RBC count 
WBC count 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Calcium 
Creatinine 
Glucose 
Potassium 
Sodium 
Triglycerides 
β-hCG 
Drug screen 
 
C-peptide 
HbA1c 
Pramlintide 
Insulin 
 
 
The site’s laboratory will be used for safety lab analysis.  A procedures manual will be provided 
to each site by the central laboratory.  This manual will cover procedures for the collection, 
processing, and shipping of blood samples, along with the Clinical Laboratory Improvement Act 
(CLIA) certification and normal ranges for the central laboratory.  
The laboratory will provide sites with all supplies needed for collection, processing, and shipping 
of all blood samples, as well as point-of-care urine pregnancy tests. 
11.3.4.1. Drug Screen 
A urine drug screening is to be performed at Screening and include cocaine, THC, opiates, 
amphetamines, methamphetamine, and phencyclidine.  Investigator will exercise discretion in 
allowing of excluding a subject from study participation based on a positive test for one of these 
additional analytes.  
At the investigator’s discretion, subjects with a positive result for drugs other than THC (which 
is allowed at the investigator’s discretion) will be allowed to participate if the subject reports use 
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of a concomitant medication that explains the result (eg, positive urine test for opiates in a 
subject reporting use of cough syrup containing dextromethorphan). 
11.3.4.2. Pregnancy Screen 
Female participants of childbearing potential require a negative urine pregnancy test at Screening 
and Visits 2 through 5. 
11.3.5. 
Local Tolerability  
Local tolerability will be assessed at Visits 2, 3, and 4 as follows: 
 The investigator will use the modified Draize scale (Appendix 1) to assess erythema 
and edema formation at the injection site at 30, 90, and 360 minutes (± 2  minutes) 
after injection of study drug(s).  If any scores remain > 1 at the 360-minute 
evaluation, the subject may leave the clinic but will be instructed to contact a study 
staff member if the condition fails to resolve.  Every effort should be made to ensure 
that the same investigator will assess the injection sites on the subject at each visit. 
 Subjects will complete a 11-point Numeric Rating Scale (NRS) questionnaire 
regarding injection site discomfort 10 and 30 minutes (± 2 minutes) after injection of 
study drug (Appendix 2). Question Q1c is to be answered at 360 mins post-study drug 
injection. 
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12. 
SAFETY AND ADVERSE EVENT (AE) REPORTING 
12.1. 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and which is not necessarily required to have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether considered related to 
the medicinal product.  Examples of AEs include: 
 Abnormal test findings 
 Clinically significant symptoms and signs 
 Changes in PE findings which are untoward and deemed clinically significant by the 
investigator 
 Allergy/hypersensitivity 
The criteria for determining whether an abnormal objective test finding may be reported as an 
AE are as follows: 
 Test result is associated with accompanying symptoms 
 Test result requires additional diagnostic testing or medical/surgical intervention 
 Test result leads to a change in study dosing or discontinuation from the study 
significant additional concomitant drug treatment or other treatment 
 Test result is considered to be an AE by the investigator or sponsor 
Repeat of a test based on an abnormal result in the absence of the above conditions does not 
constitute an AE.  Any abnormal test result determined to be an error does not require reporting 
as an AE. 
A treatment-emergent AE (TEAE) is an AE that either commenced following initiation of study 
treatment or was present prior to study treatment but increased in frequency or severity following 
initiation of study treatment. 
Standard medical terminology should be used in describing AEs.  Informal descriptions should 
be avoided. 
12.1.1. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI) (serious or non-serious) is one of scientific and 
medical concern specific to the sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor could be appropriate. Such an event 
might require further investigation in order to characterize and understand it (ICH E2F, 2008).  
AESIs for PRAM9 are as follows: hypoglycemia, nausea, and vomiting. 
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12.2. 
Reporting Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship 
to the study treatment will be reported with 2 exceptions.  Injection site reactions will not be 
considered an AE unless a skin reaction or pain requires medical intervention.   
For all AEs, the investigator must pursue and attempt to obtain information adequate to 
determine the outcome of the AE and to assess whether it meets the FDA criteria for 
classification as an SAE, requiring immediate notification to Xeris Pharmaceuticals.   
For all AEs, follow-up by the investigator is required until the event resolves or stabilizes at a 
level acceptable to the investigator to consider it resolved.  For unresolved AEs to be considered 
stable, the Xeris Medical Monitor must concur with that assessment. 
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined to be serious (according to the FDA definitions of an SAE) will be reported by the 
sponsor as an SAE.  To assist in the determination of case seriousness, further information may 
be requested from the investigator to provide clarity and understanding of the event in the 
context of the clinical study. 
12.3. 
Reporting Period 
For all AEs, the reporting period to Xeris Pharmaceuticals begins from the subject providing 
informed consent, through the Follow-Up Visit.  All AEs will be followed until resolution or the 
subject is medically stable. 
12.4. 
Serious Adverse Events 
An SAE is any untoward medical occurrence at any dose which: 
 Results in death 
 Is life-threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity  
 Is a congenital anomaly/birth defect  
 Is an important medical event (IME) 
Medical and scientific judgment should be exercised in determining whether expedited reporting 
is appropriate in other situations, such an IME that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed in the definition above.  These events should also 
usually be considered serious.  Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm or blood dyscrasias or convulsions which do not 
result in hospitalization. 
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12.5. 
Severity Assessment 
On the AE eCRF, the investigator will use the adjectives “mild,” “moderate,” or “severe” to 
describe the maximum intensity of the AE.  These intensity grades are defined as follows in 
Table 7, which follows. 
Table 7: 
Adverse Event Severity Assessment 
Mild 
Does not interfere with subject’s usual function 
Moderate 
Interferes to some extent (< 50%) with subject’s usual function 
Severe 
Interferes significantly (≥ 50%) with subject’s usual function 
The terms “serious” and “severe” are not synonymous.  The term “severe” is often used to 
describe the intensity (severity) of a specific event.  The event itself, however, may be of 
relatively minor medical significance.  This is not the same as “serious,” which is based on 
subject/event outcome or action criteria.  Accordingly, a severe event is not necessarily a serious 
event. 
12.6. 
Causality Assessment 
The investigator will use the following question when assessing causality of an AE to the study 
drug, where an affirmative answer designates the event as a suspected adverse reaction: “Is there 
a reasonable possibility that the drug caused the event?” A ‘‘reasonable possibility’’ means that 
there is evidence to suggest a causal relationship between the drug and the AE.  The 
investigator’s assessment of causality must be provided for all AEs (related or unrelated).  The 
investigator must record the causal relationship in the eCRF, as appropriate, and report such an 
assessment in accordance with the SAE reporting requirements, if applicable (Section 12.9).  All 
investigator assessments of AEs must be documented in the source documentation. 
12.7. 
Withdrawal Due to Adverse Events 
Withdrawal due to AE should be distinguished from withdrawal due to insufficient response and 
recorded on the appropriate eCRF.  When a subject withdraws due to an SAE, the SAE must be 
reported in accordance with the reporting requirements (see Section 12.9). 
12.8. 
Eliciting Adverse Event Information and Reporting 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject.  Each study subject will be questioned about AEs.  Each AE is to be assessed to 
determine if it meets the criteria for SAEs.  If an SAE occurs, expedited reporting will follow the 
provisions of Section 12.9. 
12.9. 
Serious Adverse Event Reporting Requirements 
If an SAE occurs, Xeris Pharmaceuticals is to be notified within 24 hours of awareness of the 
event by the investigator.  If the SAE is fatal or life-threatening, notification to Xeris 
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Pharmaceuticals must be made immediately, irrespective of the extent of available AE 
information.  This time frame also applies to follow-up on previously forwarded SAE reports. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, a study subject initially seeks treatment elsewhere), the investigator is to report 
the event within 24 hours after learning of the event and document the time of first awareness of 
the AE.   
A death occurring during the study, during the study follow-up period, or within 14 days after 
stopping treatment with test drug must be reported to Xeris Pharmaceuticals or its designee(s) 
immediately, whether it is considered treatment-related.  Initial SAE reports must be followed by 
detailed descriptions.  These should include copies of hospital case records and other documents 
when requested.  Telephone and email reports must be confirmed promptly either by facsimile or 
by overnight courier or mail. 
Under 21 CFR 312.32(c), Xeris Pharmaceuticals or its designee(s) is required to notify FDA and 
all participating investigators in an IND safety report (ie, 7- or 15-day expedited report) of 
potentially serious risks from clinical trials or any other source as soon as possible, but no later 
than 15 calendar days after the safety information is received and a determination is made that 
the information qualifies for reporting. 
12.10. 
Nonserious Adverse Event Reporting Requirements 
All AEs will be reported on the AE page(s) of the eCRF.  AEs should be reported using concise 
medical terminology on the eCRFs as well as on the form for collection of the SAE information. 
12.11. 
AE Reporting Requirements to Regulatory Authorities 
AE reporting by the sponsor, including suspected serious unexpected adverse reactions, will be 
carried out in accordance with applicable regulations. 
The investigator must notify the IRB/Independent Ethics Committee (IEC) of the occurrence of 
any SAE, in writing, as soon as is practicable and in accordance with local regulations.  A copy 
of this notification must be provided to Xeris Pharmaceuticals or its designee. 
In the event of an SAE that meets the criteria for expedited reporting, an SAE report will be 
prepared for submission to the FDA and any other applicable authorities by Xeris 
Pharmaceuticals or its designee. 
12.12. 
Pregnancy  
The active pharmaceutical products in Xeris Pharmaceuticals’ PRAM9 pramlintide-insulin are in 
Pregnancy Category B.  Female subjects of childbearing potential will be tested (urine) for 
pregnancy at the Screening Visit.  A woman is considered to be of childbearing potential if she is 
post menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus). 
Any subject found to be pregnant at the Screening Visit (Visit 1) will not be randomized to a 
treatment sequence.  Any subject who is found to be pregnant at one of the treatment visits will 
be withdrawn from the study immediately and no further study treatments will be given.  
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Pregnancy at the Follow-Up Visit will be noted, but the visit will be completed.  Any pregnancy 
in a subject who received at least one dose of study drug will be followed until resolution (ie, 
birth or voluntary or spontaneous termination of the pregnancy).  Any pregnancy outcome that 
meets the criteria for an SAE will be reported as an SAE. 
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12.13. 
Subject Monitoring 
Subjects will be monitored for AEs throughout the study by the study unit staff.  The principal 
investigator or designated sub-investigator will be on site for drug administration and until 
6 hours after administration of study drug to the last subject.  The principal investigator or 
designated sub-investigator will also be available (eg, “on call”) for the remainder of the 
treatment visit.  If necessary, a physician, either at the study site or in a nearby hospital, will 
administer treatment for any AEs. 
Safety parameters, including laboratory results, will be assessed by the principal investigator or 
his delegate using the site’s criteria for clinical laboratory acceptance ranges as suggested 
guidelines in making the medical assessment. 
Scheduled safety measurements will be repeated according to appropriate SOPs or upon request 
from a physician.  Any abnormal repeated measurement will be evaluated by a physician and 
repeated if judged necessary.  Further action may be taken on the physician’s request. 
Subjects will be advised to notify their health care professionals (eg, physician, dentist, and/or 
pharmacist) that they are participating in a clinical research study of a drug called PRAM9 
before taking any medicines or undergoing any medical procedure. 
 
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13. 
DATA ANALYSIS AND STATISTICAL METHODS 
13.1. 
General Approach 
Detailed methodology for PK, PD, descriptive and inferential statistical analyses of the data 
collected in this study will be documented in the SAP.   
Descriptive statistics will be used to summarize the clinical and laboratory data.  Continuous data 
will be represented by number of subjects, mean, median, standard deviation (SD), and range, 
while categorical variables will be presented by number and percentage of subjects.  Baseline 
values are determined by the last evaluable measurement before study drug injection in each 
treatment period.  Point estimates may be derived with 2-sided 95% confidence intervals.  An 
analysis of variance (ANOVA) will be performed to evaluate effect of study treatment and 
period.  There is no reason to think that sequence will have an effect on the outcome. 
13.1.1. 
Sample Size Calculation 
Up to 21 subjects will be qualified for the study and will complete the overnight stay as part of 
Visit 2 to ensure that 18 total subjects are randomized to a study treatment sequence.  The target 
of 18 randomized subjects is considered sufficient to allow an initial evaluation of PK/PD 
response and safety of these novel pramlintide-insulin formulations.  Formal sample sizes were 
not conducted.   
13.2. 
Primary Endpoint Analysis 
All PK/PD analyses will be performed using the PK/PD analysis population. 
The following variable will be compared among the treatments for PD purposes: 
 AUC0-180 (mg/dL × minutes) for plasma glucose > 180 mg/dL 
13.3. 
Secondary Endpoint Analysis 
13.3.1. 
Safety Endpoints 
All safety analyses will be performed using the safety population.  
The following variables will be compared between the treatments for safety purposes: 
 Incidence of AEs and SAEs 
 Change from baseline in laboratory safety variables  
 Change from baseline in vital sign measurements 
 Change from baseline in body weight 
 Local tolerability assessments, including: 
o Incidence of erythema and or edema formation at site of injection assessed 
using the Draize scale (Appendix 1). 
o Subjective injection site discomfort as reported by subjects using a 11-point 
NRS  (Appendix 2). 
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13.3.2. 
Pharmacodynamic and Pharmacokinetic Endpoints 
All PK/PD analyses will be performed using the PK/PD analysis population.  
The following variables will be compared between the treatments for PD and PK purposes: 
 Mean proportional time with plasma glucose > 180 mg/dL for 0-180 minutes  
 Mean proportional time after glucose challenge for plasma glucose levels between 
126 to 180 mg/dL  
 Mean proportional time* for plasma glucose < 70 mg/dL 
 Mean proportional time* for plasma glucose < 54 mg/dL 
 Mean proportional time* for plasma glucose > 180 mg/dL 
 Mean proportional time* for plasma glucose > 250 mg/dL  
 AUC0-360 (mg/dL × minutes) for plasma glucose > 180 mg/dL 
 AUC0-360 (mg/dL × minutes) for plasma glucose > 250 mg/dL 
 AOC0-360 (mg/dL × minutes) for plasma glucose < 70 mg/dL 
 AOC0-360 (mg/dL × minutes) for plasma glucose < 54 mg/dL 
 Plasma glucose Cmax and Tmax 
 Plasma levels (AUC0-90 min, AUC0-180 min, AUC0-360 min, Cmax, and Tmax) for both insulin 
and pramlintide 
 
* Mean proportional time during 0 to 360 minutes post-injection of study drug. 
13.4. 
Adverse Events 
All safety analyses will be performed using the safety analysis population.  TEAEs will be 
summarized using the Medical Dictionary for Regulatory Activities (MedDRA®) system organ 
class (SOC) and preferred term (PT), classified from verbatim terms.  Listings of all AEs 
(including non-TEAEs), treatment-emergent SAEs, and TEAEs leading to study drug 
discontinuation will be provided by treatment group, subject, verbatim term, MedDRA SOC and 
PT, start and end dates, seriousness, severity, relationship to study drug, action taken with study 
treatment, frequency, and outcome. 
AEs will be summarized overall by the number and percentage of subjects who experienced at 
least one AE of the following categories in each treatment group: any AE, any TEAE, any drug-
related TEAE, any severe or life-threatening TEAE, any serious TEAEs, any drug-related SAE, 
any SAE leading to death, any TEAE leading to premature discontinuation of study drug, and 
any SAE leading to premature study drug discontinuation.  
The number and percentage of subjects reporting a TEAE in each treatment group will be 
tabulated by SOC and PT; by SOC, PT, and severity (mild, moderate, and severe/life-
threatening/death); and by SOC, PT, and relationship (unrelated or related to study drug).  
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The numbers and percentages of subjects reporting an SAE or reporting a TEAE leading to 
premature discontinuation of study drug in each treatment group will be summarized by SOC 
and PT.   
13.5. 
Laboratory Safety Assessments 
Laboratory values will be flagged if outside the normal range.  A listing of clinically significant 
abnormal values will be presented.  The individual values will be listed indicating values outside 
normal range.  Laboratory assessments will be summarized at Screening and at the end of the 
study.  Significant deviations/changes from the Screening Visit to the Follow-Up Visit will be 
documented as AEs if the investigator judges these as being clinically significant. 
13.6. 
Physical Examination 
Subjects with any findings in the PE evaluation at Screening will be listed on the Medical 
History CRF.  Changes to PE from Screening to end of trial will be recorded as AEs if they meet 
the definition of an AE or if the investigator judges these changes as being clinically significant. 
13.7. 
Vital Signs and Body Weight 
Vital signs will be summarized by descriptive statistics.  Changes from pre- to post-dosing at 
each of the Treatment Period Visits will be conducted.  If there are changes that meet the 
definition of an AE or if the investigator judges these as being clinically significant, they will be 
recorded on the eCRF as an AE.  
Observed values as well as change from baseline data will be summarized descriptively in 
tabular format.  The pre-study drug collections of vital signs at each Treatment Period will be 
considered as baseline.  
13.8. 
Electrocardiogram 
Any clinically significant ECG results will be recorded and followed as appropriate.  The 
investigator’s evaluations will be summarized in a data listing.   
13.9. 
Local Tolerability  
The incidence of any injection site discomfort (score > 0 on the ordinal rating scale) will be 
analyzed descriptively.  The incidences of erythema and edema will be analyzed in a similar 
manner.  Descriptive statistics will be provided for time of onset and duration (of discomfort) 
and discomfort description (ie, pain, irritation, itching, etc.).  
Mean NRS scores will be compared between the treatments. 
13.10. 
Prior and Concomitant Medications 
Prior and concomitant medications will be mapped to a World Health Organization (WHO) drug 
classification.  The number and percent of subjects taking concomitant medications will be 
summarized. 
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13.11. 
Subgroup Analysis  
No subgroup analyses are planned. 
13.12. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for all subjects overall and by 
Treatment Period.  Summary statistics (eg, number of subjects, mean, median, SD and range) 
will be generated for continuous variables (eg, age and weight) and the number and percentage 
of subjects within each category will be presented for categorical variables (eg, sex, ethnicity, 
and race). 
13.13. 
Subject Disposition 
A detailed description of subject disposition will be provided and will include the following: 
 A summary of overall subject enrollment status (consented, screened, screen failures, 
randomized, replaced) 
 A summary of subjects who discontinued the study 
 An account of identified protocol deviations 
All subjects who are consented for the study will be accounted for in the summation.  The 
number of subjects who do not qualify for certain analysis populations and who did not complete 
all 3 treatment periods will also be summarized. 
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14. 
DATA HANDLING, RECORD KEEPING, MONITORING AND 
AUDITS 
14.1. 
Case Report Forms/Electronic Data Record 
Data collection is the responsibility of the clinical study staff under the supervision of the 
investigator.  During the study, the investigator will maintain complete and accurate 
documentation for the study. 
As defined in the ICH Guidelines for Good Clinical Practice (E6(R2)), Section 1.52, source 
documents may include:  original documents, data, and records (eg, hospital records, clinical and 
office charts, laboratory notes, memoranda, participant’s diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies, or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, X-rays, participant files, and records kept 
at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
study). 
As used in this protocol, the term CRF is understood to refer to an electronic data record, ie, an 
eCRF.  An eCRF is required and should be completed for each individual subject.  The 
completed original eCRFs are the property of Xeris Pharmaceuticals and should not be made 
available in any form to third parties, except for authorized representatives of Xeris 
Pharmaceuticals or appropriate regulatory authorities, without written permission from Xeris 
Pharmaceuticals.  
Queries generated by Data Management and within the EDC will be sent to the study site for 
resolution.  The investigator is responsible for the review and approval of all responses to eCRF 
queries. 
14.2. 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or Xeris Pharmaceuticals, the 
investigator agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, eCRFs and hospital records), all original signed informed consent 
documents, copies of all eCRFs, safety reporting forms, source documents, and detailed records 
of treatment disposition, and adequate documentation of relevant correspondence (eg, letters, 
meeting minutes, telephone calls reports).  The records should be retained by the investigator 
according to the ICH, local regulations, or as specified in the Clinical Study Agreement, 
whichever is longer.  The investigator must obtain Xeris Pharmaceuticals’ written permission 
before disposing of any records, even if retention requirements have been met. 
14.3. 
Monitoring 
Monitoring and auditing procedures developed by Xeris Pharmaceuticals and/or its designee will 
be implemented to ensure compliance with FDA and ICH GCP and Good Laboratory Practices 
(GLP) guidelines. 
The Xeris Pharmaceuticals’ designated representative (the monitor or auditor) will contact the 
investigator and conduct regular visits to the clinical site.  The monitor will be expected and 
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allowed to verify the investigator’s qualifications, to inspect clinical site facilities, and to inspect 
study records, including proof of IRB/IEC review, with the stipulation that subject 
confidentiality will be maintained in accordance with local and federal regulations, including 
Health Insurance Portability and Accountability Act HIPAA) requirements.  The monitor will 
also be responsible for confirming adherence to the study protocol, inspecting eCRFs and source 
documents, and ensuring the integrity of the data.  eCRFs will be checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents, 
including laboratory test reports and other subject records.  Instances of missing or 
uninterpretable data will be resolved in coordination with the investigator.  
The monitor/auditor will also investigate any questions concerning adherence to regulatory 
requirements.  Any administrative concerns will be clarified and followed.  The monitor will 
maintain contact with the site through frequent direct communications with the study site by 
email, telephone, facsimile, and mail.  The investigator and all other site personnel agree to 
cooperate fully with the monitor and will work in good faith with the monitor to resolve all 
questions raised, and difficulties detected by the monitor. 
14.4. 
Audits and Inspections 
The investigator understands that regulatory authorities, the IRB/IEC, and/or Xeris 
Pharmaceuticals or their designees have the right to access all eCRFs, source documents, and 
other study documentation for on-site audit or inspection and will retain this right from the start 
of the study to at least 2 years after the last approval of a marketing application or for at least 
2 years after clinical development of the study drug for the indication being studied has been 
discontinued.  The investigator is required to guarantee access to these documents and to 
cooperate with and support such audits and inspections.  
 
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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
During study conduct, Xeris Pharmaceuticals or its agent will conduct periodic visits to ensure 
that the protocol and Good Clinical Practices are being followed.  The monitor may review 
source documents to confirm that the data recorded on eCRFs is accurate.  The investigator and 
institution will allow Xeris Pharmaceuticals’ monitor or its designee, and appropriate regulatory 
authorities, direct access to source documents to perform this verification. 
The study site may be subjected to review by the Institutional Review Board and/or to quality 
assurance audits performed by Xeris Pharmaceuticals or its designee, and/or to inspection by 
appropriate regulatory authorities.  It is important that the investigator and study staff are 
available during the monitoring visits and possible audits or inspections and that sufficient time 
is devoted to the process. 
 
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16. 
ETHICAL CONSIDERATIONS 
16.1. 
Conduct 
The investigator will ensure that the study described in this protocol is conducted in full 
conformance with those principles, the protocol, current FDA regulations, ICH Good Clinical 
Practices (GCP) guidelines, GLP guidelines, local ethical and regulatory requirements, including 
the Federal Food, Drug and Cosmetic Act, US applicable Code of Federal Regulations (Title 21), 
any IRB/IEC requirements relative to clinical studies.  
Should a conflict arise, the investigator will follow whichever law or guideline affords the 
greater protection to the individual subject.  The investigator will also ensure thorough 
familiarity with the appropriate administration and potential risks of administration of the study 
drug, as described in this protocol and the Investigator’s Brochure, prior to the initiation of the 
study. 
16.2. 
Institutional Review Board and Ethics Committee 
The IRB/IEC must be a properly constituted board or committee operating in accordance with 
21 CFR Part 56, “Institutional Review Boards.”  This protocol, any protocol amendments, the 
associated informed consent forms, and the informed consent procedures must be submitted to 
the IRB for review and approved before the enrollment of any subject into the trial.  Study drug 
may not be shipped to the investigator until Xeris Pharmaceuticals has received a copy of the 
letter or certificate of approval from the IRB/IEC for the protocol and any protocol amendments. 
All types of subject recruitment or advertising information must be submitted to Xeris 
Pharmaceuticals or its designee and to the IRB/IEC for review and approval prior to 
implementation.  IRB approval of any protocol amendments must be received before any of the 
changes outlined in the amendments are put into effect, except when the amendment has been 
enacted to eliminate a potential hazard to study subjects.  In such cases, the chair of the IRB/IEC 
should be notified immediately, and the amendment forwarded to the IRB/IEC for review and 
approval. 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements from the IRB/IEC.  All correspondence with the IRB/IEC should be 
retained in the investigator file.  Copies of IRB/IEC approvals should be forwarded to Xeris 
Pharmaceuticals. 
16.3. 
Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names on 
any sponsor forms, reports, publications, or in any other disclosures.  Subject names, address, 
date of birth and other identifiable data will be replaced by a numerical code consisting of a 
numbering system provided by Xeris Pharmaceuticals to de-identify the study subject.  In the 
case of data transfer, Xeris Pharmaceuticals will maintain confidentiality and protection of 
subject personal data. 
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The informed consent document used in this study, and any changes made during the study, must 
be prospectively approved by both the IRB/IEC and Xeris Pharmaceuticals before use.  The 
investigator must ensure that each study subject is fully informed about the nature and objectives 
of the study and possible risks associated with participation.  The investigator, or a study staff 
designated by the investigator, will obtain written informed consent from each subject before any 
study-specific activity is performed.  The investigator will retain the original of each subject’s 
signed consent document.  Receipt of written informed consent will be documented in each 
subject’s or potential subject’s eCRF.  The signed informed consent document must remain on 
file at the study site and be available for verification by the study monitors at all times. 
16.4. 
Subject Recruitment 
All types of subject recruitment or advertising information must be submitted to Xeris 
Pharmaceuticals or its designee and to the IRB/IEC for review and approval prior to 
implementation.  Advertisements approved by the IRB/IEC may be used as recruitment 
procedures. 
16.5. 
Reporting of Safety Issues and Serious Breaches of the Protocol 
In the event of any prohibition or restriction imposed (ie, clinical hold), or if the investigator is 
aware of any new information which might influence the evaluation of the benefits and risks of 
the investigational product, Xeris Pharmaceuticals should be notified immediately.  In addition, 
the investigator will inform Xeris Pharmaceuticals immediately of any urgent safety measures 
taken by the investigator to protect study subjects against any immediate hazard, and of any 
serious breaches of this protocol. 
During study conduct, Xeris Pharmaceuticals or its agent will conduct periodic visits to ensure 
that the protocol and GCPs are being followed.  The monitor may review source documents to 
confirm that the data recorded on eCRFs is accurate.  The investigator and institution will allow 
Xeris Pharmaceuticals’ monitor or its designee, and appropriate regulatory authorities, direct 
access to source documents to perform this verification. 
The study site may be subjected to review by the Institutional Review Board and/or to quality 
assurance audits performed by Xeris Pharmaceuticals or its designee, and/or to inspection by 
appropriate regulatory authorities.  It is important that the investigator and study staff are 
available during the monitoring visits and possible audits or inspections and that sufficient time 
is devoted to the process. 
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17. 
PROCEDURES FOR MODIFYING THE PROTOCOL OR 
TERMINATING THE STUDY 
17.1. 
Protocol Modifications and Deviations 
The principal investigator must sign this protocol and its amendments (if any) before initiating 
the study at a particular site.  The investigator will make all reasonable efforts to comply with the 
written protocol.  Protocol modifications to ongoing studies that affect the safety of subjects or 
that alter the scope of the investigation, the scientific quality of the study, the experimental 
design, dosing, study assessments, the number of subjects exposed to test drug, or subject 
selection criteria must be made only after consultation between Xeris and the investigator.  All 
protocol modifications must be reviewed and approved by the IRB/IEC before the revised 
protocol can be implemented.  Emergency revisions that eliminate an apparent hazard to subjects 
do not require preapproval by the IRB/IEC.  However, the IRB/IEC must be notified in writing 
as soon as possible after the modification has been made.  A copy of this communication must be 
forwarded to Xeris.  All departures from the protocol must be fully documented in the source 
documents and the eCRFs of the subjects involved.  Protocol deviations will be tracked in an 
electronic system implemented by the sponsor or designated representative. 
17.2. 
Study Termination  
The study may be prematurely terminated at any time because of a regulatory authority decision, 
change in opinion of the IRB/Ethics Committee, safety problems resulting in subject deaths, or at 
the discretion of Xeris Pharmaceuticals or the principal Investigator. 
Circumstances that may warrant premature study termination include, but are not limited, to the 
following: 
 Determination of unexpected, significant, or unacceptable risk to subjects,  
 Failure to enter subjects at an acceptable rate, 
 Insufficient adherence to the requirements of the protocol, 
 Insufficient provision of complete and evaluable data, or 
 Plans to modify, suspend, or discontinue development of the study drug. 
If the study is prematurely terminated or discontinued, Xeris Pharmaceuticals will promptly 
notify the Investigators and document the reason for study termination. Specific procedures for 
termination will be arranged by the Sponsor in coordination with the Investigators.  After 
notification, the Investigators must contact all participating subjects within 7 days.  All study 
materials must be collected and all CRFs completed to the greatest extent possible, and all study 
materials must be returned to Xeris Pharmaceuticals or its designee within an additional 28 days. 
 
 
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18. 
LIST OF REFERENCES 
 
American Diabetes Association. Guideline for treatment of hypoglycemia by IV glucose for 
use with IV insulin regimens. 2008. Accessed at: 
https://professional.diabetes.org/abstract/guideline-treatment-hypoglycemia-iv-glucose-
use-iv-insulin-regimens Accessed on 06 Sep 2019. 
AstraZeneca Pharmaceuticals, LP. SYMLIN®, package insert. 2016. Accessed at: 
https://www.azpicentral.com/symlin/symlin.pdf#page=1. 
Bell KJ, King BR, Shafat A, Smart CE. The relationship between carbohydrate and the 
mealtime insulin dose in type 1 diabetes. J Diabetes and Its Complications. 
2015;29:1323-29. 
da Silva DC, Lima LMTR. Physico-chemical properties of co-formulated fast-acting insulin 
with pramlintide. Int J Pharm. 2018;Aug 25;547(1-2):621-629. 
DECODE Study Group. Glucose tolerance and cardiovascular mortality: comparison of 
fasting and 2-hour diagnostic criteria. Arch Intern Med. 2001;161:397–405. 
Diabetes Control and Complications Trial Research Group: Hypoglycemia in the Diabetes 
Control and Complications Trial. Diabetes. 1997;46:271–286. 
Downie WW, Leatham PA, Rhind VM, Wright V, Branco JA, Anderson JA. Studies with 
pain rating scales. Ann Rheum Dis. 1978;37:378–381 
Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of 
substances applied topically to the skin and mucous membranes. Journal of 
Pharmacology and Experimental Therapeutics.  November 1944;82(3):377-390. 
Guidance for Industry, Skin Irritation and Sensitization Testing of Generic Transdermal Drug 
Products. US Department of Health and Human Services Food and Drug Administration 
Center for Drug Evaluation and Research (CDER). December 1999. Appendix A. 
Hawker GA, Mian S, Kendzerska T, French M.  Measures of adult pain: Visual Analog Scale 
for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain 
Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain 
Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of 
Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care & Research. 
November 2011;63(S11):S240-S252. 
Herrmann K, Zhou M, Wang A, de Bruin TWA. Cardiovascular safety assessment of  
pramlintide in type 2 diabetes: results from a pooled analysis of five clinical trials. Clin 
Diabetes Endocrinol. 2016;May 11;2:12. 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH). ICH Topic E2F: Development Safety Update Report. June 2008. 
Accessed at: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-2-f-
development-safety-update-report-step-3_en.pdf. Accessed on 05 Jun 2019.   
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Joslin Diabetes Center and Beth Israel Deaconess Medical Center. Guideline for management 
of uncontrolled glucose in the hospitalized adult. May 2013. Accessed at: 
https://www.joslin.org/unc_gluc_in_hosp_guideline_final_5_13.pdf  Accessed on 
06 Sep 2019. 
King AB, Kuroda A, Matsuhisa M, Hobbs T. A review of insulin-dosing formulas for 
continuous subcutaneous insulin infusion (CSII) for adults with type 1 diabetes. 
2016;16(83):1-8. 
Klein R, Klein BE, Moss SE, Cruickshanks KJ. The medical management of hyperglycemia 
over a 10-year period in people with diabetes. Diabetes Care. 1996;19:744–750. 
Koda JE, Fineman M, Rink TJ, et al. Amylin concentrations and glucose control. Lancet. 
1992;339:1179–1180. 
Ludvik B, Lell B, Hartter E, et al. Decrease of stimulated amylin release precedes 
impairment of insulin secretion in type II diabetes. Diabetes. 1991;40:1615–1619. 
Purnell JQ, Hokanson JE, Marcovina SM, et al. Effect of excessive weight gain with 
intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the 
DCCT: Diabetes Control and Complications Trial. JAMA 1998;280:140–146. 
Riddle MC, Yuen KC, de Bruin TW, et al. Fixed ratio dosing of pramlintide with regular 
insulin before a standard meal in patients with type 1 diabetes. Diabetes Obes Metab. 
2015;17:904–907. 
The DCCT Research Group: Weight gain associated with intensive therapy in the Diabetes 
Control and Complications Trial: the DCCT Research Group. Diabetes Care. 
1988;11:567–573. 
Utah State Government. Diabetes Clinic Insulin to Carbohydrate Ratio. Accessed on 08 May 
2019. Accessed at: http://choosehealth.utah.gov/documents/pdfs/school-nurses/Diabetes-
Clinic-insulintoCarbohydrateRatios.pdf. 
Whitehouse F, Kruger DF, Fineman M, et al. A randomized study and open-label extension 
evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 
diabetes. Diabetes Care. 2002;Apr;25(4):724-730. 
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19. 
APPENDICES 
 
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Appendix 1. DRAIZE SCALE 
 
Study Personnel Instructions:  The modified Draize Scale as shown in the table below will be 
used for physical examination/rating of abnormalities at the injection site. 
The injection site should be examined for formation of both erythema and edema and results 
recorded in the eCRF.  Evaluations of the injection site should be performed at 30, 90, and 
360 minutes (± 2  minutes) post-treatment.   
If any scores remain > 1 at the 360-minute evaluation, the subject may leave the clinic but will 
be instructed to contact study staff if the condition fails to resolve. 
 
Erythema Formation 
Edema Formation 
Description 
Score 
Description 
Score 
No erythema 
0 
No edema 
0 
Very slight erythema 
Barely perceptible 
1 
Very slight edema 
Barely perceptible 
1 
Well defined erythema 
2 
Slight edema (edges of area 
well defined by definite raising) 
2 
Moderate erythema 
3 
Moderate edema 
Raised approx. 1 mm 
3 
Severe erythema 
Beet redness to slight 
eschar formation 
4 
Severe edema 
Raised more than 1 mm and 
beyond exposure area 
4 
 
Sources: 
Guidance for Industry, Skin Irritation and Sensitization Testing of Generic Transdermal Drug Products. 
US Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). December 1999. Appendix A. 
Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of substances applied 
topically to the skin and mucous membranes. Journal of Pharmacology and Experimental 
Therapeutics.  November 1944;82(3):377-390. 
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Appendix 2. INJECTION SITE DISCOMFORT ASSESSMENT 
Numeric Rating Scale (NRS) for Injection Site Discomfort 
Investigative Site Instructions: The subject should complete the 11-point NRS for Injection Site 
Discomfort at 10 and 30 minutes (± 2  minutes) after injection of study drug. The subject will complete 
the NRS by drawing a circle around the number corresponding to the perceived intensity (severity) of 
discomfort according to the instructions below. The goal is for the subject to report the amount of 
discomfort, if any, remaining at each time point, as opposed to reporting the transient pain associated with 
needle insertion. 
Note: If a subject is unable to physically complete the questionnaire, the subject will indicate the number 
on the NRS corresponding to their level of discomfort, and study staff will circle it. Documentation will be 
provided on each completed questionnaire as to who completed the form. 
Subject Instructions: Ignoring any pain from insertion of the needle, please draw a circle around the 
number on the scale below that corresponds to the intensity (severity) of any discomfort you are feeling 
right now at the study drug injection site. 
For example,  if you are currently feeling no discomfort, you should circle the number “0” on the left end 
of scale. If you are currently feeling the worst discomfort possible, you should circle number “10” on the 
right end of the scale. 
 
 
 
 
 
 
 
NRS Source:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077524.  Accessed 17 April 2019. 
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Injection Site Discomfort Description and Duration Questionnaire 
Study Personnel Instructions:  Question 1a should be completed by the subject at 10 ± 2 minutes after 
injection of study drug. If response is anything other than “None,” the subject should also answer 
Question 1b.  All subjects should also answer Question 1c at 30 ± 2 minutes post-injection.   
The goal is for the subject to report the qualitative nature and duration of discomfort, if any, associated 
with injection of study drug, ignoring any transient pain associated with needle insertion. 
Note: If a subject is unable to physically complete the questionnaire, the subject will provide verbal 
responses, which will be recorded on the questionnaire by study staff. Documentation will be provided on 
each completed questionnaire as to who completed the form. 
Subject Instructions: Please answer question 1a and 1c, and, if applicable to you, question 1b. In 
answering these questions, you should ignore any pain from insertion of the needle. 
1a. How would you describe any discomfort you felt from the study drug? (Check all that apply): 
______None (Please ignore question 1b.) 
______Pain (eg, throbbing, soreness, muscle ache) 
______Itching 
______Tingling, twitching, or numbness 
______Irritation (eg, burning, stinging) 
 
Other or additional comments:_____________________________________________________ 
1b. About how long did the discomfort last after the injection? (Check one): 
_____Less than 1 minute 
_____1-2 minutes 
_____3-5 minutes 
_____6-9 minutes 
_____at least 10 minutes (Please complete question 1c before leaving the clinic.) 
 
1c. In total, how long did the discomfort last after the injection? (Please enter a number below): 
_____ Minutes 
 
Reference:   
McCaffery M, Beebe A, et al. Pain: Clinical Manual for Nursing Practice. 1989. Mosby:St Louis. 
Downie WW, Leatham PA, Rhind VM, Wright V, Branco JA, Anderson JA. Studies with pain rating 
scales. Ann Rheum Dis. 1978;37:378–381. 
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Hawker GA, Mian S, Kendzerska T, French M.  Measures of adult pain: Visual Analog Scale for Pain 
(VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form 
McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain 
Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care 
& Research. November 2011;63(S11):S240-S252. 
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APPENDIX 3. INSULIN TO CARBOHYDRATE RATIO  
Insulin-to-Carb Ratio 
This ratio tells you how many grams of carb are covered by one unit of bolus insulin. 
Use your insulin-to-carb ratio every time you eat a meal. You may use it with snacks if advised 
by your provider. 
The starting insulin to carb ratio is calculated by using the 450 Rule. Here’s how it works: 
 Determine your total daily dose (TDD) of insulin.  
o This includes both your meal time and basal insulin used within a day.  
o TDD = _______  
 Divide 450 by the TDD to get your ratio.  
o Insulin Carbohydrate Ratio = 450/TDD = _______ 
 To use the ratio, add up the grams of carb that you plan to eat at your meal, and 
divide this number by your ratio to obtain your regular insulin dose.  
 
Example 1: 
Someone’s TDD = 45 units (e.g., the total amount of say Humalog and Lente insulins they used 
per day). 450 divided by 45 = 10. Therefore, 10 grams of carbohydrate are covered by each unit 
of regular insulin.  
 
The insulin to carbohydrate has a ratio of 1:10, meaning that 1 unit of regular insulin “covers” 10 
grams of carbohydrate. 
 
If you will be eating 70 grams of carbohydrate, then divide 70 by 10, which equals 7. This means 
that you would take 7 units of insulin to cover the 70 grams of carb. 
 
Example 2: 
Someone’s TDD = 50 units (e.g., the total amount of say Humalog and Lente insulins they used 
per day). 450 divided by 50 equals 9. Therefore, 9 grams of carbohydrate are covered by each 
unit of regular insulin.  
 
The insulin to carbohydrate the starting insulin to carb ratio is 1:9, meaning that 1 unit of regular 
insulin “covers” 9 grams of carbohydrate. 
 
If you will be eating 72 grams of carbohydrate, then divide 72 by 9, which equals 8. This means 
that you would take 8 units of insulin to cover the 72 grams of carb. 
 
Based upon your ratio, the accompanying tables may be helpful to estimate the regular insulin 
mealtime dose: 
 
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Insulin to Carbohydrate Ratio: ½:10  
½ unit of insulin for every 10 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
6-15  
0.5  
16-25  
1  
26-35  
1.5  
36-45  
2  
46-55  
2.5  
56-65  
3  
66-75  
3.5  
76-85  
4  
86-95  
4.5  
96-105  
5  
106-115  
5.5  
  
  
Insulin to Carbohydrate Ratio: ½:12  
½ unit of insulin for every 12 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
10-18  
0.5  
19-31  
1  
32-42  
1.5  
43-56  
2  
57-68  
2.5  
69-81  
3  
82-93  
3.5  
94-106  
4  
107-118  
4.5  
119-130  
5  
131-148  
5.5  
  
  
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Insulin to Carbohydrate Ratio: ½:15  
½ unit of insulin for every 15 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
7-22  
0.5  
23-37  
1  
38-52  
1.5  
53-67  
2  
68-82  
2.5  
83-97  
3  
98-112  
3.5  
113-127  
4  
128-142  
4.5  
143-157  
5  
158-172  
5.5  
  
  
Insulin to Carbohydrate Ratio: ½:20  
½ unit of insulin for every 20 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
11-30  
0.5  
31-50  
1  
51-70  
1.5  
71-90  
2  
91-110  
2.5  
111-130  
3  
131-150  
3.5  
151-170  
4  
171-190  
4.5  
191-210  
5  
  
  
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Insulin to Carbohydrate Ratio: ½:25  
½ unit of insulin for every 25 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
12-38  
0.5  
39-63  
1  
64-88  
1.5  
89-113  
2  
114-138  
2.5  
139-163  
3  
164-188  
3.5  
189-213  
4  
214-238  
4.5  
239-263  
5  
264-288  
5.5  
  
  
Insulin to Carbohydrate Ratio: ½:30  
½ unit of insulin for every 30 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
15-45  
0.5  
46-75  
1  
76-105  
1.5  
106-135  
2  
136-165  
2.5  
166-195  
3  
196-225  
3.5  
226-255  
4  
256-285  
4.5  
286-315  
5  
316-345  
5.5  
  
  
***APPROVED COPY*** PRO-19-00045 Version 4.0

PRAM9 (pramlintide-insulin injection) 
Type 1 Diabetes 
Protocol DPI-201 
Version 4.0 
 
Xeris Pharmaceuticals, Inc 
Confidential 
Page 72 of 78 
 
Insulin to Carbohydrate Ratio: ½:35  
½ unit of insulin for every 30 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
18-52  
0.5  
53-87  
1  
88-122  
1.5  
123-157  
2  
158-192  
2.5  
193-227  
3  
228-262  
3.5  
263-297  
4  
298-332  
4.5  
333-367  
5  
368-402  
5.5  
  
  
Insulin to Carbohydrate Ratio: ½:40  
½ unit of insulin for every 40 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
21-60  
0.5  
61-100  
1  
101-140  
1.5  
141-180  
2  
181-220  
2.5  
221-260  
3  
261-300  
3.5  
301-340  
4  
341-380  
4.5  
381-420  
5  
421-460  
5.5  
  
  
***APPROVED COPY*** PRO-19-00045 Version 4.0

PRAM9 (pramlintide-insulin injection) 
Type 1 Diabetes 
Protocol DPI-201 
Version 4.0 
 
Xeris Pharmaceuticals, Inc 
Confidential 
Page 73 of 78 
 
Insulin to Carbohydrate Ratio: 1:5  
1 unit of insulin for every 5 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
3-7  
1  
8-12  
2  
13-17  
3  
18-22  
4  
23-27  
5  
28-32  
6  
33-37  
7  
38-42  
8  
43-47  
9  
48-52  
10  
53-57  
11  
58-62  
12  
63-67  
13  
68-72  
14  
73-77  
15  
78-82  
16  
83-87  
17  
88-92  
18  
  
  
Insulin to Carbohydrate Ratio: 1:6  
1 unit of insulin for every 6 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
3-9  
1  
10-15  
2  
16-21  
3  
22-27  
4  
28-33  
5  
34-39  
6  
40-45  
7  
46-51  
8  
52-57  
9  
58-63  
10  
64-69  
11  
70-75  
12  
76-81  
13  
82-87  
14  
88-93  
15  
94-99  
16  
100-105  
17  
106-111  
18  
***APPROVED COPY*** PRO-19-00045 Version 4.0

PRAM9 (pramlintide-insulin injection) 
Type 1 Diabetes 
Protocol DPI-201 
Version 4.0 
 
Xeris Pharmaceuticals, Inc 
Confidential 
Page 74 of 78 
 
  
  
Insulin to Carbohydrate Ratio: 1:7  
1 unit of insulin for every 7 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
4-10  
1  
11-17  
2  
18-24  
3  
25-31  
4  
32-38  
5  
39-45  
6  
46-52  
7  
53-59  
8  
60-66  
9  
67-73  
10  
74-80  
11  
81-87  
12  
88-95  
13  
96-102  
14  
103-109  
15  
110-116  
16  
117-124  
17  
125-132  
18  
  
  
Insulin to Carbohydrate Ratio: 1:8 or 2:15  
1 unit of insulin for every 8 grams of carbohydrate, or  
2 units of insulin for every 15 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
5-11  
1  
12-19  
2  
20-27  
3  
28-35  
4  
36-43  
5  
44-51  
6  
52-59  
7  
60-67  
8  
68-74  
9  
75-83  
10  
84-89  
11  
90-99  
12  
100-104  
13  
105-115  
14  
  
***APPROVED COPY*** PRO-19-00045 Version 4.0

PRAM9 (pramlintide-insulin injection) 
Type 1 Diabetes 
Protocol DPI-201 
Version 4.0 
 
Xeris Pharmaceuticals, Inc 
Confidential 
Page 75 of 78 
 
  
Insulin to Carbohydrate Ratio: 1:10  
1 unit of insulin for every 10 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
6-15  
1  
16-25  
2  
26-35  
3  
36-45  
4  
46-55  
5  
56-65  
6  
66-75  
7  
76-85  
8  
86-95  
9  
96-105  
10  
106-115  
11  
116-125  
12  
126-135  
13  
136-145  
14  
  
  
Insulin to Carbohydrate Ratio: 1:12  
1 unit of insulin for every 12 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
10-18  
1  
19-30  
2  
31-42  
3  
43-54  
4  
55-66  
5  
67-78  
6  
79-90  
7  
91-102  
8  
103-114  
9  
115-126  
10  
127-138  
11  
139-150  
12  
156-162  
13  
  
  
***APPROVED COPY*** PRO-19-00045 Version 4.0

PRAM9 (pramlintide-insulin injection) 
Type 1 Diabetes 
Protocol DPI-201 
Version 4.0 
 
Xeris Pharmaceuticals, Inc 
Confidential 
Page 76 of 78 
 
Insulin to Carbohydrate Ratio: 1:15  
1 unit of insulin for every 15 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
7-22  
1  
23-37  
2  
38-52  
3  
53-67  
4  
68-82  
5  
83-97  
6  
98-112  
7  
113-127  
8  
  
  
Insulin to Carbohydrate Ratio: 1:18  
1 unit of insulin for every 18 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
9-27  
1  
28-45  
2  
46-63  
3  
64-81  
4  
82-99  
5  
100-117  
6  
118-135  
7  
136-153  
8  
  
  
Insulin to Carbohydrate Ratio: 1:20  
1 unit of insulin for every 20 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
11-30  
1  
31-50  
2  
51-70  
3  
71-90  
4  
91-110  
5  
111-130  
6  
131-150  
7  
151-170  
8  
  
  
***APPROVED COPY*** PRO-19-00045 Version 4.0

PRAM9 (pramlintide-insulin injection) 
Type 1 Diabetes 
Protocol DPI-201 
Version 4.0 
 
Xeris Pharmaceuticals, Inc 
Confidential 
Page 77 of 78 
 
Insulin to Carbohydrate Ratio: 1:25  
1 unit of insulin for every 25 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
10-35  
1  
36-60  
2  
61-85  
3  
86-110  
4  
111-159  
5  
160-185  
6  
  
  
Insulin to Carbohydrate Ratio: 1:30  
1 unit of insulin for every 30 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
15-45  
1  
46-75  
2  
76-105  
3  
106-135  
4  
136-165  
5  
166-195  
6  
  
  
Insulin to Carbohydrate Ratio: 1:35  
1 unit of insulin for every 35 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
17-52  
1  
53-87  
2  
88-122  
3  
123-157  
4  
158-192  
5  
192-227  
6  
  
  
Insulin to Carbohydrate Ratio: 1:40  
1 unit of insulin for every 40 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
21-60  
1  
61-100  
2  
101-140  
3  
141-180  
4  
181-220  
5  
221-260  
6  
  
  
***APPROVED COPY*** PRO-19-00045 Version 4.0

PRAM9 (pramlintide-insulin injection) 
Type 1 Diabetes 
Protocol DPI-201 
Version 4.0 
 
Xeris Pharmaceuticals, Inc 
Confidential 
Page 78 of 78 
 
Insulin to Carbohydrate Ratio: 1:45  
1 unit of insulin for every 45 grams of carbohydrate  
Grams of Carbohydrates  
Units of Insulin  
22-68  
1  
69-113  
2  
114-158  
3  
159-204  
4  
205-249  
5  
250-294  
6  
 
Source:   
Bell KJ, King BR, Shafat A, Smart CE. The relationship between carbohydrate and the mealtime 
insulin dose in type 1 diabetes. J Diabetes and Its Complications. 2015;29:1323-29. 
King AB, Kuroda A, Matsuhisa M, Hobbs T. A review of insulin-dosing formulas for continuous 
subcutaneous insulin infusion (CSII) for adults with type 1 diabetes. 2016;16(83):1-8. 
Utah State Government. Diabetes Clinic Insulin to Carbohydrate Ratio. Accessed on 
08 May 2019. Accessed at: http://choosehealth.utah.gov/documents/pdfs/school-nurses/Diabetes-
Clinic-insulintoCarbohydrateRatios.pdf. 
***APPROVED COPY*** PRO-19-00045 Version 4.0

Document Approvals
Approved Date: 12/13/2019, PRO-19-00045 Version 4
Approval Task
Verdict:  Approve
Khaled Junaidi,
(kjunaidi@xerispharma.com)
Medical Affairs Approval
12-Dec-2019 22:30:30 GMT+0000
Approval Task
Verdict:  Approve
Joy Geallis,
(jgeallis@xerispharma.com)
SME Approval
12-Dec-2019 23:03:41 GMT+0000
Approval Task
Verdict:  Approve
Nicole Close,
(nclose@xerispharma.com)
SME Approval
13-Dec-2019 07:53:03 GMT+0000
Approval Task
Verdict:  Approve
Aziz Alam,
(aalam@xerispharma.com)
Regulatory Approval
13-Dec-2019 13:38:24 GMT+0000
QA Approval Task
Verdict:  Approve
Ed Drower,
(edrower@xerispharma.com)
Quality Assurance Approval
13-Dec-2019 13:42:38 GMT+0000
***APPROVED COPY*** PRO-19-00045 Version 4.0