Clinical trial NCT02971228
Conditions: Diabetes Mellitus, Type 1
Keywords: glucagon Type 1 diabetes mellitus Bionic Pancreas diabetes iLet iPhone Beta Bionics Anti-hypoglycemia Glucagon Analog
Sponsor: Zealand Pharma
Start date: 2016-11-01; Completion date: 2017-06-07
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study was to determine whether the Bionic Pancreas with ZP4207 (dasiglucagon\*) was feasible to improve glycemic control in adults with type 1 diabetes mellitus.

\*dasiglucagon is the proposed International Nonproprietary Name (pINN) for ZP4207

Detailed description:
This was a single-center, open-label, 2-part, randomized cross-over trial. The trial was to enrol up to 20 adult patients with type 1 diabetes mellitus and assess the safety and efficacy of the Bionic Pancreas (BP) using either the iLet or iPhone platform when used with the glucagon analogue ZP4207 (dasiglucagon) versus Lilly glucagon.

In Part 1, patients participated in two 1-day treatment arms in random order (iPhone-based BP using ZP4207 (dasiglucagon) and iPhone-based BP using Lilly glucagon) according to a pre-generated randomization scheme. In Part 2, it was planned to enrol additional patients to participate in two 1-day treatment arms in random order (iLet using ZP4207 (dasiglucagon) and iLet using Lilly glucagon) according to a pre-generated randomization scheme. However, due to unavailability of the iLet, the sponsor decided to stop the trial upon completion of Part 1. Part 2 of the trial using the iLet was consequently not conducted.

One day the BP will use glucagon analogue ZP4207 (dasiglucagon) and the other day the BP will use Lilly glucagon. Subjects will also receive insulin lispro through the BP on both days. The trial will be conducted at single center, the Massachusetts General Hospital Diabetes Center in Boston, MA.

Arms: arm 1: In Part 1, 12 patients participated in 1-day treatment arms in random order (iPhone-based Bionic Pancreas using Lilly glucagon and iPhone-based Bionic Pancreas using ZP4207 (dasiglucagon) {experimental drug} with insulin lispro) according to pre-generated randomization scheme. arm 2: In Part 1, 12 patients participated in 1-day treatment arms in random order (iPhone-based Bionic Pancreas using Lilly glucagon and iPhone-based Bionic Pancreas using ZP4207 (dasiglucagon) {experimental drug} with insulin lispro) according to pre-generated randomization scheme. arm 3: In Part 2, it was planned to enrol up to 10 new patients to participate in 1-day treatment arms in random order (iLet-based Bionic Pancreas using Lilly glucagon and iLet-based Bionic Pancreas using ZP4207 (dasiglucagon) {experimental drug} with insulin lispro) according to pre-generated randomization scheme. However, due to unavailability of the iLet, the sponsor decided to stop the trial upon completion of Part 1. Part 2 of the trial using the iLet was consequently not conducted. arm 4: In Part 2, it was planned to enrol up to 10 new patients to participate in 1-day treatment arms in random order (iLet-based Bionic Pancreas using Lilly glucagon and iLet-based Bionic Pancreas using ZP4207 (dasiglucagon) {experimental drug} with insulin lispro) according to pre-generated randomization scheme. However, due to unavailability of the iLet, the sponsor decided to stop the trial upon completion of Part 1. Part 2 of the trial using the iLet was consequently not conducted.
Interventions: intervention 1: Insulin Lispro intervention 2: ZP4207 (dasiglucagon) intervention 3: Glucagon intervention 4: iPhone-based bionic pancreas intervention 5: iLet-based bionic pancreas
Intervention descriptions: intervention 1: Used to lower blood glucose. Commercially available by prescription and is indicated for patients with type 1 diabetes mellitus (T1DM), but not for use in a bionic pancreas. Individualized dose based on metabolic needs and frequent monitoring of blood glucose. intervention 2: A glucagon analog not yet approved by the FDA. Subcutaneous administration in one BP arm. intervention 3: A hormone normally made by the pancreas to raise blood glucose. Used to treat low blood sugar. Commercially available by prescription and is indicated for patients with T1DM in severe hypoglycemia, but not for use in a BP. Subcutaneous administration in one BP arm. intervention 4: An experimental device. intervention 5: An experimental device.

Protocol documents:
SAP_002.pdf: 
A P P E N DI X  1 6. 1. 9:    D O C U M E N T A TI O N  O F  S T A TI S TI C A L  M E T H O D S 
St atisti c al  A n al ysis  Pl a n,  V ersi o n  1. 0,  1 2  D e c e m b er  2 0 1 6 .............................................................. 2 
 
Zeala n d P har ma A/ S 
Cli nical Trial Re p ort Z P 4 2 0 7- 1 6 0 5 1 
C o nfi de ntial & Pr o prietar y 
Fi nal Versi o n 1. 0, 1 0 N o ve m ber 2 0 1 7 
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Prot_003.pdf: 
 
 
 
16. 
APPENDICES 
APPENDIX 16.1: 
TRIAL INFORMATION 
APPENDIX 16.1.1: PROTOCOL AND PROTOCOL AMENDMENTS 
Protocol Clarification Memorandum for Amendment 7.0, 25 January 2017 ..................................2 
Summary of Changes, Amendment 7.0, 09 January 2017 ...............................................................4 
Protocol Version 8.0, Amendment 7.0, 06 January 2017 ................................................................9 
Summary of Changes, Amendment 6.0, 29 September 2016 ........................................................70 
Protocol Version 7.0, Amendment 6.0, 28 September 2016 .........................................................75 
Summary of Changes, Amendment 5.0, 12 September 2016 ......................................................138 
Protocol Version 6.0, Amendment 5.0, 09 September 2016 .......................................................145 
Summary of Changes, Amendment 4.0, 02 September 2016 ......................................................207 
Protocol Version 5.0, Amendment 4.0, 02 September 2016 .......................................................217 
Summary of Changes, Amendment 3.0, 17 August 2016 ............................................................279 
Protocol Version 4.0, Amendment 3.0, 17 August 2016 .............................................................285 
Summary of Changes, Amendment 2.0, 03 August 2016 ............................................................345 
Protocol Version 3.0, Amendment 2.0, 03 August 2016 .............................................................352 
Summary of Changes, Amendment 1.0, 29 June 2016 ................................................................412 
Protocol Version 2.0, Amendment 1.0, 28 June 2016 .................................................................423 
Protocol Version 1.0, 03 May 2016 .............................................................................................482 
 
 
Zealand Pharma A/S 
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Confidential & Proprietary 
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Summary of Changes, Amendment 7.0, ZP4207-16051 
Confidential & Proprietary 
 
09 January 2017 
1
 
SUMMARY OF CHANGES DOCUMENT 
PROTOCOL NUMBER ZP4207-16051 
AMENDMENT NUMBER 7.0 
 
PROTOCOL TITLE: The Bionic Pancreas Feasibility Trial Testing the Bionic Pancreas with 
ZP4207 
AMENDMENT DATE: 06 January 2017 
SUMMARY AND JUSTIFICATION OF CHANGES: 
This amendment was developed to include operational changes regarding basal insulin rate 
adjustments, blood glucose (BG) levels during exercise, safety lab sampling, questionnaires, 
Investigational Medicinal Product (IMP) accountability, and Sponsor discontinuation criteria.  
After the basal rate of the patient’s own insulin infusion pump is changed to be 2-fold higher 
than weighted mean of the basal rate during the trial period (intended to increase the usage of 
glucagon during the treatment visit), the basal insulin rate may be decreased during the 
treatment visit at the discretion of the Investigator. To the extent possible, the same basal rate 
should be used at Visit 3 and Visit 4. 
If, during exercise, the patient’s BG is <50 mg/dL, the exercise will be terminated regardless of 
heart beats achieved. 
Chemistry and hematology samples will be collected immediately after end of exercise. 
The patient questionnaires have been removed. 
Accountability for used pre-filled syringes will be made in accordance with the IMP standard 
operating procedures (SOPs). 
The Sponsor, Investigator, or a pertinent regulatory authority may decide to stop the trial or part 
of the trial at any time (e.g., upon completion of Part 1 [iPhone-based BP]), but agreement on 
procedures to be followed must be obtained. 
The schedule of procedures was updated to reflect the changes specified in this document. 
Other minor edits were made throughout the protocol to provide greater clarity and consistency. 
SUMMARY OF CHANGES: 
The amended protocol sections and the details of the changes are summarized in the following 
sections. Revisions to the protocol are presented as strikethrough (ie, subject) for text that was 
removed and bold (ie, subject) for text that was added. 
 
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09 January 2017 
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Section 6.2, Storage and Drug Accountability of IMPs, Page 27 
Original Text: 
All used, partly used, and unused vials or prefilled syringes must be kept by the Investigator 
and stored between +2ºC and +8ºC (unused) or at room temperature (partly used and used). 
Used and unused pre-filled syringes must be stored separately. 
New Text: 
All used, partly used, and unused vials or prefilled syringes must be kept by the Investigator 
and stored between +2ºC and +8ºC (unused) or at room temperature (partly used and used). 
Used and unused Accountability for used pre-filled syringes must will be stored separately 
made in accordance with the IMP standard operating procedures (SOPs). 
Section 7.4.1, Visit Procedures, Page 34 
Original Text: 
 
The control algorithm will be initialized only with the patient’s weight. Diagnostics will be 
performed to ensure that the CGM device is appropriately calibrated and that all of the 
components of the BP systems are in working order. 
 
The basal rate of the patient’s own insulin infusion pump will be changed to be 2-fold higher 
than weighted mean of the basal rate during the trial period. This is intended to increase 
the usage of glucagon during the treatment visit.  
 
The patients will continue to wear their own infusion pump infusing at the temporary 2-fold 
basal rate throughout the visit until the start of the structured exercise period, in addition to 
the BP. 
New Text: 
 
The control algorithm will be initialized only with the patient’s weight. Diagnostics will be 
performed to ensure that the CGM device is appropriately calibrated and that all of the 
components of the BP systems are in working order. 
 
The basal rate of the patient’s own insulin infusion pump will be changed to be 2-fold higher 
than weighted mean of the basal rate during the trial period. This is intended to increase 
the usage of glucagon during the treatment visit. The basal insulin rate may be decreased 
during the treatment visit at the discretion of the Investigator. To the extent possible, 
the same basal rate should be used at Visit 3 and Visit 4. 
 
The patients will continue to wear their own infusion pump infusing at the temporary 2 fold 
basal rate throughout the visit until the start of the structured exercise period, in addition to 
the BP. 
Section 7.4.1, Visit Procedures, Page 35 
Original Text: 
 
At approximately 15 minutes before the meal, patients will administer a bolus for the meal 
with their own insulin pump based on the carbohydrate count for the meal. 
 
After lunch is completed, the patients will not be allowed any carbohydrate intake 
(non-caloric drinks will be permitted) until the trial is completed (except as necessary to 
treat hypoglycemia), to allow the BP to control the post-prandial BG without further 
interruption.  
Zealand Pharma A/S 
Clinical Trial Report ZP4207-16051 
Confidential & Proprietary 
Final Version 1.0, 10 November 2017 
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Summary of Changes, Amendment 7.0, ZP4207-16051 
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09 January 2017 
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New Text: 
 
At approximately 15 minutes before the meal, patients will administer a bolus for the meal 
with their own insulin pump based on the carbohydrate count for the meal in agreement 
with the Investigator. 
 
After lunch is completed, the patients will not be allowed any carbohydrate intake 
(non-caloric drinks will be permitted) until the trial is completed (except as necessary to 
treat hypoglycemia), to allow the BP to control the post-prandial BG without further 
interruption.  
Section 7.4.1, Visit Procedures, Page 35 
Original Text: 
 
Patients will exercise on a stationary bike with a heart rate from 120-140 beats per minute 
for a total of 4,000 heart beats (approximately 30 minutes). Patients will rate their exercise 
intensity using the Borg scale every 5 minutes, with the target intensity level between 
12 and 14. Heart rate will be measured every 5 minutes. 
 
BG measurements will be obtained off of the IV line every 10 minutes. If BG is <80 mg/dL, 
BG measurements will be obtained off of the IV line every 5 minutes. 
o Carbohydrates will be given for any BG <50 mg/dL according to the following 
protocol: Dextrose (g) = BSA (m2)/[1.7 m2 (women) or 1.9 m2 (men)] *15 g. 
o Repeat treatments will be given at 15-minute intervals as long as BG remains 
<50 mg/dL.  
New Text: 
 
Patients will exercise on a stationary bike with a heart rate from 120-140 beats per minute 
for a total of 4,000 heart beats (approximately 30 minutes). Patients will rate their exercise 
intensity using the Borg scale every 5 minutes, with the target intensity level between 
12 and 14. Heart rate will be measured every 5 minutes. 
 
Chemistry and hematology samples will be collected immediately after end of 
exercise (see Appendix B). 
 
BG measurements will be obtained off of the IV line every 10 minutes. If BG is <80 mg/dL, 
BG measurements will be obtained off of the IV line every 5 minutes. 
o If BG is <50 mg/dL, the exercise will be terminated regardless of heart 
beats achieved. 
o Carbohydrates will be given for any BG <50 mg/dL according to the following 
protocol: Dextrose (g) = BSA (m2)/[1.7 m2 (women) or 1.9 m2 (men)] *15 g. 
o Repeat treatments will be given at 15-minute intervals as long as BG remains 
<50 mg/dL.  
Section 7.4.1, Visit Procedures, Page 36 
Original Text: 
 
Patients will answer questionnaires (see Appendix C). 
 
Chemistry and hematology samples will be collected at visit end (see Appendix B). 
 
The BP and glucose meters will be collected and downloaded. 
Zealand Pharma A/S 
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09 January 2017 
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New Text: 
 
Patients will answer questionnaires (see Appendix C). 
 
Chemistry and hematology samples will be collected at visit end (see Appendix B). 
 
The BP and glucose meters will be collected and downloaded. 
Section 7.4.2, Data Collected During the Treatment Visits, Page 36 
Original Text: 
 
Timing and amount of carbohydrates taken for hypoglycemia 
 
Data from a questionnaire about attitudes and expectations regarding the BP before and 
after each treatment arm (see Appendix C) 
 
Time patients were not under BP control for any reason 
New Text: 
 
Timing and amount of carbohydrates taken for hypoglycemia 
 
Data from a questionnaire about attitudes and expectations regarding the BP before and 
after each treatment arm (see Appendix C) 
 
Time patients were not under BP control for any reason 
Section 7.4.2, Data Collected During the Treatment Visits, Page 37 
Original Text: 
 
Concomitant medications 
 
Chemistry and hematology samples (see Appendix B) at visit start and visit end 
 
ADA (Visit 3 only) 
New Text: 
 
Concomitant medications 
 
Chemistry and hematology samples (see Appendix B) at visit start and visit immediately 
after end of exercise 
 
ADA (Visit 3 only) 
Section 12.3, Data Entry, Page 50 
Original Text: 
Data must be recorded using the electronic data capture (EDC) system as the trial is in 
progress. The patient questionnaires will be transcribed into the EDC system by site personnel. 
All site personnel must log into the system using their secure user name and password in order 
to enter, review, or correct trial data. These procedures must comply with Title 21 of the Code 
of Federal Regulations (21 CFR Part 11) and other appropriate international regulations. All 
passwords will be strictly confidential. 
Zealand Pharma A/S 
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Confidential & Proprietary 
Final Version 1.0, 10 November 2017 
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Summary of Changes, Amendment 7.0, ZP4207-16051 
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09 January 2017 
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New Text: 
Data must be recorded using the electronic data capture (EDC) system as the trial is in 
progress. The patient questionnaires will be transcribed into the EDC system by site personnel. 
All site personnel must log into the system using their secure user name and password in order 
to enter, review, or correct trial data. These procedures must comply with Title 21 of the Code 
of Federal Regulations (21 CFR Part 11) and other appropriate international regulations. All 
passwords will be strictly confidential. 
Section 13.9, Sponsor Discontinuation Criteria, Page 54 
Original Text: 
The Sponsor, Investigator, or a pertinent regulatory authority may decide to stop the trial or part 
of the trial at any time but agreement on procedures to be followed must be obtained. 
New Text: 
The Sponsor, Investigator, or a pertinent regulatory authority may decide to stop the trial or part 
of the trial at any time (e.g., upon completion of Part 1 [iPhone-based BP]), but agreement 
on procedures to be followed must be obtained. 
Appendix A, Schedule of Procedures, Footnote 10, Page 60 
Original Text: 
10. 
At visit start and visit end  
New Text: 
10. 
At visit start and visit immediately after end of exercise 
 
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Clinical Trial Protocol 
ZP4207-16051 
Version number: 8.0 
Amendment 7.0 
Date: 06 January 2017 
Zealand Pharma A/S 
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Page 1 of 61 
CLINICAL TRIAL PROTOCOL 
The Bionic Pancreas Feasibility Trial Testing the Bionic Pancreas with ZP4207 
Investigational Product: ZP4207 
Protocol Number: ZP4207-16051 
IND Number: 129980 
Phase: 2  
Principal Investigator: 
Steven J. Russell, MD, PhD1 
Co-Investigator: 
 RN, CDE1 
1Diabetes Research Center, Massachusetts General Hospital, Boston, Massachusetts 
Sponsor: 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Tel: +45 88 77 36 00 
Fax: +45 88 77 38 98 
Original Version: 03 May 2016 
Amendment Number 1.0: 28 June 2016 
Amendment Number 2.0: 03 August 2016 
Amendment Number 3.0: 17 August 2016 
Amendment Number 4.0: 02 September 2016 
Amendment Number 5.0: 09 September 2016 
Amendment Number 6.0: 28 September 2016 
Amendment Number: 7.0 
Protocol Version Number: 8.0 
Date: 06 January 2017 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Zealand Pharma A/S except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical trial for Zealand Pharma A/S. 
You are allowed to disclose the contents of this document only to your Institutional Review 
Board (IRB) and trial personnel directly involved with conducting this protocol. Persons to 
whom the information is disclosed must be informed that the information is confidential and 
proprietary to Zealand Pharma A/S and that it may not be further disclosed to third parties. 
Zealand Pharma A/S 
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Confidential & Proprietary 
Final Version 1.0, 10 November 2017 
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Clinical Trial Protocol
ZP4207-16051
Version number: 8.0
Amendment 7.0
Date: 06 January 2017
Zealand Pharma A/S
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INVESTIGATOR AGREEMENT
By signing below I agree that:
I have read this protocol. I approve this document and I agree that it contains all necessary 
details for carrying out the trial as described. I will conduct this trial in accordance with the 
design and specific provision of this protocol and will make a reasonable effort to complete 
the trial within the time designated. I will provide copies of this protocol and access to all 
information furnished by Zealand Pharma A/S to trial personnel under my supervision. I will 
discuss this material with them to ensure they are fully informed about the trial product and 
trial procedures. I will let them know that this information is confidential and proprietary to 
Zealand Pharma A/S and that it may not be further disclosed to third parties. I understand 
that the trial may be terminated or enrollment suspended at any time by Zealand Pharma 
A/S, with or without cause, or by me if it becomes necessary to protect the best interests of 
the trial patients.
I agree to conduct this trial in full accordance with Food and Drug Administration 
Regulations, Institutional Review Board/Ethic Committee Regulations, and ICH Guidelines 
for Good Clinical Practices.
_____
__
____________________
Investigator’s Signature
Date
______________________________________________
Investigator’s Printed Name
Steven J. Russell, MD, PhD
January 9, 2017
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Clinical Trial Protocol 
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Date: 06 January 2017 
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SYNOPSIS 
TITLE: The Bionic Pancreas Feasibility Trial Testing the Bionic Pancreas with ZP4207 
PROTOCOL NUMBER: ZP4207-16051 
INVESTIGATIONAL PRODUCT: ZP4207 
PHASE: 2 
INDICATION: ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid 
formulation which is being studied to improve glycemic control in adults (and children) with 
type 1 diabetes mellitus (T1DM) as part of a bihormonal bionic pancreas (BP). 
OBJECTIVES: 
Primary: The primary objective is to conduct a trial testing the safety and tolerability of the BP 
using either the iLet or the iPhone platform when used with ZP4207 in 20 adult (≥18 years of 
age) patients with T1DM. 
Secondary: The secondary objectives are to measure glycemic regulation, including 
hypoglycemia exposure (percent of time spent with continuous glucose monitor [CGM] 
glucose <60 mg/dL), evaluate BP device reliability, and to document the satisfaction of 
patients with the BP with the goal of optimizing the functionality and user interface of the BP. 
POPULATION: Up to 40 adult (≥18 years of age) patients who already manage their T1DM 
using continuous subcutaneous (SC) insulin infusion pump therapy can be enrolled. It is 
expected that up to 10 patients will complete each part of the trial protocol. 
TRIAL DESIGN: This trial is a single-center, open-label, 2-part, randomized cross-over trial. 
The trial will enroll adult patients with T1DM and will assess the safety and efficacy of the BP 
using either the iLet or the iPhone platform using the glucagon analog ZP4207 versus Lilly 
glucagon. In Part 1, up to 10 patients will participate in two 1-day treatment arms in random 
order (iPhone-based BP using ZP4207 and iPhone-based BP using Lilly glucagon) according 
to a pre-generated randomization scheme. In Part 2, up to 10 new patients will participate in 
two 1-day treatment arms in random order (iLet using ZP4207 and iLet using Lilly glucagon) 
according to a pre-generated randomization scheme. Patients can only participate in 1 part of 
the trial. An interim database lock may occur upon completion of Part 1 of the trial to analyze 
the iPhone-based BP data. The iLet and the iPhone-based BP will also administer insulin 
(insulin lispro, Lilly Humalog) using the same blood glucose (BG) control algorithm for all 
4 treatment arms. The trial will be conducted at a single center, the Massachusetts General 
Hospital Diabetes Center in Boston, MA. 
TRIAL TREATMENT: The trial involves SC administration of insulin lispro (Humalog, Lilly), 
which is commercially available by prescription and is indicated for patients with T1DM, but 
not for use in a BP. 
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Clinical Trial Protocol 
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The trial also involves SC administration of Lilly glucagon in 1 iLet arm and 1 iPhone-based 
BP arm. Lilly glucagon is commercially available by prescription and is indicated for patients 
with T1DM in severe hypoglycemia, but not for use in a BP. 
The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, in the 
other iLet arm and the other iPhone-based BP arm. ZP4207 will be made available by Zealand 
Pharma A/S, Denmark as liquid formulation in prefilled syringes of 0.6 mL. 
PRIMARY ENDPOINT: The primary endpoint is the safety and tolerability of ZP4207 in the 
BP using either the iLet or the iPhone platform as assessed by: 
•
Number and type of adverse events (AEs)
•
Clinical laboratory measurements
•
Vital signs
•
12-lead electrocardiogram (ECG)
•
Local tolerability and infusion site reactions as measured with the Draize scale
•
Immunogenicity as measured by anti-drug antibodies
•
Pain as measured on a 10 cm visual analog scale (VAS)
•
Nausea as measured on a 10 cm VAS
SECONDARY ENDPOINTS: The secondary endpoints include measurements of BP function 
as well as glycemic and non-glycemic measurements. 
Bionic Pancreas Function 
This endpoint data will be generated from the BP data during each treatment visit: 
•
Average percent insulin dose amounts calculated by the BP control algorithm that are
successfully delivered by the pump
•
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully delivered by the pump
•
Average percent dose amounts successfully issued to the pump by the BP control
algorithm that are successfully delivered by the pump (calculated doses are not issued
unless the pump is accessible and its delivery channel is available)
o
Average percent insulin dose amounts successfully issued to the pump by the
BP control algorithm that are successfully delivered by the pump
o
Average percent glucagon/ZP4207 dose amounts successfully issued to the
pump by the BP control algorithm that are successfully delivered by the pump
•
Average percent dose amounts calculated by the BP algorithm that are successfully
issued to the pump by the BP (calculated doses are not issued unless the pump is
accessible and its delivery channel is available)
o
Average percent insulin dose amounts calculated by the BP control algorithm
that are successfully issued by the BP
o
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully issued by the BP
•
Average percent of 5-minute steps during which the BP is functioning nominally in all
respects based on real-time CGM data (new CGM glucose reading captured, dose
calculated, and dose issued to pumps)
Zealand Pharma A/S 
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• 
Average percent of 5-minute steps during which the BP is functioning nominally with 
or without a new CGM glucose reading captured (dose calculated and dose issued to 
pumps). If a CGM signal is not available, the dose calculated may be based on weight 
or historical basal rates. 
• 
CGM reliability index, calculated as percent of possible values actually recorded by 
CGM 
• 
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter 
download 
• 
List of technical faults associated with the BP including cause and resolution 
 
Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit: 
• 
Fraction of time spent within each of the following glucose ranges: 
o <50 mg/dL 
o <60 mg/dL 
o <70 mg/dL 
o 70-120 mg/dL 
o 70-140 mg/dL 
o 70-180 mg/dL  
o >180 mg/dL 
o >250 mg/dL 
o >300 mg/dL 
• 
Number of severe hypoglycemic events (patients unable to self-treat, requiring the 
assistance of another person) 
• 
Number of episodes of symptomatic hypoglycemia 
• 
Number of carbohydrate interventions for hypoglycemia 
• 
Total grams of carbohydrates taken for hypoglycemia 
• 
Mean CGM glucose 
 
Non-glycemic 
• 
Glucagon/ZP4207 total delivery per kg of body mass 
• 
Insulin total delivery per kg of body mass 
• 
Number of unscheduled infusion set replacements 
• 
Number of unscheduled CGM sensor changes 
 
EVALUATION OF TRIAL DATA: The following variables will be evaluated according to 
treatment for safety purposes: AEs, local tolerability, laboratory safety assessments, physical 
examination, vital signs, and 12-lead ECGs.  
 
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
 
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
 
Zealand Pharma A/S 
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Clinical Trial Protocol 
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A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow. 
SPONSOR: 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Tel: +45 88 77 36 00 
Fax: +45 88 77 38 98 
Zealand Pharma A/S 
Clinical Trial Report ZP4207-16051 
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Clinical Trial Protocol 
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Amendment 7.0 
Date: 06 January 2017 
 
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TABLE OF CONTENTS  
SIGNATURE PAGE ............................................................................................................. 2 
INVESTIGATOR AGREEMENT .......................................................................................... 3 
SYNOPSIS ........................................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................... 8 
LIST OF FIGURES ............................................................................................................ 11 
LIST OF ABBREVIATIONS .............................................................................................. 12 
1 
INTRODUCTION AND BACKGROUND INFORMATION ...................................... 14 
1.1 
Background and Rationale ..................................................................................... 14 
1.2 
Bihormonal Bionic Pancreas System ..................................................................... 15 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System ........................ 16 
1.4 
ZP4207 ................................................................................................................... 18 
1.5 
Risk/Benefit ............................................................................................................ 19 
2 
TRIAL OBJECTIVES .............................................................................................. 22 
2.1 
Primary Objective ................................................................................................... 22 
2.2 
Secondary Objectives ............................................................................................. 22 
3 
TRIAL DESCRIPTION ............................................................................................ 22 
3.1 
Summary of Trial Design ........................................................................................ 22 
3.2 
Indication ................................................................................................................ 23 
3.3 
Number of Patients ................................................................................................. 23 
4 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................ 23 
4.1 
Inclusion Criteria ..................................................................................................... 24 
4.2 
Exclusion Criteria .................................................................................................... 24 
4.3 
Target Population ................................................................................................... 26 
4.4 
Withdrawal Criteria ................................................................................................. 26 
5 
ASSIGNMENT TO TREATMENT GROUPS........................................................... 26 
6 
TRIAL TREATMENT .............................................................................................. 27 
6.1 
Investigational Medicinal Products ......................................................................... 27 
6.2 
Storage and Drug Accountability of IMPs ............................................................... 27 
6.3 
Dispensing and Return of IMPs .............................................................................. 27 
6.4 
Doses ..................................................................................................................... 28 
6.5 
iPhone-based Bionic Pancreas .............................................................................. 28 
6.6 
iLet Bionic Pancreas ............................................................................................... 29 
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6.7 
Other Trial Devices ................................................................................................. 30 
6.8 
Concomitant Medications ....................................................................................... 30 
6.8.1 
Permitted Medications and/or Procedures ...................................................... 30 
6.8.2 
Excluded Medications and/or Procedures ....................................................... 31 
7 
TRIAL PROCEDURES ........................................................................................... 31 
7.1 
Informed Consent ................................................................................................... 31 
7.2 
Screening Visit (Visit 1) .......................................................................................... 31 
7.2.1 
Data Collected at Screening ............................................................................ 32 
7.3 
Training Visit (Visit 2) .............................................................................................. 32 
7.4 
Treatment Visits (Visit 3 and Visit 4) ....................................................................... 33 
7.4.1 
Visit Procedures .............................................................................................. 33 
7.4.2 
Data Collected During the Treatment Visits .................................................... 36 
7.4.3 
Response to Hypoglycemia ............................................................................. 37 
7.4.4 
Response to Hyperglycemia ........................................................................... 38 
7.4.5 
Response to Nausea/Vomiting ........................................................................ 38 
7.4.6 
Response to Other Medical Needs ................................................................. 38 
7.4.7 
Monitoring of Bionic Pancreas Performance ................................................... 38 
7.4.8 
Supervision by Trial Staff ................................................................................ 38 
7.5 
Anti-drug Antibodies Assessment Visit (Visit 5) ...................................................... 38 
7.6 
Follow-up Visit (Visit 6) ........................................................................................... 38 
8 
ENDPOINTS ........................................................................................................... 39 
8.1 
Primary Endpoint .................................................................................................... 39 
8.2 
Secondary Endpoints ............................................................................................. 39 
8.2.1 
Bionic Pancreas Function ................................................................................ 39 
8.2.2 
Glycemic .......................................................................................................... 40 
8.2.3 
Non-glycemic ................................................................................................... 40 
9 
LABORATORY ASSESSMENTS ........................................................................... 40 
9.1 
Safety Laboratory Assessments ............................................................................. 40 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) .............................................. 40 
9.3 
Exposure Assessments (ZP4207 and Glucagon) ................................................... 41 
9.4 
Anti-drug Antibodies Assessments ......................................................................... 41 
10 
SAFETY REPORTING ............................................................................................ 41 
10.1 
Adverse Events ...................................................................................................... 41 
10.1.1 
Follow-up of Adverse Events ........................................................................... 42 
10.1.2 
Precautions ..................................................................................................... 42 
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10.1.3 
Assessment of Adverse Events by the Investigator ........................................ 42 
10.2 
Serious Adverse Events ......................................................................................... 43 
10.3 
Adverse Event Reporting – Procedures for Investigators ....................................... 44 
10.4 
Pregnancy Reporting .............................................................................................. 46 
10.5 
Hypoglycemia ......................................................................................................... 46 
10.6 
Safety Monitoring .................................................................................................... 47 
10.6.1 
Data and Safety Monitoring Board .................................................................. 47 
10.6.2 
Zealand Pharma Safety Committee ................................................................ 47 
11 
STATISTICS ........................................................................................................... 47 
11.1 
Analysis Populations .............................................................................................. 47 
11.2 
Statistical Methods ................................................................................................. 48 
11.2.1 
Analysis of Safety ............................................................................................ 48 
11.2.2 
Analysis of Efficacy ......................................................................................... 49 
11.2.3 
Interim Analysis ............................................................................................... 49 
11.2.4 
Sample Size Determination ............................................................................. 49 
12 
DATA MANAGEMENT AND RECORD KEEPING ................................................ 50 
12.1 
Data Handling ......................................................................................................... 50 
12.2 
Computer Systems ................................................................................................. 50 
12.3 
Data Entry ............................................................................................................... 50 
12.4 
Medical Information Coding .................................................................................... 50 
12.5 
Data Validation ....................................................................................................... 50 
12.6 
Record Keeping ...................................................................................................... 51 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ........................... 51 
13.1 
Ethical Conduct of the Trial .................................................................................... 51 
13.2 
Institutional Review Board ...................................................................................... 51 
13.3 
Informed Consent ................................................................................................... 51 
13.4 
Trial Monitoring Requirements ............................................................................... 52 
13.5 
Disclosure of Data .................................................................................................. 53 
13.6 
Retention of Records .............................................................................................. 53 
13.7 
Publication Policy ................................................................................................... 53 
13.8 
Legal Aspects ......................................................................................................... 54 
13.9 
Sponsor Discontinuation Criteria ............................................................................ 54 
13.10 
Patient Compensation ......................................................................................... 54 
14 
TRIAL ADMINISTRATIVE INFORMATION ............................................................ 55 
14.1 
Protocol Amendments ............................................................................................ 55 
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14.2 
Address List ............................................................................................................ 55 
14.2.1 
Sponsor ........................................................................................................... 55 
14.2.2 
Supplier of Device ........................................................................................... 55 
14.2.3 
Principal Investigator (Site) ............................................................................. 55 
14.2.4 
Contract Research Organization (Including Monitoring) ................................. 56 
14.2.5 
Medical Monitoring .......................................................................................... 56 
14.2.6 
Pharmacovigilance .......................................................................................... 56 
14.2.7 
Central Laboratory (Safety Laboratory and Plasma Glucose) ......................... 56 
14.2.8 
Special Laboratory (ZP4207 Exposure and ADA Analyses) ........................... 56 
14.2.9 
Special Laboratory (Glucagon Exposure) ....................................................... 57 
15 
REFERENCES ........................................................................................................ 58 
APPENDIX A: SCHEDULE OF PROCEDURES – PARTS 1 AND 2 ................................ 59 
APPENDIX B: CLINICAL LABORATORY ANALYTES ................................................... 61 
LIST OF FIGURES 
Figure 1. 
Outpatient Results Summarizing the Distribution of Mean CGM Glucose 
Levels and Hypoglycemia in the BP and Control Arms ............................. 17 
Figure 2. 
Trial Design Schematic ................................................................................. 23 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
BG 
Blood glucose 
BP 
Bionic pancreas 
BTLE 
Bluetooth Low Energy 
BU 
Boston University 
CFR 
Code of Federal Regulations 
CGM 
Continuous glucose monitor 
CRO 
Contract research organization 
DBP 
Diastolic blood pressure 
DBR 
Database review 
DPP-4 
Dipeptidyl peptidase-4 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FHD 
First Human Dose 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GUI 
Graphical user interface 
HCG 
Human chorionic gonadotropin 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IV 
Intravenous 
MD 
Doctor of Medicine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH 
Massachusetts General Hospital 
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Abbreviation 
Definition 
MPC 
Model-predictive control 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
RN 
Registered nurse 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SGLT-2 
Sodium-glucose co-transporter-2 
SIV 
Site Initiation Visit 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 diabetes mellitus 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background and Rationale 
To date, clinical trials conducted by Boston University (BU) and Massachusetts General 
Hospital (MGH) in patients with type 1 diabetes mellitus (T1DM) have demonstrated the 
practicality of a wearable automated bionic pancreas (BP) control system for robust glucose 
regulation using a continuous glucose monitor (CGM) to provide the input to the control 
system. Despite current technical limitations in CGMs and infusion pumps, the trials by 
BU/MGH have shown that a bihormonal BP is capable of achieving safe and effective blood 
glucose (BG) control automatically, with minimal hypoglycemia during 11 continuous days in 
the face of unrestrained meals and exercise and with trivial patient input (optional 
announcement of meals).  
The BP provides automatic BG regulation and reduces hypoglycemic episodes. Additionally, 
the system spares the wearer the relentless tasks of carbohydrate counting, frequent BG 
monitoring, estimating the effects of specific meals and exercise activity on BG levels, and 
manual drug administration, which are inexact, demanding, aggravating, and require 
continuous diligence and vigilance. The degree of glycemic control achieved by the BP is 
predicted to dramatically reduce the deleterious and debilitating complications of T1DM. 
In its last tested embodiment, the BP consisted of a Dexcom G4 CGM, and an iPhone that are 
hardwired together, with the iPhone running the control algorithm and communicating via 
Bluetooth with 2 Tandem t:slim pumps to dose insulin and glucagon. The connections are 
repeatedly lost among these 4 components throughout the day, an issue that has the potential 
to adversely impact BG control, whether due to missed CGM values or missed doses. In 
addition, the troubleshooting required to repair these recurring disconnections can be 
burdensome to the user. Integrating these components into a single device would establish 
seamless connectivity among them, which would eliminate the need for such troubleshooting. 
This would lead to smoother device operation with fewer interruptions, which would enhance 
its user friendliness, optimize its BG control potential, and further improve the quality of life of 
its users.  
The BU Investigators have recently designed, built, and tested a proprietary first-generation 
of such a fully integrated BP system, referred to as the iLet and the iLet infusion set. The iLet 
is a dual-chamber infusion system that currently incorporates the Dexcom G4 CGM 
technology, a custom user interface with touchscreen display, and all of the mathematical 
dosing algorithms that were tested in and validated using the iPhone-based BP in outpatient 
studies over the past 3 years. The iLet infusion set provides 2 independent subcutaneous (SC) 
fluid pathways from the iLet to the patient (1 for insulin and the other for glucagon). One tube 
connects to the prefilled insulin cartridge and the other tube connects to the fillable (single-use) 
glucagon cartridge. 
In order to provide automatic BG regulation, the iLet and the iPhone-based BP have the ability 
to deliver both insulin and glucagon. However, currently available glucagon formulations have 
limited stability at room temperature, necessitating frequent changes to the glucagon infusion 
set. Therefore, the current trial is designed to test the glucagon analog ZP4207 in the iLet and 
the iPhone-based BP, as this peptide analog of human glucagon is provided in a liquid 
formulation stable at room temperature. 
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The current trial is a first feasibility trial designed to use the first-generation iLet and iLet 
infusion set and the iPhone-based BP to compare ZP4207 with marketed glucagon (Lilly). The 
trial is intended to demonstrate the safety and tolerability of ZP4207 in the iLet and the 
iPhone-based BP and the feasibility of achieving comparable autonomous glycemic control. It 
is not intended to comprehensively demonstrate the definitive efficacy of the BP in extended, 
continuous daily use, but rather to demonstrate its functionality and accuracy in a practical, 
albeit very controlled, clinical setting. The trial is expected to provide practical information that 
will benefit the design of a next-generation iLet and iLet infusion set and help pave the way for 
a more comprehensive outpatient home-use Phase 2 trial and ultimately a pivotal trial where 
comprehensive safety and efficacy through continuous full daily use of the iLet with ZP4207 
will be documented. 
The data derived from this trial will permit evaluation of the robustness of the iLet as well as 
the safety and efficacy of ZP4207 when used in conjunction with the iLet and the iPhone-based 
BP. The data obtained will be used to further improve the iLet and will allow BU/MGH to 
expand to larger outpatient trials using the iLet or the iPhone-based BP with ZP4207.  
1.2 
Bihormonal Bionic Pancreas System 
The BP is an autonomous, self-learning system that requires only the patient's weight for 
initialization, and then autonomously adapts, modestly or dramatically, as needed, to cope 
with the wide range of insulin requirements of adults, adolescents, and pre-adolescents with 
T1DM. The BP obviates the need for the patient to know, or even appreciate, their insulin 
requirements, and renders obsolete any need for patients or caregivers to know 
carbohydrate-to-insulin ratios, basal rates, or insulin correction factors. 
The core technology is a suite of control algorithms that orchestrate the automated dosing of 
insulin and glucagon to regulate BG levels. An insulin controller orchestrates all SC insulin 
dosing. At its centerpiece is a model-predictive control (MPC) algorithm, which bases insulin 
doses on the glucose data and insulin absorption kinetics, compensating for the slow 
absorption rate of SC insulin analogs (peak time in blood of 30-90 minutes, clearance in 
4-8 hours). This enables the algorithm to refrain from stacking and overdosing insulin. 
Furthermore, the MPC algorithm automatically adjusts its insulin-dosing aggressiveness 
continuously and in real-time to different insulin needs between individuals and variable needs 
within the same individual. Running in parallel with the MPC algorithm is an algorithm that 
automatically modulates basal insulin delivery over multiple time scales, and another algorithm 
that automatically adapts insulin doses in response to optional meal announcements. Unlike 
current insulin pumps and the insulin-only control algorithms, the adaptive basal insulin 
algorithm obviates the need for the user to set, or even know, his or her “basal-rate profile.” 
Instead, it is capable of automatically adapting to, and compensating for, changes in an 
individual's basal insulin need, such as might occur over a period of hours, days, or weeks 
(e.g., circadian hormonal fluctuations, intercurrent illness, physical activity, or emotional state) 
or as might occur over a period of months or years due to developmental changes 
(e.g., hormonal changes that occur during puberty or menopause). The adaptive meal dose 
controller obviates the need for the user to set, or even know, his or her 
“carbohydrate-to-insulin ratios,” as it makes automatic adjustments based on dosing history 
for similar meal announcements made on previous days, and customizes the dose for each 
individual and for time of day.  
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The BP also includes a proportional-derivative algorithm governing SC micro-doses of 
glucagon to help prevent impending hypoglycemia. Glucagon dosing is based on the glucose 
level and rate of descent. It may occur preemptively even if glucose is above range, and it 
includes a feedback term to account for the pending effects of recent glucagon doses.  
Taken together, these mathematical algorithms provide a universal framework for a glycemic 
control strategy that requires no quantitative input from, or participation by, the user (besides 
entering body weight to initialize the system), but which automatically adapts insulin and 
glucagon dosing to meet the individual needs of each user. Another challenge met is enabling 
the technology to remain completely autonomous in managing insulin and glucagon delivery 
even when the CGM is offline. Specifically, when the CGM is offline, the BP invokes the 
high-resolution “basal rate profile” that it had recently learned and stored when the CGM was 
online. On the basis of what the system learned and stored about meal announcements when 
the CGM was online, it is able to respond to meal announcements in the same manner when 
the CGM is offline. Finally, it automatically responds to user-entered BG values when the CGM 
is offline by issuing a correction dose of insulin or glucagon based on what it learned about 
the user's insulin and glucagon needs when the CGM was online. Thus, the BP never relies 
on, or burdens the user with, the determination of subjective dosing decisions, which inevitably 
vary in quality and reliability among different users. The BP provides a turnkey solution for 
people with T1DM that comprehensively manages glycemia across a broad range of individual 
needs and across a large spectrum of circumstances and challenges to glycemic control. 
A significant challenge for the use of glucagon in a bihormonal BP is the lack of a commercially 
available glucagon formation that is stable and well-suited to infusion over several days in a 
pump reservoir. However, BU/MGH have proceeded with studies using a relatively unstable 
marketed formulation that must be reconstituted from a lyophilized powder on a daily basis. 
This allowed BU/MGH to proceed with studies of the bihormonal system while awaiting the 
production of stable glucagon formulations or stable glucagon analogs. 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System 
The BP hardware platform has evolved over the years from a laptop-driven system, which was 
used in all inpatient studies to the first truly mobile wearable iPhone-driven platform, which 
has been used in a number of outpatient studies. Using the iPhone-based BP system, 
>110 outpatient experiments of 5-11 days in duration in each subject have been conducted 
(>800 patient days or >2 patient years of data) across subjects ranging in age between 6 and 
76 years old and in body mass between 21 and 128 kg. The robust adaptation capabilities of 
the BP is evident in the fact that the average total daily dose of insulin among these subjects 
varied by over 13-fold (from 11 to 145 units/day). 
In November 2012, Food and Drug Administration (FDA) approval was obtained to conduct 
the first outpatient study testing the BP in adults 21 years or older with T1DM. This study, 
referred to as the Beacon Hill Study, followed a random-order cross-over design in which 
20 adults with T1DM participated in 5 days on the iPhone-based BP and 5 days of usual care 
in which they wore a CGM with blinded display and muted alarms. In the BP arm, subjects 
kept to a 3-square-mile geographic area centered around the Beacon Hill neighborhood in 
Boston. They ate as they chose at local restaurants, and exercised at will with access to 
2 gyms. Analysis was pre-specified to focus on Days 2-5, since glycemic control is more 
representative of BP performance after most of the adaptation by the BP occurs on Day 1 
(Russell, 2014). Results are summarized in Figure 1.  
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In April 2013, FDA approval was obtained to conduct the first outpatient study testing the BP 
in adolescents 12-20 years old with T1DM. This study, referred to as the 2013 Summer Camp 
Study, followed a random-order cross-over design in which 32 adolescents with T1DM 
participated in 5 days on the BP and 5 days of supervised camp care in which they wore a 
CGM with blinded display and muted alarms. Subjects were fully integrated into normal camp 
activities without restrictions on diet or exercise. The study used the same iPhone-based BP 
that was used in the Beacon Hill Study. Results are summarized in Figure 1 (Russell, 2014). 
In April 2014, FDA approval was obtained to conduct the first outpatient study testing the BP 
in pre-adolescents 6-11 years old with T1DM. This study, referred to as the 2014 Summer 
Camp Study, was similar in design to the 2013 Summer Camp Study. Results are summarized 
in Figure 1 (Russell, 2016).  
In April 2014, FDA approval was obtained to conduct the first multi-center study, which was 
also the first home study, to test the BP in adults 18 years or older with T1DM. This study, 
referred to as the Bionic Pancreas Multi-Center Study, followed a random-order cross-over 
design in which 39 adults participated in 11 days on the BP and 11 days of usual care. 
Participants went to work as usual, and lived and slept at home, all without clinical supervision. 
There were no restrictions placed on diet or exercise. The study included 4 medical centers 
(10 subjects per center), which included MGH, the University of Massachusetts Medical 
School, Stanford University, and the University of North Carolina at Chapel Hill. Results are 
summarized in Figure 1.  
All of these studies used marketed glucagon (glucagon for injection, Eli Lilly). Due to its limited 
stability, Lilly glucagon must be reconstituted immediately before use. Animal studies have 
previously shown that despite its limited chemical stability, Lilly glucagon maintains its 
biological activity for up to 7 days in solution. Using this data, an Investigational New Drug 
(IND) exemption was obtained from the FDA for its use in a pump for up to 27 hours. This 
allowed these studies to be performed by asking volunteers to reconstitute a new vial of 
glucagon and fill the glucagon pump at approximately the same time every day. However, 
marketed Lilly glucagon has no path forward for approval for chronic BP use. 
1.4 
ZP4207 
ZP4207 is a peptide analog of human glucagon that is being developed to treat hypoglycemia 
in patients with T1DM and type 2 diabetes mellitus. ZP4207 exhibits improved physical and 
chemical stability in aqueous media and is suitable for liquid formulation. ZP4207 is comprised 
of 29 amino acids and has 7 amino acid substitutions when compared to native glucagon.  
Two clinical Phase 1 trials have been conducted to establish safety and tolerability of ZP4207 
after single and multiple dosing to healthy patients and T1DM patients under insulin-induced 
hypoglycemic conditions. 
The First Human Dose (FHD) trial (ZP4207-14013) was finalized in April 2015. The trial was 
a randomized, double-blinded trial with the objectives to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of ZP4207 as compared to an active 
comparator. Part 1 included a single ascending dose in healthy volunteers in cohorts of 8. In 
each cohort, the patients were randomized 3:1 to ZP4207 (n=6) or Novo Nordisk GlucaGen® 
(n=2). Five cohorts with SC administration (0.01, 0.1, 0.3, 1.0, and 2.0 mg ZP4207 compared 
to 1 mg GlucaGen) and 3 cohorts with intramuscular (IM) administration (0.3, 1.0, and 2.0 mg 
ZP4207 compared to 1 mg GlucaGen) were included. Part 2 included 2 sequence groups of 
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10 hypoglycemic T1DM patients. The patients were treated with fixed single IM doses of 
0.7 mg ZP4207 and 1.0 mg GlucaGen in a sequential cross-over design in a randomized 
treatment order.  
 
The second clinical trial (ZP4207-15007) was a single-center, double-blind, Phase 1b trial 
investigating the safety and tolerability, PK and PD of ZP4207 following repeated 
administration in healthy volunteers compared to placebo. It was finalized in July 2015. Each 
of the 3 cohorts comprised 8 subjects, who received 5 repeated SC doses of ZP4207 or 
placebo in a 3:1 treatment allocation. The first cohort started with the lowest dose of 0.1 mg. 
Cohort 2 and 3 continued with 0.3 and 1.0 mg, respectively. 
 
The Phase 1 results did not give rise to specific safety concerns, beyond those related to the 
pharmacological effect of ZP4207. All adverse events (AEs) recorded in the trials were of mild 
or moderate severity. The most frequent systemic AE related to treatment with ZP4207 was 
nausea, which is a known side-effect following administration of glucagon. The most frequent 
injection site reaction was transient erythema, occurring in all ZP4207, glucagon, and placebo 
treatment groups, irrespective of dose. No anti-drug antibodies (ADA) incidences were 
observed. 
 
The observed PD response, in terms of increased plasma glucose, in insulin-induced 
hypoglycemic patients with T1DM following dosing with 0.7 mg ZP4207 administered IM was 
similar to that observed following IM dosing with 1.0 mg glucagon (GlucaGen, Novo Nordisk). 
An increase in plasma glucose of ≥20 mg/dL from hypoglycemic levels was achieved within 
30 minutes for all patients. 
 
In terms of PK, ZP4207 had a short half-life and high clearance and dose proportionality for 
both maximum plasma concentration and area under the concentration-time curve from 
time 0 to 300 minutes in the dose range 0.1 to 2.0 mg following SC administration. Following 
IM administration, dose proportionality was shown in the investigated dose range of 0.3 to 
2.0 mg. The PK properties of 0.7 mg ZP4207 IM were comparable with those of 1.0 mg 
glucagon (GlucaGen, Novo Nordisk) with IM administration. 
 
1.5 
Risk/Benefit   
While the potential risks are minimal, the findings of this trial may reveal information that can 
substantially improve medical care for persons with diabetes. Therefore, the overall 
risk/benefit for patients participating in this trial is assessed as acceptable. 
 
Potential Risks and Discomforts  
 
Trial patients will be informed by the Investigator of the potential risks of ZP4207 and other 
trial-related procedures before they enter the trial.  
 
In this trial, patients with T1DM will be included to test the safety and efficacy of the BP using 
either the iLet or the iPhone platform when used with ZP4207 versus Lilly glucagon. The 
cross-over design with inclusion of 1 group of 10 T1DM patients into the 2 iLet treatment arms 
and the inclusion of a second group of 10 T1DM patients into the 2 iPhone-based BP treatment 
arms in a randomized order will allow for a direct comparison of the safety and efficacy of the 
2 treatments, based on intra-patient variability only.  
  
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Patients may experience mild discomfort associated with the insertion of the infusion sets and 
sensor into the SC tissues. The risk of discomfort due to insertion of infusion sets and sensors 
is expected to be slightly greater than in their lives outside the trial because more infusion sets 
will be inserted and a CGM sensor will be inserted. Most patients will use only 1 infusion set 
and not all will use a CGM sensor in usual care.  
There is a potential risk of hypoglycemia, since recombinant insulin analog will be 
administered. Due to frequent monitoring of glucose and direct supervision by a registered 
nurse (RN) or Doctor of Medicine (MD) at all times, the risk of a hypoglycemic episodes leading 
to significant harm to patients is expected to be substantially lower than their risk during their 
usual therapy.  
There is a risk of hyperglycemia. This risk is expected to be less than the risk during the 
patients’ lives outside of the trial based on data from earlier BP trials and the design of this 
trial.  
Treatment with ZP4207 and marketed glucagon can result in undesired effects or complaints. 
Undesired effects and complaints such as gastrointestinal side effects including nausea, 
vomiting, and diarrhea are known side effects of glucagon administration at higher dose levels. 
The frequency of nausea associated with the administration of 1 mg of glucagon according to 
the Summary of Product Characteristics (SPC) for Glucagon is described to be between 1/10 
and 1/100. The frequency of vomiting is described to be between 1/100 and 1/1000 
(Novo Nordisk, 2015). Similar gastrointestinal side effects have also been observed to a 
limited degree in the 2 clinical trials conducted with ZP4207, again at higher dose levels. The 
individual doses of ZP4207 and Lilly glucagon delivered by the BP are expected to be 
significantly lower than doses typically associated with nausea. Episodes of low blood 
pressure have also been observed after administration of higher doses of glucagon and 
ZP4207. As with every novel drug substance, new and yet unknown side effects may also 
occur. 
There are limited data available to describe the immunogenic potential of glucagon products 
available on the market, but the data available indicate that marketed glucagon only has a 
small immunogenic potential. A Phase 1 trial performed with recombinant human glucagon 
and animal derived glucagon in 75 healthy patients did not show signs of ADA measured 
13 weeks after trial product administration (Eli Lilly, 2005). In the ZP4207 FHD trial, 
ZP4207-14013, no confirmed anti-ZP4207 or anti-glucagon antibodies were detected in any 
of the samples. In addition, the 5 sequential administrations of ZP4207, as applied in trial 
ZP4207-15007, were not associated with the development of antibodies against ZP4207 in 
the 18 subjects enrolled to receive ZP4207. The optimized formulation of ZP4207, as applied 
in the present trial is not expected to change the immunogenic potential of the Investigational 
Medicinal Product (IMP).  
In relation to diabetes therapy, development of insulin-antibodies is documented more 
substantially and route of administration has been shown to influence immunogenic potential 
of insulins. However, these antibodies against insulin generally do not have an impact on 
insulin action and are thus not clinically relevant. 
In terms of consequence, development of high titer antibodies against ZP4207 could, in theory 
reduce the activity of endogenous glucagon, which again, in theory could influence 
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hypoglycemic episodes. However, most patients with T1DM do not secrete glucagon normally 
in response to hypoglycemia, so they would be less likely to be negatively impacted by 
anti-glucagon antibodies. Limited suppression of glucagon would, however, not be considered 
critical, as low glucose levels can also be corrected by other means, including oral intake of 
glucose and by other endogenous hormones such as oxyntomodulin.  
Overall, ZP4207 is judged to be a low-risk molecule, based upon the available clinical data as 
well as the outcome of the risk-based approach to the immunogenicity assessment made. The 
present trial will include sampling for measurement of antibodies against ZP4207 prior to first 
dosing (Visit 3), at the ADA Assessment Visit (Visit 5), and at the Follow-up Visit (Visit 6). In 
line with regulatory guidance documents, these samples will be appropriately analyzed and 
the results will be included in the overall assessment of the immunogenic potential of ZP4207 
after completion of each trial and as the clinical development program advances. 
Administration of ZP4207 may be associated with a risk of allergic reactions similar to those 
observed for other therapeutic peptides or proteins. Patients with known or suspected allergies 
to the trial products or related products will be excluded from the trial. Mild or moderate allergic 
reactions may include symptoms of rash, fever, flu-like symptoms, nausea, headache, and 
myalgia. Acute generalized hypersensitivity reactions are usually very rare but may include 
symptoms of flushing, sweating, dizziness, change in blood pressure, and difficulties in 
breathing. The risk of acute hypersensitivity reactions is described to be less than 1/10,000 
for native glucagon. No severe acute hypersensitivity reactions have been observed in the 
2 clinical trials conducted with ZP4207.  
Potential Benefits 
Based on experiences from previous trials of the BP and the design of this trial, patients 
enrolled in the trial may benefit from a reduction in risk of hypoglycemia and hyperglycemia 
and a better mean glucose compared to their usual diabetes care during their short trial 
participation.  
The data derived from this trial will allow evaluation of safety and tolerability of ZP4207 in the 
iLet and the iPhone-based BP, and the robustness and effectiveness of the new BP control 
system. The data obtained will be used to further improve the iLet and will allow the expansion 
to larger outpatient trials using the iLet or the iPhone-based BP with ZP4207.  
This trial is a necessary step in preparing the BP with ZP4207 to become available to people 
with T1DM. Wide availability of the BP with ZP4207 could improve the medical care of adults 
and children with T1DM. 
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2 
TRIAL OBJECTIVES  
2.1 
Primary Objective 
The primary objective is to conduct a trial testing the safety and tolerability of the BP using 
either the iLet or the iPhone platform when used with ZP4207 in 20 adult (≥18 years of age) 
patients with T1DM. 
2.2 
Secondary Objectives 
The secondary objectives are to measure glycemic regulation, including hypoglycemia 
exposure (percent of time spent with CGM glucose <60 mg/dL), evaluate BP device reliability, 
and to document the satisfaction of patients with the BP with the goal of optimizing the 
functionality and user interface of the BP. 
3 
TRIAL DESCRIPTION 
3.1 
Summary of Trial Design 
This trial is a single-center, open-label, 2-part, randomized cross-over trial. The trial will enroll 
adult patients with T1DM and will assess the safety and efficacy of the BP using either the iLet 
or the iPhone platform using the glucagon analog ZP4207 versus Lilly glucagon. In Part 1, up 
to 10 patients will participate in two 1-day treatment arms in random order (iPhone-based BP 
using ZP4207 and iPhone-based BP using Lilly glucagon) according to a pre-generated 
randomization scheme. In Part 2, up to 10 new patients will participate in two 1-day treatment 
arms in random order (iLet using ZP4207 and iLet using Lilly glucagon) according to a 
pre-generated randomization scheme. Patients can only participate in 1 part of the trial. An 
interim database lock may occur upon completion of Part 1 of the trial to analyze the 
iPhone-based BP data. The iLet and the iPhone-based BP will also administer insulin (insulin 
lispro, Lilly Humalog) using the same BG control algorithm for all 4 treatment arms. The trial 
will be conducted at a single center, the MGH Diabetes Center in Boston, MA. 
The overall trial design schematic is displayed in Figure 2. 
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Figure 2. 
Trial Design Schematic 
Part 1: 
Part 2: 
Patients can only participate in 1 part of the trial. 
ADA = anti-drug antibodies; BP = bionic pancreas. 
3.2 
Indication 
ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid formulation which 
is being studied to improve glycemic control in adults (and children) with T1DM as part of a 
bihormonal BP. 
3.3 
Number of Patients 
Up to 40 adult patients with T1DM can be enrolled. The upper bound is based on the 
expectation that some patients will be excluded after the Screening Visit and the possibility 
that some patients may have to be discontinued before completion (due to, for instance, 
inter-current illness or patient withdrawal). It is expected that up to 10 patients will complete 
each part of the trial protocol. 
4 
SELECTION AND WITHDRAWAL OF PATIENTS 
The trial will enroll patients who already manage their T1DM using continuous SC insulin 
infusion pump therapy. This requirement is imposed because multiple daily injection therapy 
involves the use of medium-acting or long-acting basal insulin that would require an extended 
washout period. 
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4.1 
Inclusion Criteria 
1.
Male and female patients with T1DM for at least 1 year, as defined by the American
Diabetes Association
2.
Age ≥18 years
3.
Diabetes managed using an insulin pump for ≥6 months
4.
Prescription medication regimen stable for >1 month (except for medications that will
not affect the safety of the trial and are not expected to affect any outcome of the trial,
in the judgment of the Investigator)
5.
Informed consent obtained before any trial-related activities (trial-related activities are
any procedure that would not have been performed during normal management of the
patient)
6.
Patients in good health according to age (medical history, physical examination, vital
signs, 12-lead electrocardiograms [ECGs], laboratory assessments), as judged by the
Investigator
4.2 
Exclusion Criteria  
1.
Unable to provide informed consent (e.g., impaired cognition or judgment)
2.
Unable to safely comply with trial procedures and reporting requirements
(e.g., impairment of vision or dexterity that prevents safe operation of the BP, impaired
memory, unable to speak and read English)
3.
Participation in another clinical trial of an investigational agent or device concurrently
or within 1 month (or 5 half-lives) prior to the Screening Visit
4.
Previous exposure to ZP4207
5.
Females of childbearing potential who are pregnant (positive urine human chorionic
gonadotropin [HCG]), breast feeding, plan to become pregnant in the immediate future,
or sexually active without using highly effective contraception methods (highly effective
methods are considered those with a failure rate less than 1% undesired pregnancies
per year including surgical sterilization, hormonal intrauterine devices [coil], oral
hormonal contraceptives, sexual abstinence, or a surgically sterilized partner) or
postmenopausal 
women 
amenorrheic 
for 
less 
than 
1 year 
with 
serum
follicle-stimulating hormone (FSH) level ≤40 IU/L and not using highly effective
contraceptive methods during the trial and until 1 month after last dosing in the trial
6.
Male who is sexually active and not surgically sterilized who or whose partner(s) is not
using highly effective contraceptive methods (highly effective contraceptive measures
include surgical sterilization, hormonal intrauterine devices [coil], oral hormonal
contraceptives, each in combination with spermicide-coated condoms), or who is not
willing to refrain from sexual intercourse from the first dosing until 1 month after last
dosing in the trial
7.
Current alcohol abuse (intake averaging >3 drinks daily in last 30 days) or use within
the last 6 months of controlled substances without a prescription (other than marijuana)
8.
New onset clinically significant illness within 4 weeks prior to screening, as judged by
the Investigator
9.
Unwilling or unable to refrain on the treatment visits from:
a.
Acetaminophen in any form
b.
Use of drugs that may dull the sensorium, reduce sensitivity to symptoms of
hypoglycemia, or hinder decision making during the period of participation in
the trial (use of beta blockers will be allowed as long as the dose is stable and
the patient does not meet the criteria for hypoglycemia unawareness while
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taking that stable dose, but use of benzodiazepines or narcotics, even if by 
prescription, may be excluded according to the judgment of the Investigator) 
10. History of liver disease that is expected to interfere with the anti-hypoglycemia action 
of glucagon (e.g., liver failure or cirrhosis). Other liver disease (i.e., active hepatitis, 
steatosis, active biliary disease, any tumor of the liver, hemochromatosis, glycogen 
storage disease) may exclude the patient if it causes significant compromise to liver 
function or may do so in an unpredictable fashion. 
11. Aspartate 
aminotransferase >2 
× 
upper limit of 
normal (ULN), alanine 
aminotransferase >2 × ULN, or bilirubin >1.5 × ULN on screening laboratories 
12. Renal failure on dialysis or estimated glomerular filtration rate <30 mL/min/1.73 m2 on 
screening laboratories 
13. Hemoglobin <12 gm/dL for men and <11 gm/dL for women 
14. Personal history of cystic fibrosis, pancreatitis, pancreatic tumor, or any other 
pancreatic disease besides T1DM 
15. Any known history of coronary artery disease including, but not limited to, history of 
myocardial infarction, stress test showing ischemia, history of angina, or history of 
intervention such as coronary artery bypass grafting, percutaneous coronary 
intervention, or enzymatic lysis of a presumed coronary occlusion) 
16. Congestive heart failure with New York Heart Association Functional Classification III 
or IV  
17. History of transient ischemic attack or stroke in the last 12 months 
18. Seizure disorder, history of any non-hypoglycemic seizure within the last 2 years, or 
ongoing treatment with anticonvulsants 
19. History of hypoglycemic seizures (grand-mal) or coma in the last 12 months 
20. History of hypoglycemic unawareness in the last 12 months 
21. History of pheochromocytoma: fractionated metanephrines will be tested in patients 
with history increasing the risk for a catecholamine secreting tumor: 
a. Episodic or treatment refractory (requiring 4 or more medications to achieve 
normotension) hypertension 
b. Paroxysms of tachycardia, pallor, or headache 
c. Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or 
von Hippel-Lindau disease 
22. History of adrenal disease or tumor 
23. Hypertension with systolic blood pressure (SBP) ≥160 mm Hg or diastolic blood 
pressure (DBP) ≥100 mm Hg despite treatment 
24. Hypotension (SBP <90 mm Hg or DBP <60 mm Hg), either sitting or standing, or 
orthostatic hypotension (decrease in SBP >20 mm Hg or decrease in DBP >10 mm Hg 
within 3 minutes of standing from a seated position) 
25. Untreated or inadequately treated mental illness (indicators would include symptoms 
such as psychosis, hallucinations, mania, and any psychiatric hospitalization in the last 
year), or treatment with anti-psychotic medications that are known to affect glucose 
regulation 
26. Electrically powered implants (e.g., cochlear implants, neurostimulators) that might be 
susceptible to radio frequency interference 
27. History of adverse reaction to glucagon (including allergy) besides nausea and 
vomiting 
28. History of severe hypersensitivity to milk proteins or lactose 
29. Established history of allergy or severe reaction to adhesive or tape that must be used 
in the trial 
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according to a pre-generated randomization scheme. Up to 2 patients may participate in the 
trial per day. The order of the treatment visits will be randomized in blocks of 2 patients. 
6 
TRIAL TREATMENT 
6.1 
Investigational Medicinal Products 
Insulin: The trial involves SC administration of insulin lispro (Humalog, Lilly), which is 
commercially available by prescription and is indicated for patients with T1DM, but not for use 
in a BP. 
Glucagon: The trial also involves SC administration of Lilly glucagon in 1 iLet arm and 
1 iPhone-based BP arm. Lilly glucagon is commercially available by prescription and is 
indicated for patients with T1DM in severe hypoglycemia, but not for use in a BP. 
ZP4207: The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, 
in the other iLet arm and the other iPhone-based BP arm. ZP4207 will be made available by 
Zealand Pharma A/S, Denmark as liquid formulation in prefilled syringes of 0.6 mL. 
6.2 
Storage and Drug Accountability of IMPs 
All IMPs will be stored and handled in accordance with the Sponsor’s instructions and/or the 
product labeling at the Investigator’s site, e.g., refrigerated (+2ºC to +8ºC) and should not be 
exposed to excessive heat, direct sunlight and never be frozen. 
All used, partly used, and unused vials must be kept by the Investigator and stored between 
+2ºC and +8ºC (unused) or at room temperature (partly used and used). Accountability for 
used pre-filled syringes will be made in accordance with the IMP standard operating 
procedures (SOPs). 
The Investigator must ensure the availability of proper storage conditions and record and 
evaluate the temperature. Temperature of the refrigerator used for drug storage is monitored 
continuously, an alarm system is established. The Investigator must inform the monitor 
immediately if any IMP has been stored outside specified conditions (e.g., outside temperature 
storage). Investigational Medicinal Product that has been stored improperly must not be 
dispensed to any patient before it has been re-evaluated and approved for further use. The 
Investigator must take appropriate action to ensure correct storage. 
For the IMP, the Investigator must keep an accurate record of all IMPs received and the 
products used for each patient in a Drug Accountability Record. Storage locations, batch 
numbers, and expiry dates are also documented in this form. 
The drug accountability must be performed in a timely manner by the monitor. 
6.3 
Dispensing and Return of IMPs 
No IMPs may be dispensed to any person not enrolled in the trial. 
Upon completion of the trial, the Sponsor will be responsible for destruction or storage of IMPs 
(used, partially used, or unused). These duties can be delegated to a contract research 
organization (CRO) and must be documented in the trial files. 
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6.4 
Doses 
The iLet and the iPhone-based BP can administer isolated insulin-glucagon doses once every 
5 minutes. A single automated bolus of insulin will not exceed 3 units per 5-minute dose (30 µl 
of U-100 insulin) in both systems, and a single meal-priming dose, in response to a meal 
announcement made by the user, will not exceed 12 units (120 µl of U-100 insulin). A single 
bolus of glucagon will not exceed 80 µg (80 µl of 1 mg/mL Lilly glucagon or 1 mg/mL ZP4207). 
In prior studies, typical doses of glucagon were in the range of 2.5-40 µg per dose. The iLet 
and the iPhone-based BP are capable of administering as little as ~0.5 µl (0.05 units of U-100 
insulin or 0.5 µg of 1 mg/mL ZP4207). 
 
It is expected that the mean total daily doses of glucagon/ZP4207 will be <1.0 mg daily as in 
previous studies. The mean daily glucagon dose in a previous 11-day outpatient trial was 
0.5 mg/day (range 0.2-0.9 mg/day). Currently, single doses of up to 2 mg ZP4207 have been 
administered in clinical trials. The recommended dose of marketed glucagon for adult patients 
suffering from severe hypoglycemia is 1 mg as a single injection. Mean glucagon levels in 
previous inpatient studies have been above the normal fasting range for glucagon only 1% of 
the time. Therefore, the glucagon exposure of patients is expected to be modest. 
 
6.5 
iPhone-based Bionic Pancreas 
Infusion Set: Patients will wear 2 FDA-approved commercially available infusion sets, 1 for 
insulin infusion and 1 for glucagon infusion. Infusion sets that are compatible with the Tandem 
t:slim infusion pump (luer lock connection) will be provided. 
 
Continuous Glucose Monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to 
the controller. The sensor is powered by the battery within the transmitter that clips to the 
sensor and the whole assembly is held to the skin with an adhesive patch and communicates 
wirelessly with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM 
signal), it will be replaced promptly.  
 
Bionic Pancreas Control Unit: The control unit consists of a stock iPhone 4S and a Dexcom 
G4 Platinum receiver connected with a custom hardware interface and placed back-to-back 
in a custom enclosure. The G4 receiver converts the raw wireless signal from the transmitter 
into an estimated BG signal that is sent via a hardwired connection to the iPhone.  
 
 
The iPhone runs iOS 6 in “Guided Access” mode, where the only app accessible to the patient 
is the Beta Bionics app, which runs the control algorithm. The home screen, where typical user 
options reside, is password protected. Access to other functions on the iPhone (primarily the 
Settings options) is separately password protected and only accessible to the study staff. This 
prevents accidental activation of other apps that could interfere with the function of the BP. 
The control algorithm app has a graphical user interface (GUI) that displays the current CGM 
glucose, a graphical history of the CGM glucose, and doses of insulin and glucagon delivered 
by the control algorithm. The GUI can also be used to input meal announcements, designating 
the size of the meal as larger than typical, typical in size, smaller than typical, or just a bite, 
and the type of meal as breakfast, lunch, or dinner. This will trigger a partial meal-priming 
bolus the size of which will adapt during the course of the trial to meet a target of 75% of the 
insulin needs for that size and type of meal.  
 
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The target glucose level will be programmed to 100 mg/dL by the study engineers prior to the 
start of each experiment. This will be locked for each arm of the study; the patient will be 
unable to accidentally change or tamper with this setting.  
 
The GUI can be used to manage meal boluses and correction boluses during periods when 
the CGM is offline, such as the period after a sensor is replaced and before the new sensor 
has been calibrated. During these times the control algorithm will determine and direct the 
administration of insulin basal rates based on the patient's weight. The controller will also 
administer insulin and/or glucagon as appropriate in response to any entered BG values, just 
as if they were CGM values. 
 
The GUI also displays visual alarms associated with an audio signal if communication is 
dropped between the CGM transmitter and the BP control unit or between the control unit and 
the 2 insulin pumps. 
 
 
The iPhone communicates wirelessly via the Bluetooth Low Energy (BTLE) protocol with 
2 Tandem t:slim insulin pumps to deliver insulin and glucagon. 
 
Tandem t:slim Pumps: These pumps are FDA-approved insulin pumps with reservoirs 
capable of holding 300 units (3 mL) of insulin or 3 mL of glucagon or ZP4207 solution. The 
pumps have a mechanical dosing resolution of 1/120 (0.00833) unit and can deliver liquids at 
a maximal rate of ~33 µl per minute (2 mL per hour). They are slave to the BP control unit and 
are controlled wirelessly via the BTLE protocol by the iPhone 4S. 
 
6.6 
iLet Bionic Pancreas  
Infusion Set: A novel, dual cannula infusion set has been designed specifically for use with 
the iLet. Patients will wear dual channel tubing that will be attached to 2 infusion sets with 
1 steel cannula each, 1 for insulin infusion and the other for glucagon infusion. The tubing and 
infusion sets will have undergone sterilization prior to being delivered in a sealed pouch. The 
steel cannulae will be inserted in the abdominal SC tissue. 
 
Continuous Glucose Monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to 
the controller. The sensor is powered by the battery within the transmitter that clips to the 
sensor and the whole assembly is held to the skin with an adhesive patch and communicates 
wirelessly with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM 
signal), it will be replaced promptly.  
 
Bionic Pancreas Control Unit: The iLet is being built according to Class III medical device 
standards, adheres to a comprehensive and robust quality system, and is fully compliant with 
International Organization for Standardization (ISO) 13485 standards and document control 
practices. The iLet is a fully-integrated dual-hormone BP system that integrates the CGM 
technology (currently the Dexcom G4 Share system) as well as 2 independent motor-drivetrain 
pumping assemblies, which independently actuate the delivery of insulin and glucagon from 
pre-filled cartridges that are separately loaded into the iLet housing. Each drivetrain assembly 
utilizes a lead screw, which is driven by a precision micromotor, a gear case assembly, and a 
motor controller unit, in a manner similar to what is commonly found in most insulin infusion 
pumps on the market today. The iLet has dosing accuracy that is comparable to 
FDA-approved insulin pumps currently on the market. The iLet has a built-in BTLE radio that 
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also allows automatic communication with the paired CGM, as well as the Nova StatStrip® 
Xpress BG meter (Nova Biomedical). The iLet does not contain a cellular nor a WiFi radio, 
and does not accept input data from another mobile device (e.g., smartphone), other than the 
paired CGM and BG meter(s). 
The mathematical control algorithms (which are the same as those used in the iPhone-based 
BP), the CGM glucose engine (Dexcom), and the native user interface software, are all 
interconnected through controller framework software and reside as embedded systems on 
printed circuit boards contained within the device housing. The touchscreen-enabled, 
menu-driven user interface and onboard processor provide a comprehensive and standalone 
platform, which allows the iLet to operate independently of smartphones or other devices and 
without the need for internet support during routine operation. The graphical user interface of 
the iLet has the same user options and capabilities of the iPhone BP, including having its 
home screen password protected and its settings options only accessible to trial staff via a 
separate password. 
6.7 
Other Trial Devices 
YSI 2300 STAT Plus™ (Yellow Springs Instruments): The YSI 2300 STAT Plus is an 
FDA-approved glucose analyzer. Blood glucose measurements using the YSI 2300 STAT 
Plus will be obtained off of the intravenous (IV) line during both treatment visits.   
Nova Biomedical StatStrip Xpress Glucose Meter: The Nova StatStrip Xpress glucose 
meter is an FDA-approved glucose meter that is commercially available. Blood glucose 
measurements for CGM calibration will be obtained with the Nova StatStrip Xpress during both 
treatment visits if the YSI 2300 STAT Plus fails and via fingerstick with the Nova StatStrip 
Xpress during any periods when IV blood samples are not available for any reason or the IV 
fails. 
Exercise Bike: The trial will utilize a stationary exercise bike (ergometer) for the in-clinic 
exercise at the treatment visits. This bike will be stored at the Diabetes Research Center when 
not in use. 
6.8 
Concomitant Medications 
6.8.1 
Permitted Medications and/or Procedures 
Patients may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference with 
CGM sensing. All concomitant medications, including over-the-counter medications, should 
be recorded. 
Use of beta blockers will be allowed as long as the dose is stable and the patient does not 
meet the criteria for hypoglycemia unawareness while taking that stable dose. 
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911. 
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6.8.2 
Excluded Medications and/or Procedures  
During the trial, patients will not use any recreational drugs or drugs of abuse. The need to 
take prescription drugs that dull the sensorium, reduce sensitivity to symptoms of 
hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion from the 
trial or discontinuation of participation, a decision that will be made by the Investigator. 
 
Use of benzodiazepines or narcotics, even if by prescription, may be excluded according to 
the judgment of the Investigator. Use of oral anti-diabetic medications (e.g., thiazolidinediones, 
biguanides, sulfonylureas, glitinides, DPP-4 inhibitors, SGLT-2 inhibitors) will also be 
excluded. 
7 
TRIAL PROCEDURES  
7.1 
Informed Consent  
After potential patients have had time to review the consent document, and prior to any 
trial-related activities, they will meet with a trial MD or designee who will explain the trial, 
answer any questions, and administer informed consent. In the event that a volunteer is a 
patient of 1 of the trial MDs, another staff MD or designee will answer questions and administer 
consent. The patients will be fully informed of their responsibilities and their rights while 
participating in the trial as well as of the possible risks and potential benefits of participation in 
the trial. They will have the opportunity to discuss all questions and ample time to consider 
participation. 
 
Trial-related activities are any procedures that would not have been performed during normal 
management of the patient. Patients who wish to participate in the trial will be asked to 
personally date and sign an informed consent form (ICF). Likewise, the Investigator must also 
personally date and sign the ICF. All patients will be provided with a copy of their own signed 
and dated ICF. 
 
Trial staff will answer any questions that the patients may have during their participation. They 
will share any new information in a timely manner that may be relevant to the patient's 
willingness to continue participating in the trial. The patients may choose to discontinue their 
participation at any time.  
 
7.2 
Screening Visit (Visit 1) 
All patients will have a Screening Visit to confirm eligibility. The patient will be interviewed and 
the electronic Case Report Form (eCRF) will be completed by trial staff to establish whether 
the patient is eligible. 
 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits per the 
medical judgment of the Investigator. 
 
Once all of the results have been returned, a trial MD will review the eCRF to determine patient 
eligibility. If a patient is not eligible to continue in the trial, the results of abnormal tests will be 
reported to the patient and to a health care provider of their choosing. 
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7.2.1 
Data Collected at Screening 
•
Age, sex, race, and ethnicity
•
Date of last menstrual period in female patients
•
Medical, surgical, and social history, allergies, and review of systems relevant to
inclusion and exclusion criteria, including:
o
Date of diabetes diagnosis
o
Duration of insulin pump use and type of insulin used in pump
o
Type/model of insulin pump
o
Insulin regimen (basal rate, sensitivity factor, and carbohydrate ratio)
o
Average total daily dose of insulin in the last 30 days as available (from pump
history)
o
Usage of CGM, if any (type of CGM, days per month worn, usage of data,
whether insulin is dosed based on CGM alone, alarm settings)
•
Concomitant illness (any illness present at screening)
•
Concomitant medications (prescription and non-prescription) and date of last change
in medication regimen
•
Height, weight, physical examination, and vital signs including body temperature and
blood pressure
•
Orthostatic vital signs (heart rate and blood pressure) in the seated position and within
3 minutes of standing
•
12-lead ECG
•
Hemoglobin A1c
•
Chemistry and hematology samples (see Appendix B)
•
Urine HCG pregnancy test for women of childbearing potential
•
FSH level for postmenopausal women amenorrheic for less than 1 year
•
Fractionated plasma metanephrines (if indicated by history)
7.3 
Training Visit (Visit 2) 
A Training Visit will take place before the first treatment visit. Patients will be trained in the 
insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. Trial staff 
will verify that the patients have understood the material and are competent to participate 
safely in the trial. Concomitant medications will also be reviewed. 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits per the 
medical judgment of the Investigator. The goals of diabetes management for patients during 
the fasting period are to avoid hypoglycemia, to treat hypoglycemia if it occurs, and to arrive 
at the treatment visit in the morning with a BG between 80 and 250 mg/dL. If insulin pump 
basal rates are properly configured, patients should be able to fast from 12:00 AM until the 
time of arrival for the visit without a high likelihood that they will become hypoglycemic or 
severely hyperglycemic. Patients will be asked whether they believe that they can safely fast 
from 12:00 AM until their arrival time at approximately 7:00 AM without adjusting their basal 
rates. If they have concerns, a trial physician will consult with them regarding pump basal rate 
adjustments. In all cases, subjects will be instructed to self-treat with carbohydrates according 
to the 15/15 rule (15 grams of carbohydrates, repeated in 15 minutes if necessary) during the 
overnight fasting period and at any time prior to their arrival at the trial site for the treatment 
visits. 
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7.4 
Treatment Visits (Visit 3 and Visit 4) 
• 
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 
30 days after screening (Visit 1). 
• 
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum 
of 3 weeks between Visit 3 and Visit 4. 
• 
Up to 2 patients may participate per day.  
• 
In Part 1, each patient will participate in 2 treatment visits: 1 with the iPhone-based BP 
using ZP4207 and 1 with the iPhone-based BP using Lilly glucagon in a randomized 
order. 
• 
In Part 2, each patient will participate in 2 treatment visits: 1 with the iLet using ZP4207 
and 1 with the iLet using Lilly glucagon in a randomized order. 
• 
The night before the treatment visit, patients will place a Dexcom G4 CGM sensor in 
the abdominal skin and calibrate the sensor when prompted using the provided Nova 
StatStrip Xpress meter. Patients will be instructed to call if they encounter any difficulty 
with their CGM.  
• 
Patients will be responsible for their own medications other than insulin during the trial. 
Any medical advice needed by the patients during their participation that is not directly 
related to BG control should be obtained from them in their usual manner. Patients 
may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference 
with CGM sensing. If patients experience urgent or emergent medical concerns 
outside the scope of diabetes care and their primary care physicians, they will be taken 
to the MGH walk-in clinic or emergency room, or if necessary call 911. 
• 
During the trial, patients will not use any recreational drugs or drugs of abuse. The 
need to take prescription drugs that dull the sensorium, reduce sensitivity to symptoms 
of hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion 
from the trial or discontinuation of participation, a decision that will be made by the 
Investigator.  
• 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits 
per the medical judgment of the Investigator.  
• 
Patients will not tamper with the BP, including changing any settings. 
• 
Patients may not remove the BP during the trial unless the BP failed or they are 
withdrawing from the trial. 
• 
The exact time of each procedure and assessment will be documented. 
7.4.1 
Visit Procedures  
• 
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the 
BP having fasted since 12:00 AM the night before (treatment with simple carbohydrate 
of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled 
within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the 
visit window. If BG is <50 mg/dL, the patient will be treated with simple carbohydrate 
according to the 15/15 rule (15 grams of carbohydrates, repeated in 15 minutes if 
necessary). The visit will not need to be rescheduled unless the patient experiences a 
severe hypoglycemic event and requires treatment with glucagon or IV dextrose. If the 
visit needs to be rescheduled due to hypoglycemia or hyperglycemia, trial staff will 
assist the patient with insulin or medication adjustments to address glycemic control. 
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The patient will be instructed to contact trial staff later in the day if his or her BG remains 
uncontrolled. 
•
Upon arrival to the visit, the patient’s weight and vital signs including body temperature
and blood pressure will be documented.
•
Orthostatic vital signs (heart rate and blood pressure) will be measured in the seated
position and within 3 minutes of standing.
•
Patient reports of symptoms, any other complaints, and AEs will be reviewed.
•
Concomitant medications will be recorded.
•
Chemistry and hematology samples will be collected at visit start (see Appendix B).
•
ADA samples will be collected before the start of dosing (Visit 3 only).
•
A 12-lead ECG will be performed.
•
A urine HCG pregnancy test will be performed in female patients of childbearing
potential. If the test is positive, the patient will be informed of the result and the visit
will be ended.
•
Patients will complete a baseline survey about their attitudes and experience with their
usual diabetes care.
•
An IV catheter will be placed for blood sampling.
•
Trial staff will assist the patient to calibrate their CGM, review the trial procedures again
and assist with the setup of the BP system, including inserting and priming infusion
sets.
•
The control algorithm will be initialized only with the patient’s weight. Diagnostics will
be performed to ensure that the CGM device is appropriately calibrated and that all of
the components of the BP systems are in working order.
•
The basal rate of the patient’s own insulin infusion pump will be changed to be 2-fold
higher than weighted mean of the basal rate during the trial period. This is intended to
increase the usage of glucagon during the treatment visit. The basal insulin rate may
be decreased during the treatment visit at the discretion of the Investigator. To the
extent possible, the same basal rate should be used at Visit 3 and Visit 4.
•
The patients will continue to wear their own infusion pump infusing at the temporary
basal rate throughout the visit until the start of the structured exercise period, in
addition to the BP.
•
The staff will start the BP as close as possible to a minute divisible by 5 minutes
(i.e., on a 5-minute mark). The starting time will be considered Hour 0.
•
Additional calibrations will be performed at any of the BG checks throughout the day if
the CGM value does not meet the ISO standard (<15 mg/dL difference for BG values
<75 mg/dL; <20% absolute difference for BG values >75 mg/dL) at the time of the BG
measurement AND it is a good time to calibrate (the CGM trend arrow is flat and there
has been no carbohydrate intake in the last 30 minutes or glucagon boluses in the last
15 minutes).
•
Blood samples will be taken from the IV at least hourly and processed for plasma
ZP4207/glucagon. If BG is <150 mg/dL, more frequent samples for plasma
ZP4207/glucagon may be drawn at the discretion of the Investigator. The actual time
of sampling will be recorded in the eCRF.
•
Plasma glucose samples will be taken from the IV at least hourly in parallel with
ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT Plus.
If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes.
If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then
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sampling will be every 10 minutes. The actual time of sampling will be recorded in the 
eCRF. 
•
Patients will be asked to rate any nausea and/or infusion site pain on 10 cm visual
analog scales (VAS) at the beginning of the visit once the infusion sites have been
placed but no drug has yet been administered, then approximately at the top of every
hour during the visit, and at the end of the visit. Trial staff will also evaluate their infusion
sites to document any erythema or edema at the same times. If moderate or severe
pain is reported or swelling or redness occurs at the infusion site, the infusion site will
be replaced in a different location. If moderate or severe pain, swelling, or redness
continues at the old site for more than 30 minutes after the infusion site is removed, or
if moderate or severe pain, swelling, or redness occurs at the new site, all infusion
sites will be removed and the patient will be discontinued from the study. Any such
symptoms will be followed until resolution.
•
From the start of closed loop control until approximately Hour 3, the patients will
continue to fast.
•
Between approximately Hour 3 and Hour 4, patients will be provided with a lunch meal
of their choice in the Diabetes Research Center from a menu of choices from nearby
restaurants. They will be asked to choose a meal that is a “typical meal” for them. The
content of their meal will not be restricted in any way, with the exception that the
number of carbohydrates should be in the “typical” range for them at lunch, and that
they must eat the same meal at the same time during both visits.
•
At approximately 15 minutes before the meal, patients will administer a bolus for the
meal with their own insulin pump based on the carbohydrate count for the meal in
agreement with the Investigator.
•
After lunch is completed, the patients will not be allowed any carbohydrate intake
(non-caloric drinks will be permitted) until the trial is completed (except as necessary
to treat hypoglycemia), to allow the BP to control the post-prandial BG without further
interruption.
•
Between approximately Hour 6 and Hour 7, the patients will start a period of structured
exercise.
•
At the start of the exercise period, patients will restore their normal basal insulin profile
so that they will not have elevated insulin levels at the end of the study period when
they are to transition back to their usual care.
•
Patients will exercise on a stationary bike with a heart rate from 120-140 beats per
minute for a total of 4,000 heart beats (approximately 30 minutes). Patients will rate
their exercise intensity using the Borg scale every 5 minutes, with the target intensity
level between 12 and 14. Heart rate will be measured every 5 minutes.
•
Chemistry and hematology samples will be collected immediately after end of exercise
(see Appendix B).
•
BG measurements will be obtained off of the IV line every 10 minutes. If BG is
<80 mg/dL, BG measurements will be obtained off of the IV line every 5 minutes.
o
If BG is <50 mg/dL, the exercise will be terminated regardless of heart beats
achieved.
o
Carbohydrates will be given for any BG <50 mg/dL according to the following
protocol: Dextrose (g) = BSA (m2)/[1.7 m2 (women) or 1.9 m2 (men)] *15 g.
o
Repeat treatments will be given at 15-minute intervals as long as BG remains
<50 mg/dL.
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•
If there is an interruption in the Dexcom CGM output, trial staff will assist the patient in
recovering CGM data streaming. If this requires replacement of the CGM sensor, BGs
will be checked every 10 minutes (every 5 minutes if BG is <80 mg/dL) using blood
from the IV until the CGM is able to be calibrated again. These BGs will be entered
into the BP, which will treat them as CGM values and dose insulin and/or glucagon
appropriately.
•
If there is a complete failure of the BP operation, patients will take over their own BG
control using their personal insulin pump until the BP can be brought back online. If BP
control cannot be promptly resumed (e.g., within 30 minutes), the patient may be asked
to repeat that trial day once.
•
Patients may choose to withdraw from the trial at any time. If they withdraw from the
trial, they should alert a provider immediately.
•
Just prior to the end of the study visit, vital signs including body temperature and blood
pressure will be obtained and a 12-lead ECG will be performed. Orthostatic vital signs
(heart rate and blood pressure) will be measured in the seated position and within
3 minutes of standing. If patients have hypotension or orthostatic hypotension,
discharge will be delayed until their blood pressure is normal and stable.
•
After approximately Hour 8, but not earlier than at least 60 minutes after end of
exercise, the BP will be stopped and the patient will continue with their personal insulin
pump.
•
If the patient experiences seizure or unconsciousness, persistent nausea or vomiting,
diabetic ketoacidosis, persistent hyperglycemia with ketonemia, hemodynamic
changes such as hypotension, or other medically significant findings, a longer
observation period at the trial site may be necessary until the patient is considered
stable for discharge. If the Investigator or trial staff determines that the patient requires
further observation or treatment, the patient may be transferred to the emergency room
for additional monitoring and/or medical care. At discharge, patients will be provided
with any necessary instructions concerning personal insulin pump usage, food intake,
and driving arrangements.
•
The maximum amount of blood loss per study visit will be approximately 230 mL. The
total blood loss for the entire study will be up to 460 mL.
•
The BP and glucose meters will be collected and downloaded.
•
A trial MD will review the last several hours of insulin and glucagon dosing and assist
the patient in resuming their usual diabetes care. A longer observation period at the
trial site may be necessary. Patients will be instructed to call trial staff with any
questions, issues, or concerns.
7.4.2 
Data Collected During the Treatment Visits 
•
CGM glucose every 5 minutes from the Dexcom G4 Platinum CGM
•
All BG measurements taken
•
Insulin total dose by the BP and the patient’s own insulin pump
•
Glucagon total dose
•
Timing and content of the meal eaten and carbohydrate amount
•
Timing of meal announcement and size of meal announced
•
Timing and glucose values at calibrations
•
Timing and amount of carbohydrates taken for hypoglycemia
•
Time patients were not under BP control for any reason
•
List of technical faults associated with the BP including cause and resolution
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•
ZP4207/glucagon sampling will be collected at least hourly. If BG is <150 mg/dL, more
frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the
Investigator.
•
Plasma glucose sampling will be collected at least hourly in parallel with
ZP4207/glucagon exposure sampling. If BG is <150 mg/dL, then sampling will be every
30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is
<80 mg/dL, then sampling will be every 10 minutes.
•
Nausea and infusion site pain on a VAS at visit start (after insertion and before any
drug administration), hourly, and at visit end
•
Infusion site reaction according to the Draize scale at visit start (after insertion and
before any drug administration), hourly, and at visit end
•
Patient reports of symptoms, any other complaints, and AEs
•
Vital signs including body temperature and blood pressure (at visit start and visit end)
and weight
•
Orthostatic vital signs (heart rate and blood pressure) in the seated position and within
3 minutes of standing
•
Concomitant medications
•
Chemistry and hematology samples (see Appendix B) at visit start and immediately
after end of exercise
•
ADA (Visit 3 only)
•
12-lead ECG at visit start and visit end
•
Urine HCG pregnancy test for women of childbearing potential
7.4.3 
Response to Hypoglycemia 
•
Patients are encouraged to check their BG for any symptoms of hypoglycemia.
•
Patients will be permitted to take 15 grams of carbohydrates for any BG value
<60 mg/dL. Trial staff will ensure proper functioning of the BP, infusion set, and insulin
pump, and will encourage the patient to wait for the BP to treat the low blood sugar for
as long as they feel comfortable.
•
Patients will be required to take 15 grams of carbohydrates for any BG value
<50 mg/dL. After treatment of hypoglycemia, a follow-up measurement will be taken
15 minutes later. Repeated measurements will be taken every 15 minutes until the
BG is >60 mg/dL. Treatment will be repeated if subsequent BG values are still
<50 mg/dL. All carbohydrate treatments for hypoglycemia will be documented by trial
staff (amount and time).
•
Trial staff will check the infusion site, BP, and insulin pump for normal operation any
time hypoglycemia occurs. If there is any suspicion of infusion set malfunction, the site
should be replaced. Trial staff will check the BP for any malfunction and correct any
problems that are found.
•
If no correctable fault is found, but there is doubt regarding the correct function of the
BP system, an entirely new backup BP system may be started.
•
If a patient experiences a seizure or unconsciousness associated with hypoglycemia,
his or her participation in the trial will be discontinued.
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7.4.4 
Response to Hyperglycemia  
• 
Trial staff will check the infusion site, BP, and insulin pump for normal operation any 
time BG is >300 mg/dL. If there is any suspicion of infusion set malfunction, the site 
should be replaced. Trial staff will check the BP for any malfunction and correct any 
problems that are found. If the BG remains >300 mg/dL for 2 hours despite 
troubleshooting, blood ketones will be measured. If the blood ketone result is 
>1.5 mmol/L, the visit will be stopped and rescheduled. The patient will be provided 
with insulin and a syringe to give an injection based on their correction factor. 
• 
If a patient experiences diabetic ketoacidosis, his or her participation in the trial will be 
discontinued. 
• 
If no correctable fault is found, but there is doubt regarding the correct function of the 
BP system, the treatment visit may be stopped and the visit rescheduled. 
7.4.5 
Response to Nausea/Vomiting 
If significant nausea (e.g., that prevents the patient from eating normally) or any vomiting 
occurs, trial staff will notify the Investigator. Trial staff will assist the patient in troubleshooting, 
such as checking BG and the calibration of the CGM (excessive glucagon dosing may occur 
if the CGM is reading lower than the true BG). If a patient experiences persistent nausea and 
vomiting thought to be related to glucagon dosing, his or her participation in the trial will be 
discontinued. 
7.4.6 
Response to Other Medical Needs  
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911.  
7.4.7 
Monitoring of Bionic Pancreas Performance  
Bionic pancreas inventors and developers 
, 
, and/or an 
engineer trained by them will be readily available by phone for consultation for the trial staff at 
all times during the course of the trial.  
7.4.8 
Supervision by Trial Staff  
A trial MD will be on call at all times during the course of the trial. An RN or MD will be with 
the trial patients in the Diabetes Research Center at all times. 
 
7.5 
Anti-drug Antibodies Assessment Visit (Visit 5) 
Patients will return for an ADA Assessment Visit 10 days ±3 days following the last day of 
dosing (Visit 4) for ADA sampling and a review of AEs and concomitant medications. 
 
7.6 
Follow-up Visit (Visit 6) 
Patients will return for a Follow-up Visit 25 days ±4 days following the last day of dosing 
(Visit 4), for chemistry, hematology, and ADA sampling, and a review of AEs and 
concomitant medications.  
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8 
ENDPOINTS  
8.1 
Primary Endpoint  
The primary endpoint is the safety and tolerability of ZP4207 in the BP using either the iLet 
or the iPhone platform as assessed by: 
•
Number and type of AEs
•
Clinical laboratory measurements
•
Vital signs
•
12-lead ECG
•
Local tolerability and infusion site reactions as measured with the Draize scale
•
Immunogenicity as measured by ADA
•
Pain as measured on a 10 cm VAS
•
Nausea as measured on a 10 cm VAS
8.2 
Secondary Endpoints 
The secondary endpoints include measurements of BP function as well as glycemic and 
non-glycemic measurements. 
8.2.1 
Bionic Pancreas Function  
This endpoint data will be generated from the BP data during each treatment visit: 
•
Average percent insulin dose amounts calculated by the BP control algorithm that are
successfully delivered by the pump
•
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully delivered by the pump
•
Average percent dose amounts successfully issued to the pump by the BP control
algorithm that are successfully delivered by the pump (calculated doses are not issued
unless the pump is accessible and its delivery channel is available)
o
Average percent insulin dose amounts successfully issued to the pump by the
BP control algorithm that are successfully delivered by the pump
o
Average percent glucagon/ZP4207 dose amounts successfully issued to the
pump by the BP control algorithm that are successfully delivered by the pump
•
Average percent dose amounts calculated by the BP algorithm that are successfully
issued to the pump by the BP (calculated doses are not issued unless the pump is
accessible and its delivery channel is available)
o
Average percent insulin dose amounts calculated by the BP control algorithm
that are successfully issued by the BP
o
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully issued by the BP
•
Average percent of 5-minute steps during which the BP is functioning nominally in all
respects based on real-time CGM data (new CGM glucose reading captured, dose
calculated, and dose issued to pumps)
•
Average percent of 5-minute steps during which the BP is functioning nominally with
or without a new CGM glucose reading captured (dose calculated and dose issued to
pumps). If a CGM signal is not available, the dose calculated may be based on weight
or historical basal rates.
•
CGM reliability index, calculated as percent of possible values actually recorded by
CGM
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•
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter
download
•
List of technical faults associated with the BP including cause and resolution
8.2.2 
Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit: 
•
Fraction of time spent within each of the following glucose ranges:
o
<50 mg/dL
o
<60 mg/dL
o
<70 mg/dL
o
70-120 mg/dL
o
70-140 mg/dL
o
70-180 mg/dL
o
>180 mg/dL
o
>250 mg/dL
o
>300 mg/dL
•
Number of severe hypoglycemic events (patients unable to self-treat, requiring the
assistance of another person)
•
Number of episodes of symptomatic hypoglycemia
•
Number of carbohydrate interventions for hypoglycemia
•
Total grams of carbohydrates taken for hypoglycemia
•
Mean CGM glucose
8.2.3 
Non-glycemic 
•
Glucagon/ZP4207 total delivery per kg of body mass
•
Insulin total delivery per kg of body mass
•
Number of unscheduled infusion set replacements
•
Number of unscheduled CGM sensor changes
9 
LABORATORY ASSESSMENTS 
Descriptions of sample handling and sample processing, storage, and shipment at the site will 
be included in the laboratory manual. 
The responsible laboratories are listed in the address list. 
9.1 
Safety Laboratory Assessments 
Chemistry and hematology samples will be collected at specified time points. See Appendix A 
for the schedule of procedures and Appendix B for a list of clinical laboratory analytes. 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) 
At Visit 3 and Visit 4, plasma glucose samples will be taken from the IV at least hourly in 
parallel with ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT 
Plus. If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for 
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is 
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<100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will 
be every 10 minutes. The actual time of sampling will be recorded in the eCRF. 
9.3 
Exposure Assessments (ZP4207 and Glucagon) 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the 
discretion of the Investigator. The actual time of sampling will be recorded in the eCRF. 
Bioanalytical Reports will be prepared. 
9.4 
Anti-drug Antibodies Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken at Visit 3, the ADA Assessment Visit (Visit 5), and the Follow-up Visit 
(Visit 6). Any patient that tests positive for ADA will be monitored until the ADA levels return 
to baseline. 
Bioanalytical Reports will be prepared. 
10 
SAFETY REPORTING 
10.1 
Adverse Events 
An AE is any untoward medical occurrence in a trial patient administered an IMP and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be 
any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not considered related to 
the IMP. Patients should be instructed to report any AE they experience to the Investigator. 
Note: This includes events from the first trial-related activity from Visit 3.  
AEs for ZP4207 include: 
•
A clinically significant worsening of a concomitant illness
•
A clinical laboratory abnormality which is clinically significant, i.e., any abnormality that
suggests a disease and/or organ toxicity and is of a severity that requires active
management. Active management includes active treatment or further investigations,
for example, change of medicine dose or more frequent follow-up due to the
abnormality.
•
Hypoglycemic episodes  
•
Injection site reactions
The following should not be recorded as AEs, if recorded prior to randomization (on the 
Screening Form or the eCRF): 
•
Pre-planned procedure, unless the condition for which the procedure was planned has
worsened from the first trial-related activity from Visit 3. 
•
Pre-existing conditions found as a result of screening procedures (pre-existing
conditions should be reported as medical history or concomitant illness). 
For known (listed) AEs for Glucagon and Humalog, please refer to SPC for Glucagon and 
Humalog. 
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10.1.1 
Follow-up of Adverse Events 
All AEs that are ongoing at the end of the patient’s participation in the trial will be followed-up 
until the event is resolved or reaches a satisfactory outcome as deemed by the Investigator. 
Follow-up actions for all serious adverse events (SAEs) will be performed according to 
appropriate clinical care practices and may depend on the nature of the event. These will be 
determined after internal review and/or Sponsor review. The follow-up information should only 
include new (updated and/or additional) information that reflects the situation at the time of the 
Investigator’s signature. 
 
Follow-up information on (S)AEs will be updated using the (S)AE Form. If a non-serious event 
becomes serious during the follow-up, the AE Form and SAE Form must be used and reporting 
timelines follow those of an SAE. 
 
The Investigator must forward follow-up information on SAEs, and if previously non-serious 
AEs become SAEs, to the Sponsor. 
10.1.2 
Precautions 
Normal precautions taken for a human trial will be taken during this trial. Qualified and 
well-trained physicians and medical staff will instruct the patients. During a patient’s 
participation in the trial, the Investigator should ensure that adequate medical care is provided 
to the patient for any AEs, including clinically significant laboratory values related to the trial. 
The Investigator should inform the patient when medical care is needed for intercurrent 
illnesses of which the Investigator becomes aware.  
 
For further information on safety precautions for ZP4207, Lilly glucagon, and Lilly Humalog, 
please refer to the current version of the Investigator’s Brochure (IB) for ZP4207 (Zealand 
Pharma A/S, 2015, or any updates hereof), and the SPC for Glucagon (Eli Lilly, 2012) and 
Humalog (Eli Lilly, 2015), respectively. 
10.1.3 
Assessment of Adverse Events by the Investigator  
 
Intensity of an Adverse Event 
The maximum intensity (severity) of all AEs must be assessed by the Investigator and 
documented. Severity should be graded when the AE outcome is known: 
• 
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
• 
Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the patient. 
• 
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
 
A “severe” reaction does not necessarily deem the AE as “serious,” and an SAE may not be 
“severe” in nature. 
 
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Causality Relationship to IMP 
Insulin (insulin lispro, Lilly Humalog), glucagon (glucagon for injection, Eli Lilly), and ZP4207 
are all regarded as IMP. 
The causality of each AE should be assessed by the Investigator according to the following 
classification: 
•
Related: Good reason and sufficient documentation to assume a causal relationship.
•
Not related: No relationship to trial product can be established.
Outcome of an Adverse Event 
The outcome of all AEs must be assessed by the Investigator and documented by his/her 
staff. The following definitions should be used: 
•
Recovered/resolved: The patient has fully recovered, or by medical or surgical
treatment the condition has returned to the level observed at the first trial-related 
activity from Visit 3. 
•
Recovering/resolving: The condition is improving and the patient is expected to recover
from the event. This term is only applicable if the patient has completed the trial.
•
Recovered/resolved with sequelae: The patient has recovered from the condition, but
with lasting effect due to a disease, injury, treatment, or procedure. If a sequela meets
an SAE criterion, the AE must be reported as an SAE.
•
Not recovered/not resolved: The condition of the patient has not improved and the
symptoms are unchanged, or the outcome is not known.
•
Fatal: This term is only applicable if the patient died from a condition related to the
reported AE. Outcomes of other reported AEs in a patient before he/she died should
be assessed as “recovered/resolved,” “recovering/resolving,” “recovered/resolved with
sequelae,” or “not recovered/not resolved.” An AE with a fatal outcome must be
reported as an SAE.
•
Unknown: This term is only applicable if the patient is lost to follow-up.
10.2 
Serious Adverse Events   
An SAE is any untoward medical occurrence that at any dose: 
•
Results in death
•
Is life-threatening
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability or incapacity
•
Is a congenital anomaly or birth defect
•
Medically important
Medical judgement must be exercised in deciding whether an AE is believed to be “medically 
important.” Medically important events may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require intervention to prevent 
1 of the other outcomes listed in the definition above. 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is an AE fulfilling 1 of the criteria of seriousness and being assessed as related to 
an IMP, the nature or severity of which is not consistent with the applicable reference 
document (e.g., ZP4207 IB or package leaflet/SPC for an approved product). 
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Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety, any life-threatening problem or 
death caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the application; or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. 
 
10.3 
Adverse Event Reporting – Procedures for Investigators  
The Principal Investigator and co-investigators will review any AEs and report any SAEs to 
the Sponsor as soon as possible and within 24 hours of obtaining knowledge of the event. The 
Principal Investigator and co-investigators will promptly report AEs to the Partner’s Institutional 
Review Board (IRB) and to the BU IRB (unless oversight is ceded by the BU IRB to the 
Partners IRB), in accordance with local requirements.  
 
Ed Damiano is the Sponsor of the Investigational Device Exception for the BP and Zealand 
Pharma A/S is the Sponsor of the IND for ZP4207.  
 
Reports of AEs will be submitted to the FDA in compliance with the terms of the Code of 
Federal Regulations. 
 
All events meeting the definition of an AE must be collected and reported from the first 
trial-related activity from Visit 3 until the end of the post-treatment follow-up period. At each 
contact with the site (visit or telephone, excluding safety visits, where the patient is not seeing 
the Investigator or staff [e.g., visits to the laboratory], the patient must be asked about AEs. 
All AEs, either observed by the Investigator or reported by the patient, must be recorded by 
the Investigator and evaluated. 
 
The Investigator should record the diagnosis, if possible. If no diagnosis can be made, the 
Investigator should record each sign and symptom as individual AEs. 
All AEs must be recorded by the Investigator. One single AE Form must be used per AE from 
start to resolution. For SAEs, the SAE Form must also be completed.  
 
AE information should include the following: 
• 
Patient identification number on all pages 
• 
Date and time of treatment start 
• 
Date and time of onset and date of outcome 
• 
Date and time of Investigator’s first information on the (S)AE 
• 
Seriousness 
• 
Severity 
• 
Causal relationship with IMP ZP4207 
• 
Causal relationship with IMP insulin 
• 
Causal relationship with IMP glucagon 
• 
Causal relationship with medical device 
• 
Causal relationship with procedures 
• 
Interruption or withdrawal of treatment with IMP or medical device and other measures 
taken 
• 
Outcome 
 
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10.4 
Pregnancy Reporting  
Female patients must be instructed to notify the Investigator immediately if they become 
pregnant or if they suspect to be pregnant during the trial. The Sponsor has a responsibility to 
monitor the outcome of all pregnancies reported during the clinical trial. 
 
Male patients must be instructed to notify the Investigator immediately if their partner becomes 
pregnant or suspects to be pregnant. The Sponsor has a responsibility to monitor the outcome 
of all pregnancies reported during the clinical trial. During an information meeting at the trial 
site, the patient’s partner will be fully informed by a physician of her participation in capturing 
the outcome data, and will be asked to provide her written consent.  
 
The Investigator must report all information on pregnancies, including AEs in the 
patient/patient’s partner, the fetus, and newborn infant/ toddler. The pregnancy report must be 
forwarded to the Sponsor preferably electronically as PDF or by fax. 
 
The Investigator must follow the pregnancy until the pregnancy outcome and the newborn 
infant(s) until the age of 1 month. The Investigator must collect information on the pregnancy 
and pregnancy complications as well as the pregnancy outcome including the health of the 
newborn infant(s) on the pregnancy forms. 
 
 The following must be collected:  
• 
Initial information of the pregnancy  
• 
Information on the outcome of the pregnancy, including the health status of the 
newborn infant(s) at the age of 1 month 
• 
All AEs in connection with the pregnancy and pregnancy outcome must be reported 
on the pregnancy forms. It must be clear in the description if the event occurs in the 
patient/patient’s partner, the fetus, or the newborn infant. 
• 
All SAEs in connection with the pregnancy and pregnancy outcome must be reported 
on the pregnancy forms following the same timelines as required for other SAEs. It 
must be clear in the description if the event occurs in the patient/patient’s partner, the 
fetus, or the newborn infant.  
 
The SAEs that must be reported include abnormal outcome – such as congenital anomalies, 
fetal death, and termination of pregnancy (spontaneous or elective abortion), including any 
anomalies of the fetus observed at gross examination or during autopsy – as well as other 
pregnancy complications (ectopic pregnancy) fulfilling the criteria of an SAE. 
 
10.5 
Hypoglycemia 
Hypoglycemia will be regarded as an AE and will be recorded and documented on an AE 
Form. For the purposes of AE reporting, the following definitions of hypoglycemia will be used: 
• 
Symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia 
are accompanied by a BG concentration ≤70 mg/dL 
• 
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of 
hypoglycemia but with a BG concentration ≤50 mg/dL 
• 
Severe hypoglycemia: an event requiring assistance of another person to actively 
administer carbohydrates, glucagon, or take other corrective actions 
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10.6 
Safety Monitoring 
10.6.1 
Data and Safety Monitoring Board 
An external DSMB will oversee the conduct of the trial, as set forth in the DSMB Charter. 
Additionally, the DSMB will be informed in the event of any serious and unexpected AEs. The 
DSMB will be informed if there are any changes to the trial protocol that could significantly 
impact the safety or scientific validity of the trial. A final DSMB meeting will convene after the 
completion of the trial. 
The participation of individual patients will be discontinued if they experience: 
•
Seizure or unconsciousness associated with hypoglycemia and associated with
participation in the trial 
•
Persistent nausea and vomiting thought to be related to glucagon dosing associated
with participation in the trial 
•
Hospitalization associated with participation in the trial
•
Pregnancy
•
Diabetic ketoacidosis
If more than 1 patient must be withdrawn from the trial for these reasons, the trial will stop and 
a vote of the DSMB will be required to restart it. All AEs that are serious and unexpected but 
related will be reported to the DSMB within 5 working days. 
Note that patients may discontinue participation at any time. Patients may be removed from 
the trial for other reasons, for instance, failure to comply with trial procedures or intercurrent 
illness that is unrelated to the BP but that precludes safe participation. Discontinuation of 
participation for these reasons will not contribute to a decision to discontinue the trial.  
10.6.2 
Zealand Pharma Safety Committee 
The internal Zealand Pharma Safety Committee is constituted to perform ongoing safety 
surveillance of clinical trials within ZP4207, including this trial. 
If safety signals are observed either based on reported SAEs, periodic review of laboratory 
parameters, planned review of all AEs reported between the safety committee meetings, or 
on notification of significant findings, the Safety Committee will take appropriate measures to 
safeguard the patients. 
11 
STATISTICS 
For all analysis, the 2 treatment arms from Part 1 (iPhone-based BP) will be compared, and 
the 2 treatment arms from Part 2 (iLet) will be compared. The analysis of Part 1 will be 
completely separate from the analysis of Part 2. 
11.1 
Analysis Populations 
The following analysis sets are defined in accordance with the ICH-E9 guidance: 
The Full Analysis Set is based on the intention-to-treat principle and includes all randomized 
patients. In exceptional cases, patients from the Full Analysis Set may be excluded (will be 
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decided in the database review [DBR] meeting). In such cases, the exclusion will be justified 
and documented. Patients will contribute to the evaluation “as randomized.” 
 
The Per-Protocol Set includes all patients of the Full Analysis Set who completed the trial 
without any major protocol violations. Patients in the Per-Protocol Set will contribute to the 
evaluation “as treated.” This analysis will only be used if it is different than the Full Analysis 
Set. 
 
The Safety Analysis Set includes all patients receiving at least 1 dose of the IMP. Patients in 
the Safety Analysis Set will contribute to the evaluation “as treated.”  
 
Analyses of efficacy endpoints will be based on the Full Analysis Set (and the Per-Protocol 
Set if necessary). This decision will be made in the DBR meeting. The analysis of the safety 
endpoints will be based on the Safety Analysis Set.  
 
Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. At this time, it will be 
determined if patients and/or data should be excluded from the analysis. Furthermore, outliers 
will be identified by data review according to ICH-E9. 
 
Obviously erroneous data points may be excluded from the analyses or re-analyzed 
(e.g., serum concentrations). The decision to re-analyze or exclude data points from the 
statistical analysis is the joint responsibility of the Sponsor, the Principal Investigator, and the 
Trial Statistician. 
 
The patients or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to database release. The documentation 
will be stored together with the remaining trial documentation. The patients and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report. 
 
11.2 
Statistical Methods  
Medpace will be responsible for the statistical analysis. The statistical planning and conduct 
of analyses of the data from this trial will follow the principles defined in relevant ICH guidelines 
and Medpace’s biostatistical SOPs. A general description of the statistical methods to be used 
is given in this section, specific details will be provided in the Statistical Analysis Plan (SAP), 
which will be prepared before database lock. All statistical analyses will be performed using 
SAS® (SAS Institute Inc., Cary, North Carolina, USA), version 9.3 or later.  
11.2.1 
Analysis of Safety 
The following variables will be evaluated according to treatment for safety purposes: 
 
Adverse Events 
All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). Individual AEs will be presented in a listing including relationship to trial 
product/device, severity, and treatment period at onset. If more than 20 treatment-emergent 
AEs (AEs with onset after [first] dosing at Visit 3 until the Follow-up Visit 6) are registered, a 
summary table including number of AEs, number of patients with at least 1 AE, and percentage 
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of exposed patients with at least 1 AE will be made by system organ class and treatment 
period at onset. 
Local Tolerability 
Local tolerability at the injection site will be summarized using descriptive statistics as 
appropriate. 
Laboratory Safety Assessments 
Laboratory assessments will be summarized. A listing of abnormal values will be provided. 
Physical Examination 
A frequency table will show the number and percentage of physical examination results. 
Vital Signs 
Vital signs will be summarized using descriptive statistics. 
12-lead ECG 
The Investigator’s evaluations of 12-lead ECGs will be summarized and abnormal individual 
evaluations will be listed together with the Investigator’s comments. Changes in 12-lead ECG 
between measurements will be recorded as AEs if the Investigator judges them to be clinically 
significant.  
11.2.2 
Analysis of Efficacy 
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis, any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. Further details will be included in the 
SAP. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow.  
11.2.3 
Interim Analysis 
An interim database lock may occur upon completion of Part 1 of the trial to analyze the 
iPhone-based BP data. 
11.2.4 
Sample Size Determination 
No formal sample size calculations were made. It is expected that between 20 and 24 patients 
will be randomized in the trial. The sample size is based on a clinical rather than statistical 
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rationale. The sample size is considered adequate to address the primary trial objective of 
exploring the safety of ZP4207 when used in the BP and with reference to Lilly glucagon used 
in the BP. 
12 
DATA MANAGEMENT AND RECORD KEEPING 
Data Management is the responsibility of Medpace. The complete Data Management process 
will be described in detail and agreed on in the Data Management Plan for this trial. 
12.1 
Data Handling 
Case Report Forms 
Electronic Case Report Forms will be used in this trial. The Data Management Department of 
Medpace will provide the eCRFs. All further information regarding the eCRFs and the data 
flow will be described and agreed on in the Data Management Plan. 
Device-Related Data 
During the trial, CGM data, calibration data, insulin dosing data, and glucagon dosing data will 
be automatically stored in the BP device (from which it will be downloaded at intervals), 
combined in a single database that will be compared against the primary data files for integrity, 
and ultimately transferred to Medpace.  
12.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
12.3 
Data Entry 
Data must be recorded using the electronic data capture (EDC) system as the trial is in 
progress. All site personnel must log into the system using their secure user name and 
password in order to enter, review, or correct trial data. These procedures must comply with 
Title 21 of the Code of Federal Regulations (21 CFR Part 11) and other appropriate 
international regulations. All passwords will be strictly confidential. 
12.4 
Medical Information Coding 
Adverse events and medical history will be coded using the latest version of MedDRA. Prior 
and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. 
12.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, 
will be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
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12.6 
Record Keeping 
Medpace will be responsible for hosting the TMF. Records of patients, source documents, 
monitoring visit logs, eCRFs, inventory of trial product, regulatory documents, and other 
Sponsor correspondence pertaining to the trial must be kept in the appropriate trial files at the 
site. Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
evaluation and reconstruction of the clinical trial. Source data are contained in source 
documents (original records or certified copies). These records will be retained in a secure file 
for the period as set forth in the Clinical Trial Agreement. Prior to transfer or destruction of 
these records, the Sponsor must be notified in writing and be given the opportunity to further 
store such records. 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
13.1 
Ethical Conduct of the Trial 
The trial will be conducted according to Medpace, MGH, and/or the Sponsor’s written 
instructions (SOPs, working instructions, or process descriptions). Content and definitions of 
the written instructions are based on the Declaration of Helsinki and the ICH GCP.  
13.2 
Institutional Review Board  
Written favorable opinion must be obtained from the responsible IRB prior to commencement 
of the trial. Clinical trial submission and reporting requirements before, during, and after 
completion of the trial will be performed in accordance with national law and local regulations. 
All amendments that affect patient safety or the trial integrity (substantial amendments) must 
not be implemented before favorable opinion has been obtained, unless necessary to 
eliminate hazards to the patients. Non-substantial amendments do not require favorable 
opinion by the IRB, but the respective IRB will be notified according to local requirements.  
The Sponsor and Investigator must approve any amendment in writing before its 
implementation. 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
IRB. The records should be filed in the Sponsor’s Trial Master File (TMF). 
13.3 
Informed Consent 
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirement(s) and adhere to the ICH GCP guideline and the 
requirements in the Declaration of Helsinki. 
Prior to any trial-related activity, the Investigator must give the patient oral and written 
information in a form that the patient can read and understand about all aspects of the trial 
that are relevant to the patient’s decision to participate. The patient will be given ample time 
to decide whether or not to participate in the trial. 
The patient must be informed that his/her personal trial-related data will be used in accordance 
with the local data protection law. The level of disclosure must also be explained to the patient. 
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The patient must be informed that his/her medical records may be examined by authorized 
monitors or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
 
A voluntary, personally signed and dated ICF must be obtained from the patient prior to any 
trial-related activity. The ICF must also be signed and dated by the physician or designee who 
conducted the informed consent procedure. A signed copy of the ICF and any additional 
patient information must be given to each patient.  
 
The responsibility for taking informed consent must remain with that of a research physician 
or designee. If information becomes available that may be relevant to the patient’s willingness 
to continue participating in the trial, the Investigator must inform the patient in a timely manner, 
and a revised written informed consent must be obtained. 
 
Should a protocol amendment become necessary, the ICF may need to be revised to reflect 
the changes to the protocol. It is the responsibility of the Sponsor to ensure that an amended 
consent form is reviewed and has received favorable opinion from IRB, and the Investigator 
must ensure that the amended consent form is signed by all patients subsequently entered 
into the trial and those currently in the trial, if affected by the amendment. 
 
13.4 
Trial Monitoring Requirements  
The monitoring procedures for this trial are described in detail in the Monitoring Manual. The 
objectives of the monitoring procedures are to ensure that (i) the safety and rights of the trial 
patients are respected, (ii) that accurate, valid, and complete data are collected, and (iii) that 
the trial is conducted in accordance with the trial protocol, the principles of GCP, and local 
legislation, including drug accountability. 
 
The monitor must be given direct access to the investigational site files and source documents 
(original documents, data, and records). Direct access includes permission to examine, 
analyze, verify, and reproduce any record(s) and report(s) that are important to evaluation of 
the clinical trial. 
 
Key tasks of the monitor include verifying the presence of informed consent, the adherence to 
the inclusion/exclusion criteria, the documentation of SAEs, and the recording of all safety and 
efficacy variables. The monitor will also confirm the completeness of patient records, the 
adherence to the protocol, ICH GCP, and the progress in patient enrollment and perform drug 
accountability.  
 
Because no information that could reveal the identity of patients may ever be removed from 
the trial site, the monitor will visit the site at regular intervals to perform these monitoring tasks. 
Other contact between the Investigator and monitors will be maintained as required through 
telephone calls and e-mail. The Investigator and/or key members of staff involved in the trial 
must be available to assist the monitors during all visits.  
 
Site Initiation Visit 
During the Site Initiation Visit (SIV) the CRO, Sponsor, and/or monitors will go through 
information on the IMP, the protocol, the eCRFs, and other key aspects of the trial with the 
Investigator and the key members of staff involved in the trial. The topics of the SIV are 
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documented in a SIV report made available to the Investigator. Documentation on the SIV 
(e.g., power point presentation) should be filed by both Investigator and Sponsor. 
13.5 
Disclosure of Data 
Data generated by this trial must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal 
physician or other appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the trial is confidential and disclosure to third 
parties other than those noted above is prohibited. 
13.6 
Retention of Records  
Massachusetts General Hospital will maintain the patient’s medical file according to local 
regulations. MGH will archive the documentation pertaining to the trial in an archive after 
completion or discontinuation of the trial if not otherwise notified. MGH should not destroy any 
documents without prior permission from the Sponsor. 
The documentation includes all the raw data generated during the clinical trial, the 
investigational site files, and a copy of the clinical trial report. The documents will be retained 
for a period of at least 15 years at archives by MGH, or its sub-contractor. After this period, 
the Sponsor will be contacted and their advice sought on the return or further retention of the 
trial records. 
The Sponsor will maintain the documentation pertaining to the trial in accordance with national 
regulations. 
13.7 
Publication Policy  
The Principal Investigator of the trial will review and sign the clinical trial report. A summary of 
the final clinical trial report will be submitted to the IRB and Competent Authority. 
According to the Declaration of Helsinki Investigators and Sponsors “have ethical obligations 
with regard to the publication and dissemination of the results of research.” The trial design 
and results may be published as 1 or more original research manuscripts/abstracts and 
presented at a scientific meeting. The Investigator and Sponsor reserve the right to review any 
proposed presentation of the results of this trial before they are submitted for publication. 
Authorship on any publication(s) resulting from this clinical trial will be assigned according to 
the recommendations of the International Committee of Medicinal Journal Editors. 
Participating patients will not be identified by name in any published reports about the clinical 
trial. 
The Sponsor is responsible for trial registration at ClinicalTrials.gov (www.clinicaltrials.gov) 
according to the requirements from the FDA. 
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13.8 
Legal Aspects  
An implicit or explicit approval must be obtained from the Competent Authority prior to 
commencement of the trial. Clinical trial submission and reporting requirements before, during, 
and after completion of the trial will be performed in accordance with national law and local 
regulations. 
 
An implicit or explicit approval will also be mandatory before implementation of substantial 
changes. Non-substantial amendments do not require approval from the Competent Authority 
but will be notified according to local requirements. 
 
The Sponsor and Investigator must approve the amendment in writing before its 
implementation. 
 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
Competent Authority. The records should be filed in the Sponsor’s TMF. 
  
Audits and Inspections  
In the event of an audit, representatives of the Sponsor or designee, or national and 
international regulatory authorities may request access to all trial records for inspection and 
copying. Such access must be stated in the ICF signed by the patient. 
 
13.9 
Sponsor Discontinuation Criteria  
The Sponsor, Investigator, or a pertinent regulatory authority may decide to stop the trial or 
part of the trial at any time (e.g., upon completion of Part 1 [iPhone-based BP]), but agreement 
on procedures to be followed must be obtained. 
 
Conditions that may warrant termination of the clinical trial include, but are not limited to: 
• 
Safety or administrative reasons 
• 
The discovery of an unexpected, relevant, or unacceptable risk to the patients enrolled 
in the clinical trial 
• 
A decision of the Sponsor to suspend or discontinue investigation of the IMP 
 
If the trial is prematurely terminated or suspended, the Investigator should promptly inform the 
patients and assure appropriate therapy and follow-up. Furthermore, the Sponsor should 
promptly inform the IRB and provide a detailed written explanation. The pertinent regulatory 
authorities should be informed according to national regulations. 
 
If after the termination of the trial the risk/benefit analysis has changed, the new evaluation 
should be provided to the IRB in case it will have an impact on the planned follow-up of the 
patients who have participated in the trial. Necessary actions needed to protect the patients 
should be described. 
 
13.10 
Patient Compensation 
Financial compensation will be provided to all patients who complete the Screening Visit. 
Patients will be paid $25 for completing the Screening Visit whether or not they are eligible to 
participate in the trial. Patients will be compensated $25 for completing the Training Visit. 
Patients will be compensated $100 for completing each of the 2 treatment visits, $25 for 
completing the ADA Assessment Visit, and $25 for completing the Follow-up Visit. Thus, the 
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APPENDIX A: SCHEDULE OF PROCEDURES – PARTS 1 AND 2 
Trial Visit 
Visit 1 [1]
Screening 
Visit 2
Training 
Visit 3 [2] [3]
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3]
[5] 
(2nd Treatment 
Visit) 
Visit 5
ADA 
Assessment 
Visit [6] 
Visit 6
Follow-Up 
[7] 
Informed consent 
X 
Assess/confirm elig bility 
X 
X 
Demographics 
X
Medical, surgical, and social history; allergies  
X 
Concomitant illness 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Height, weight, physical examination, and vital signs 
including body temperature and blood pressure [8] 
X 
X [9] 
X [9] 
12-lead ECG 
X 
X [10] 
X [10] 
Urine HCG pregnancy test and menstrual history [11]   
X 
X 
X 
FSH [12] 
X 
Screening labs – HbA1c, optional fractionated 
metanephrines [13] 
X 
Safety lab sampling including chemistry and hematology 
X 
X [10] 
X [10] 
X 
Training on devices [14] 
X 
Monitored BP use 
X 
X
Plasma glucose sampling [15] 
X 
X 
ZP4207/glucagon exposure sampling [16] 
X 
X 
Nausea and infusion site pain VAS and infusion site 
reaction Draize scale (visit start [17], hourly, & visit end) 
X 
X 
Standardized lunch [18] 
X 
X 
In-clinic exercise [19] 
X 
X 
ADA 
X [20] 
X 
X 
Adverse event review 
X 
X 
X 
X 
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1. 
Once the patient has been enrolled and eligibility has been established, the order of the treatment visits will be randomized in blocks of 2 patients. 
2. 
In Part 1, each patient will participate in 2 treatment visits: 1 with the iPhone-based BP using ZP4207 and 1 with the iPhone-based BP using Lilly glucagon in a 
randomized order. In Part 2, each patient will participate in 2 treatment visits: 1 with the iLet using ZP4207 and 1 with the iLet using Lilly glucagon in a randomized 
order. Up to 2 patients may participate in the trial per day. 
3. 
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal skin and calibrate the sensor when prompted using the provided Nova 
StatStrip Xpress meter. Patients will be asked to arrive at he visit at least 1 hour in advance of the start of the BP having fasted since 12:00 AM he night before 
(treatment with simple carbohydrate of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled within the visit window. If BG 
is >250 mg/dL, the visit will be rescheduled within the visit window. If BG is <50 mg/dL, the patient will be treated with simple carbohydrate according to the 15/15 rule 
(15 grams of carbohydrates, repeated in 15 minutes if necessary). The visit will not need to be rescheduled unless the patient experiences a severe hypoglycemic 
event and requires treatment with glucagon or intravenous dextrose. 
4. 
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 30 days after screening (Visit 1). 
5. 
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum of 3 weeks between Visit 3 and Visit 4. 
6. 
Visit 5 will take place 10 days ±3 days from Visit 4.  
7. 
Visit 6 will take place 25 days ±4 days from Visit 4. 
8. 
Height and physical examination will be measured at Visit 1 only. 
9. 
Vital signs including body temperature and blood pressure will be obtained at visit start and visit end. Blood pressure and heart rate will be measured in the seated 
position and within 3 minutes of standing. 
10. At visit start and immediately after end of exercise. 
11. Urine HCG pregnancy test only for women of childbearing potential. The date of the last menstrual period in female patients will be obtained at Visit 1 only. 
12. Test for FSH level only for postmenopausal women amenorrheic for less than 1 year. 
13. If indicated by history. 
14. Patients will be trained in the insertion and calibration of the Dexcom G4 sensor, diabetes management (e g., basal insulin rate adjustment by insulin pump) during 
fasting prior to and between the treatment visits, and trial policies and procedures. 
15. Collected at least hourly. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG 
is <80 mg/dL, then sampling will be every 10 minutes. 
16. Collected at least hourly. If BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the Investigator. 
17. Once the infusion sites have been placed but no drug has yet been administered. 
18. Between approximately Hour 3 and Hour 4. 
19. Between approximately Hour 6 and Hour 7. 
20. Before the start of dosing. 
ADA = anti-drug antibodies; BG = blood glucose; BP = bionic pancreas; CGM = continuous glucose monitor; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
HbA1c = hemoglobin A1c; HCG = human chorionic gonadotropin; VAS = visual analog scale. 
 
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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Chemistry 
Alanine aminotransferase 
Aspartate aminotransferase 
Alkaline phosphatase 
Total protein 
Albumin 
Total and direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Creatinine 
Estimated glomerular filtration rate 
Blood urea nitrogen 
Uric acid
Bicarbonate 
Sodium 
Potassium 
Calcium 
Chloride 
Phosphorus 
 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell count 
White blood cell count and differential 
Platelets 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
 
Pregnancy Test 
A urine HCG pregnancy test will be performed at screening, Visit 3, and Visit 4 only for 
women of childbearing potential. 
 
Anti-drug Antibodies Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken prior to first dosing (Visit 3), at the ADA Assessment Visit (Visit 5), 
and at the Follow-up Visit (Visit 6). 
 
ZP4207/Glucagon Exposure Sampling 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at 
the discretion of the Investigator. 
 
Screening Visit Only 
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year 
Optional fractionated plasma metanephrines (if indicated by history) 
Hemoglobin A1c 
 
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SUMMARY OF CHANGES DOCUMENT 
PROTOCOL NUMBER ZP4207-16051 
AMENDMENT NUMBER 6.0 
PROTOCOL TITLE: The Bionic Pancreas Feasibility Trial Testing the Bionic Pancreas with 
ZP4207 
AMENDMENT DATE: 28 September 2016 
SUMMARY AND JUSTIFICATION OF CHANGES: 
This amendment was developed in response to FDA feedback regarding patients with 
hypotension or orthostatic hypotension, the diabetes management instruction for patients during 
the fasting period, and the management of patients who arrive at the treatment visits with 
hypoglycemia.  
Patients with hypotension (systolic blood pressure [SBP] <90 mm Hg or diastolic blood pressure 
[DBP] <60 mm Hg), either sitting or standing, or orthostatic hypotension (decrease in SBP 
>20 mm Hg or decrease in DBP >10 mm Hg within 3 minutes of standing from a seated 
position) at screening will be excluded from participation in the trial. 
At screening and at the start and end of the treatment visits, orthostatic vital signs (heart rate 
and blood pressure) will be measured in the seated position and within 3 minutes of standing. 
Prior to discharge, if patients have hypotension or orthostatic hypotension, discharge will be 
delayed until their blood pressure is normal and stable. 
The instructions patients will receive concerning diabetes management during the fasting period 
have been clarified. 
Upon arrival at the treatment visit, if blood glucose is <50 mg/dL, the patient will be treated with 
simple carbohydrate according to the 15/15 rule (15 grams of carbohydrates, repeated in 
15 minutes if necessary). The visit will not need to be rescheduled unless the patient 
experiences a severe hypoglycemic event and requires treatment with glucagon or intravenous 
dextrose.  
The schedule of procedures was updated to reflect the changes specified in this document. 
Other minor edits were made throughout the protocol to provide greater clarity and consistency. 
SUMMARY OF CHANGES: 
The amended protocol sections and the details of the changes are summarized in the following 
sections. Revisions to the protocol are presented as strikethrough (ie, subject) for text that was 
removed and bold (ie, subject) for text that was added. 
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Section 4.2, Exclusion Criteria, Page 25 
Original Text: 
23. Hypertension with systolic blood pressure 160 mm Hg or diastolic blood pressure 
100 mm Hg despite treatment 
24. Untreated or inadequately treated mental illness (indicators would include symptoms such 
as psychosis, hallucinations, mania, and any psychiatric hospitalization in the last year), or 
treatment with anti-psychotic medications that are known to affect glucose regulation 
New Text: 
23. Hypertension with systolic blood pressure (SBP) 160 mm Hg or diastolic blood pressure 
(DBP) 100 mm Hg despite treatment 
24. Hypotension (SBP <90 mm Hg or DBP <60 mm Hg), either sitting or standing, or 
orthostatic hypotension (decrease in SBP >20 mm Hg or decrease in DBP >10 mm 
Hg within 3 minutes of standing from a seated position) 
2425. Untreated or inadequately treated mental illness (indicators would include symptoms 
 
such as psychosis, hallucinations, mania, and any psychiatric hospitalization in the last 
 
year), or treatment with anti-psychotic medications that are known to affect glucose 
 
regulation 
Section 7.2.1, Data Collected at Screening, Page 32 
Original Text: 
 
Height, weight, physical examination, and vital signs including body temperature and blood 
pressure 
 
12-lead ECG 
New Text: 
 
Height, weight, physical examination, and vital signs including body temperature and blood 
pressure 
 
Orthostatic vital signs (heart rate and blood pressure) in the seated position and 
within 3 minutes of standing 
 
12-lead ECG 
Section 7.3, Training Visit (Visit 2), Page 32 
Original Text: 
A Training Visit will take place before the first treatment visit. Patients will be trained in the 
insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. Trial staff 
will verify that the patients have understood the material and are competent to participate safely 
in the trial. Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits per the 
medical judgment of the Investigator. Concomitant medications will also be reviewed. 
 
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New Text: 
A Training Visit will take place before the first treatment visit. Patients will be trained in the 
insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. Trial staff 
will verify that the patients have understood the material and are competent to participate safely 
in the trial. Concomitant medications will also be reviewed. 
 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate adjustment 
by insulin pump) during fasting prior to and between the treatment visits per the medical 
judgment of the Investigator. Concomitant medications will also be reviewed. The goals of 
diabetes management for patients during the fasting period are to avoid hypoglycemia, 
to treat hypoglycemia if it occurs, and to arrive at the treatment visit in the morning with 
a BG between 80 and 250 mg/dL. If insulin pump basal rates are properly configured, 
patients should be able to fast from 12:00 AM until the time of arrival for the visit without 
a high likelihood that they will become hypoglycemic or severely hyperglycemic. 
Patients will be asked whether they believe that they can safely fast from 12:00 AM until 
their arrival time at approximately 7:00 AM without adjusting their basal rates. If they 
have concerns, a trial physician will consult with them regarding pump basal rate 
adjustments. In all cases, subjects will be instructed to self-treat with carbohydrates 
according to the 15/15 rule (15 grams of carbohydrates, repeated in 15 minutes if 
necessary) during the overnight fasting period and at any time prior to their arrival at the 
trial site for the treatment visits. 
Section 7.4.1, Visit Procedures, Page 34 
Original Text: 
 
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the BP 
having fasted since 12:00 AM the night before (treatment with simple carbohydrate of up to 
30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled within the 
visit window. If BG is >250 mg/dL, the visit will be rescheduled within the visit window. If BG 
is <50 mg/dL, treatment with simple carbohydrate is allowed. If the patient experiences 
persistent hypoglycemia, the visit will be rescheduled within the visit window. If the visit 
needs to be rescheduled due to hypoglycemia or hyperglycemia, trial staff will assist the 
patient with insulin or medication adjustments to address glycemic control. The patient will 
be instructed to contact trial staff later in the day if his or her BG remains uncontrolled. 
 
Upon arrival to the visit, the patient’s weight and vital signs including body temperature and 
blood pressure will be documented. 
 
Patient reports of symptoms, any other complaints, and AEs will be reviewed. 
New Text: 
 
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the BP 
having fasted since 12:00 AM the night before (treatment with simple carbohydrate of up to 
30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled within the 
visit window. If BG is >250 mg/dL, the visit will be rescheduled within the visit window. If BG 
is <50 mg/dL, treatment the patient will be treated with simple carbohydrate is allowed. If 
the patient experiences persistent hypoglycemia, according to the 15/15 rule (15 grams 
of carbohydrates, repeated in 15 minutes if necessary). The visit will not need to be 
rescheduled within the visit window unless the patient experiences a severe 
hypoglycemic event and requires treatment with glucagon or IV dextrose. If the visit 
needs to be rescheduled due to hypoglycemia or hyperglycemia, trial staff will assist the 
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patient with insulin or medication adjustments to address glycemic control. The patient will 
be instructed to contact trial staff later in the day if his or her BG remains uncontrolled. 

Upon arrival to the visit, the patient’s weight and vital signs including body temperature and
blood pressure will be documented. 

Orthostatic vital signs (heart rate and blood pressure) will be measured in the seated
position and within 3 minutes of standing. 

Patient reports of symptoms, any other complaints, and AEs will be reviewed.
Section 7.4.1, Visit Procedures, Page 36 
Original Text: 

Patients may choose to withdraw from the trial at any time. If they withdraw from the trial,
they should alert a provider immediately.

Just prior to the end of the study visit, vital signs including body temperature and blood
pressure will be obtained and a 12-lead ECG will be performed.

After approximately Hour 8, but not earlier than at least 60 minutes after end of exercise,
the BP will be stopped and the patient will continue with their personal insulin pump.
New Text: 

Patients may choose to withdraw from the trial at any time. If they withdraw from the trial,
they should alert a provider immediately.

Just prior to the end of the study visit, vital signs including body temperature and blood
pressure will be obtained and a 12-lead ECG will be performed. Orthostatic vital signs
(heart rate and blood pressure) will be measured in the seated position and within
3 minutes of standing. If patients have hypotension or orthostatic hypotension,
discharge will be delayed until their blood pressure is normal and stable.

After approximately Hour 8, but not earlier than at least 60 minutes after end of exercise,
the BP will be stopped and the patient will continue with their personal insulin pump.
Section 7.4.2, Data Collected During the Treatment Visits, Page 37 
Original Text: 

Vital signs including body temperature and blood pressure (at visit start and visit end) and
weight

Concomitant medications
New Text: 

Vital signs including body temperature and blood pressure (at visit start and visit end) and
weight

Orthostatic vital signs (heart rate and blood pressure) in the seated position and
within 3 minutes of standing

Concomitant medications
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Appendix A, Schedule of Procedures, Footnote 3, Page 60 
Original Text: 
3. The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal 
skin and calibrate the sensor when prompted using the provided Nova StatStrip Xpress 
meter. Patients will be asked to arrive at the visit at least 1 hour in advance of the start of 
the BP having fasted since 12:00 AM the night before (treatment with simple carbohydrate 
of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled 
within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the visit 
window. If BG is <50 mg/dL, treatment with simple carbohydrate is allowed. If the patient 
experiences persistent hypoglycemia, the visit will be rescheduled within the visit window. 
New Text: 
3. The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal 
skin and calibrate the sensor when prompted using the provided Nova StatStrip Xpress 
meter. Patients will be asked to arrive at the visit at least 1 hour in advance of the start of 
the BP having fasted since 12:00 AM the night before (treatment with simple carbohydrate 
of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled 
within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the visit 
window. If BG is <50 mg/dL, treatment the patient will be treated with simple 
carbohydrate is allowed. If the patient experiences persistent hypoglycemia, according to 
the 15/15 rule (15 grams of carbohydrates, repeated in 15 minutes if necessary). The 
visit will not need to be rescheduled within the visit window unless the patient 
experiences a severe hypoglycemic event and requires treatment with glucagon or 
intravenous dextrose. 
Appendix A, Schedule of Procedures, Footnote 9, Page 60 
Original Text: 
9. Vital signs including body temperature and blood pressure will be obtained at visit start 
and visit end. 
New Text: 
9. Vital signs including body temperature and blood pressure will be obtained at visit start 
and visit end. Blood pressure and heart rate will be measured in the seated position 
and within 3 minutes of standing. 
 
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CLINICAL TRIAL PROTOCOL 
The Bionic Pancreas Feasibility Trial Testing the Bionic Pancreas with ZP4207 
 
Investigational Product: ZP4207 
Protocol Number: ZP4207-16051 
IND Number: 129980 
Phase: 2  
 
Principal Investigator: 
Steven J. Russell, MD, PhD1 
 
Co-Investigator: 
, RN, CDE1 
 
 
1Diabetes Research Center, Massachusetts General Hospital, Boston, Massachusetts 
 
Sponsor: 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Tel: +45 88 77 36 00 
Fax: +45 88 77 38 98 
 
Original Version: 03 May 2016 
Amendment Number 1.0: 28 June 2016 
Amendment Number 2.0: 03 August 2016 
Amendment Number 3.0: 17 August 2016 
Amendment Number 4.0: 02 September 2016 
Amendment Number 5.0: 09 September 2016 
Amendment Number: 6.0 
Protocol Version Number: 7.0 
 
Date: 28 September 2016 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Zealand Pharma A/S except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical trial for Zealand Pharma A/S. 
You are allowed to disclose the contents of this document only to your Institutional Review 
Board (IRB) and trial personnel directly involved with conducting this protocol. Persons to 
whom the information is disclosed must be informed that the information is confidential and 
proprietary to Zealand Pharma A/S and that it may not be further disclosed to third parties. 
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Clinical Trial Protocol
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Version number: 7.0
Amendment 6.0
Date: 28 September 2016
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INVESTIGATOR AGREEMENT
By signing below I agree that:
I have read this protocol. I approve this document and I agree that it contains all necessary 
details for carrying out the trial as described. I will conduct this trial in accordance with the 
design and specific provision of this protocol and will make a reasonable effort to complete 
the trial within the time designated. I will provide copies of this protocol and access to all 
information furnished by Zealand Pharma A/S to trial personnel under my supervision. I will 
discuss this material with them to ensure they are fully informed about the trial product and 
trial procedures. I will let them know that this information is confidential and proprietary to 
Zealand Pharma A/S and that it may not be further disclosed to third parties. I understand 
that the trial may be terminated or enrollment suspended at any time by Zealand Pharma 
A/S, with or without cause, or by me if it becomes necessary to protect the best interests of 
the trial patients.
I agree to conduct this trial in full accordance with Food and Drug Administration 
Regulations, Institutional Review Board/Ethic Committee Regulations and ICH Guidelines for 
Good Clinical Practices.
____________
____________________
Investigator’s Signature
Date
______________________________________________
Investigator’s Printed Name
Steven J. Russell, MD, PhD
9/28/2016
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Date: 28 September 2016 
 
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SYNOPSIS 
TITLE: The Bionic Pancreas Feasibility Trial Testing the Bionic Pancreas with ZP4207 
 
PROTOCOL NUMBER: ZP4207-16051 
 
INVESTIGATIONAL PRODUCT: ZP4207 
 
PHASE: 2 
 
INDICATION: ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid 
formulation which is being studied to improve glycemic control in adults (and children) with 
type 1 diabetes mellitus (T1DM) as part of a bihormonal bionic pancreas (BP). 
 
OBJECTIVES: 
 
Primary: The primary objective is to conduct a trial testing the safety and tolerability of the BP 
using either the iLet or the iPhone platform when used with ZP4207 in 20 adult (≥18 years of 
age) patients with T1DM. 
 
Secondary: The secondary objectives are to measure glycemic regulation, including 
hypoglycemia exposure (percent of time spent with continuous glucose monitor [CGM] 
glucose <60 mg/dL), evaluate BP device reliability, and to document the satisfaction of 
patients with the BP with the goal of optimizing the functionality and user interface of the BP. 
 
POPULATION: Up to 40 adult (≥18 years of age) patients who already manage their T1DM 
using continuous subcutaneous (SC) insulin infusion pump therapy can be enrolled. It is 
expected that up to 10 patients will complete each part of the trial protocol. 
 
TRIAL DESIGN: This trial is a single-center, open-label, 2-part, randomized cross-over trial. 
The trial will enroll adult patients with T1DM and will assess the safety and efficacy of the BP 
using either the iLet or the iPhone platform using the glucagon analog ZP4207 versus Lilly 
glucagon. In Part 1, up to 10 patients will participate in two 1-day treatment arms in random 
order (iPhone-based BP using ZP4207 and iPhone-based BP using Lilly glucagon) according 
to a pre-generated randomization scheme. In Part 2, up to 10 new patients will participate in 
two 1-day treatment arms in random order (iLet using ZP4207 and iLet using Lilly glucagon) 
according to a pre-generated randomization scheme. Patients can only participate in 1 part of 
the trial. An interim database lock may occur upon completion of Part 1 of the trial to analyze 
the iPhone-based BP data. The iLet and the iPhone-based BP will also administer insulin 
(insulin lispro, Lilly Humalog) using the same blood glucose (BG) control algorithm for all 
4 treatment arms. The trial will be conducted at a single center, the Massachusetts General 
Hospital Diabetes Center in Boston, MA. 
 
TRIAL TREATMENT: The trial involves SC administration of insulin lispro (Humalog, Lilly), 
which is commercially available by prescription and is indicated for patients with T1DM, but 
not for use in a BP. 
 
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The trial also involves SC administration of Lilly glucagon in 1 iLet arm and 1 iPhone-based 
BP arm. Lilly glucagon is commercially available by prescription and is indicated for patients 
with T1DM in severe hypoglycemia, but not for use in a BP. 
The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, in the 
other iLet arm and the other iPhone-based BP arm. ZP4207 will be made available by Zealand 
Pharma A/S, Denmark as liquid formulation in prefilled syringes of 0.6 mL. 
PRIMARY ENDPOINT: 
The primary endpoint is the safety and tolerability of ZP4207 in the BP using either the iLet or 
the iPhone platform as assessed by: 
•
Number and type of adverse events (AEs)
•
Clinical laboratory measurements
•
Vital signs
•
12-lead electrocardiogram (ECG)
•
Local tolerability and infusion site reactions as measured with the Draize scale
•
Immunogenicity as measured by anti-drug antibodies
•
Pain as measured on a 10 cm visual analog scale (VAS)
•
Nausea as measured on a 10 cm VAS
SECONDARY ENDPOINTS: 
The secondary endpoints include measurements of BP function as well as glycemic and 
non-glycemic measurements. 
Bionic Pancreas Function 
This endpoint data will be generated from the BP data during each treatment visit: 
•
Average percent insulin dose amounts calculated by the BP control algorithm that are
successfully delivered by the pump
•
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully delivered by the pump
•
Average percent dose amounts successfully issued to the pump by the BP control
algorithm that are successfully delivered by the pump (calculated doses are not issued
unless the pump is accessible and its delivery channel is available)
o
Average percent insulin dose amounts successfully issued to the pump by the
BP control algorithm that are successfully delivered by the pump
o
Average percent glucagon/ZP4207 dose amounts successfully issued to the
pump by the BP control algorithm that are successfully delivered by the pump
•
Average percent dose amounts calculated by the BP algorithm that are successfully
issued to the pump by the BP (calculated doses are not issued unless the pump is
accessible and its delivery channel is available)
o
Average percent insulin dose amounts calculated by the BP control algorithm
that are successfully issued by the BP
o
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully issued by the BP
•
Average percent of 5-minute steps during which the BP is functioning nominally in all
respects based on real-time CGM data (new CGM glucose reading captured, dose
calculated, and dose issued to pumps)
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• 
Average percent of 5-minute steps during which the BP is functioning nominally with 
or without a new CGM glucose reading captured (dose calculated and dose issued to 
pumps). If a CGM signal is not available, the dose calculated may be based on weight 
or historical basal rates. 
• 
CGM reliability index, calculated as percent of possible values actually recorded by 
CGM 
• 
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter 
download 
• 
List of technical faults associated with the BP including cause and resolution 
 
Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit: 
• 
Fraction of time spent within each of the following glucose ranges: 
o <50 mg/dL 
o <60 mg/dL 
o <70 mg/dL 
o 70-120 mg/dL 
o 70-140 mg/dL 
o 70-180 mg/dL  
o >180 mg/dL 
o >250 mg/dL 
o >300 mg/dL 
• 
Number of severe hypoglycemic events (patients unable to self-treat, requiring the 
assistance of another person) 
• 
Number of episodes of symptomatic hypoglycemia 
• 
Number of carbohydrate interventions for hypoglycemia 
• 
Total grams of carbohydrates taken for hypoglycemia 
• 
Mean CGM glucose 
 
Non-glycemic 
• 
Glucagon/ZP4207 total delivery per kg of body mass 
• 
Insulin total delivery per kg of body mass 
• 
Number of unscheduled infusion set replacements 
• 
Number of unscheduled CGM sensor changes 
 
EVALUATION OF TRIAL DATA: The following variables will be evaluated according to 
treatment for safety purposes: AEs, local tolerability, laboratory safety assessments, physical 
examination, vital signs, and 12-lead ECGs.  
 
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
 
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
 
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A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow. 
  
SPONSOR: 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Tel: +45 88 77 36 00 
Fax: +45 88 77 38 98 
 
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TABLE OF CONTENTS 
SIGNATURE PAGE ............................................................................................................. 2 
INVESTIGATOR AGREEMENT .......................................................................................... 3 
SYNOPSIS ........................................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................... 8 
LIST OF FIGURES ............................................................................................................ 11 
LIST OF ABBREVIATIONS .............................................................................................. 12 
1 
INTRODUCTION AND BACKGROUND INFORMATION ...................................... 14 
1.1 
Background and Rationale ..................................................................................... 14 
1.2 
Bihormonal Bionic Pancreas System ..................................................................... 15 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System ........................ 16 
1.4 
ZP4207 ................................................................................................................... 18 
1.5 
Risk/Benefit ............................................................................................................ 19 
2 
TRIAL OBJECTIVES .............................................................................................. 22 
2.1 
Primary Objective ................................................................................................... 22 
2.2 
Secondary Objectives ............................................................................................. 22 
3 
TRIAL DESCRIPTION ............................................................................................ 22 
3.1 
Summary of Trial Design ........................................................................................ 22 
3.2 
Indication ................................................................................................................ 23 
3.3 
Number of Patients ................................................................................................. 23 
4 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................ 23 
4.1 
Inclusion Criteria ..................................................................................................... 24 
4.2 
Exclusion Criteria .................................................................................................... 24 
4.3 
Target Population ................................................................................................... 26 
4.4 
Withdrawal Criteria ................................................................................................. 26 
5 
ASSIGNMENT TO TREATMENT GROUPS........................................................... 26 
6 
TRIAL TREATMENT .............................................................................................. 27 
6.1 
Investigational Medicinal Products ......................................................................... 27 
6.2 
Storage and Drug Accountability of IMPs ............................................................... 27 
6.3 
Dispensing and Return of IMPs .............................................................................. 27 
6.4 
Doses ..................................................................................................................... 28 
6.5 
iPhone-based Bionic Pancreas .............................................................................. 28 
6.6 
iLet Bionic Pancreas ............................................................................................... 29 
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6.7 
Other Trial Devices ................................................................................................. 30 
6.8 
Concomitant Medications ....................................................................................... 30 
6.8.1 
Permitted Medications and/or Procedures ...................................................... 30 
6.8.2 
Excluded Medications and/or Procedures ....................................................... 31 
7 
TRIAL PROCEDURES ........................................................................................... 31 
7.1 
Informed Consent ................................................................................................... 31 
7.2 
Screening Visit (Visit 1) .......................................................................................... 31 
7.2.1 
Data Collected at Screening ............................................................................ 32 
7.3 
Training Visit (Visit 2) .............................................................................................. 32 
7.4 
Treatment Visits (Visit 3 and Visit 4) ....................................................................... 33 
7.4.1 
Visit Procedures .............................................................................................. 34 
7.4.2 
Data Collected During the Treatment Visits .................................................... 36 
7.4.3 
Response to Hypoglycemia ............................................................................. 37 
7.4.4 
Response to Hyperglycemia ........................................................................... 38 
7.4.5 
Response to Nausea/Vomiting ........................................................................ 38 
7.4.6 
Response to Other Medical Needs ................................................................. 38 
7.4.7 
Monitoring of Bionic Pancreas Performance ................................................... 38 
7.4.8 
Supervision by Trial Staff ................................................................................ 38 
7.5 
Anti-drug Antibodies Assessment Visit (Visit 5) ...................................................... 38 
7.6 
Follow-up Visit (Visit 6) ........................................................................................... 39 
8 
ENDPOINTS ........................................................................................................... 39 
8.1 
Primary Endpoint .................................................................................................... 39 
8.2 
Secondary Endpoints ............................................................................................. 39 
8.2.1 
Bionic Pancreas Function ................................................................................ 39 
8.2.2 
Glycemic .......................................................................................................... 40 
8.2.3 
Non-glycemic ................................................................................................... 40 
9 
LABORATORY ASSESSMENTS ........................................................................... 40 
9.1 
Safety Laboratory Assessments ............................................................................. 40 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) .............................................. 41 
9.3 
Exposure Assessments (ZP4207 and Glucagon) ................................................... 41 
9.4 
Anti-drug Antibodies Assessments ......................................................................... 41 
10 
SAFETY REPORTING ............................................................................................ 41 
10.1 
Adverse Events ...................................................................................................... 41 
10.1.1 
Follow-up of Adverse Events ........................................................................... 42 
10.1.2 
Precautions ..................................................................................................... 42 
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10.1.3 
Assessment of Adverse Events by the Investigator ........................................ 42 
10.2 
Serious Adverse Events ......................................................................................... 43 
10.3 
Adverse Event Reporting – Procedures for Investigators ....................................... 44 
10.4 
Pregnancy Reporting .............................................................................................. 46 
10.5 
Hypoglycemia ......................................................................................................... 47 
10.6 
Safety Monitoring .................................................................................................... 47 
10.6.1 
Data and Safety Monitoring Board .................................................................. 47 
10.6.2 
Zealand Pharma Safety Committee ................................................................ 47 
11 
STATISTICS ........................................................................................................... 48 
11.1 
Analysis Populations .............................................................................................. 48 
11.2 
Statistical Methods ................................................................................................. 48 
11.2.1 
Analysis of Safety ............................................................................................ 49 
11.2.2 
Analysis of Efficacy ......................................................................................... 49 
11.2.3 
Interim Analysis ............................................................................................... 50 
11.2.4 
Sample Size Determination ............................................................................. 50 
12 
DATA MANAGEMENT AND RECORD KEEPING ................................................ 50 
12.1 
Data Handling ......................................................................................................... 50 
12.2 
Computer Systems ................................................................................................. 50 
12.3 
Data Entry ............................................................................................................... 50 
12.4 
Medical Information Coding .................................................................................... 51 
12.5 
Data Validation ....................................................................................................... 51 
12.6 
Record Keeping ...................................................................................................... 51 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ........................... 51 
13.1 
Ethical Conduct of the Trial .................................................................................... 51 
13.2 
Institutional Review Board ...................................................................................... 51 
13.3 
Informed Consent ................................................................................................... 52 
13.4 
Trial Monitoring Requirements ............................................................................... 52 
13.5 
Disclosure of Data .................................................................................................. 53 
13.6 
Retention of Records .............................................................................................. 53 
13.7 
Publication Policy ................................................................................................... 53 
13.8 
Legal Aspects ......................................................................................................... 54 
13.9 
Sponsor Discontinuation Criteria ............................................................................ 54 
13.10 
Patient Compensation ......................................................................................... 55 
14 
TRIAL ADMINISTRATIVE INFORMATION ............................................................ 55 
14.1 
Protocol Amendments ............................................................................................ 55 
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14.2 
Address List ............................................................................................................ 55 
14.2.1 
Sponsor ........................................................................................................... 55 
14.2.2 
Supplier of Device ........................................................................................... 55 
14.2.3 
Principal Investigator (Site) ............................................................................. 56 
14.2.4 
Contract Research Organization (Including Monitoring) ................................. 56 
14.2.5 
Medical Monitoring .......................................................................................... 56 
14.2.6 
Pharmacovigilance .......................................................................................... 56 
14.2.7 
Central Laboratory (Safety Laboratory and Plasma Glucose) ......................... 56 
14.2.8 
Special Laboratory (ZP4207 Exposure and ADA Analyses) ........................... 57 
14.2.9 
Special Laboratory (Glucagon Exposure) ....................................................... 57 
15 
REFERENCES ........................................................................................................ 58 
APPENDIX A: SCHEDULE OF PROCEDURES – PARTS 1 AND 2 ................................ 59 
APPENDIX B: CLINICAL LABORATORY ANALYTES ................................................... 61 
APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES ....................................... 62 
LIST OF FIGURES 
Figure 1. 
Outpatient Results Summarizing the Distribution of Mean CGM Glucose 
Levels and Hypoglycemia in the BP and Control Arms ............................. 17 
Figure 2. 
Trial Design Schematic ................................................................................. 23 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
BG 
Blood glucose 
BP 
Bionic pancreas 
BTLE 
Bluetooth Low Energy 
BU 
Boston University 
CFR 
Code of Federal Regulations 
CGM 
Continuous glucose monitor 
CRO 
Contract research organization 
DBP 
Diastolic blood pressure 
DBR 
Database review 
DPP-4 
Dipeptidyl peptidase-4 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FHD 
First Human Dose 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GUI 
Graphical user interface 
HCG 
Human chorionic gonadotropin 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IV 
Intravenous 
MD 
Doctor of Medicine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH 
Massachusetts General Hospital 
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Abbreviation 
Definition 
MPC 
Model-predictive control 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
RN 
Registered nurse 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SGLT-2 
Sodium-glucose co-transporter-2 
SIV 
Site Initiation Visit 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 diabetes mellitus 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
 
 
 
 
 
 
 
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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background and Rationale 
To date, clinical trials conducted by Boston University (BU) and Massachusetts General 
Hospital (MGH) in patients with type 1 diabetes mellitus (T1DM) have demonstrated the 
practicality of a wearable automated bionic pancreas (BP) control system for robust glucose 
regulation using a continuous glucose monitor (CGM) to provide the input to the control 
system. Despite current technical limitations in CGMs and infusion pumps, the trials by 
BU/MGH have shown that a bihormonal BP is capable of achieving safe and effective blood 
glucose (BG) control automatically, with minimal hypoglycemia during 11 continuous days in 
the face of unrestrained meals and exercise and with trivial patient input (optional 
announcement of meals).  
The BP provides automatic BG regulation and reduces hypoglycemic episodes. Additionally, 
the system spares the wearer the relentless tasks of carbohydrate counting, frequent BG 
monitoring, estimating the effects of specific meals and exercise activity on BG levels, and 
manual drug administration, which are inexact, demanding, aggravating, and require 
continuous diligence and vigilance. The degree of glycemic control achieved by the BP is 
predicted to dramatically reduce the deleterious and debilitating complications of T1DM. 
In its last tested embodiment, the BP consisted of a Dexcom G4 CGM, and an iPhone that are 
hardwired together, with the iPhone running the control algorithm and communicating via 
Bluetooth with 2 Tandem t:slim pumps to dose insulin and glucagon. The connections are 
repeatedly lost among these 4 components throughout the day, an issue that has the potential 
to adversely impact BG control, whether due to missed CGM values or missed doses. In 
addition, the troubleshooting required to repair these recurring disconnections can be 
burdensome to the user. Integrating these components into a single device would establish 
seamless connectivity among them, which would eliminate the need for such troubleshooting. 
This would lead to smoother device operation with fewer interruptions, which would enhance 
its user friendliness, optimize its BG control potential, and further improve the quality of life of 
its users.  
The BU Investigators have recently designed, built, and tested a proprietary first-generation 
of such a fully integrated BP system, referred to as the iLet and the iLet infusion set. The iLet 
is a dual-chamber infusion system that currently incorporates the Dexcom G4 CGM 
technology, a custom user interface with touchscreen display, and all of the mathematical 
dosing algorithms that were tested in and validated using the iPhone-based BP in outpatient 
studies over the past 3 years. The iLet infusion set provides 2 independent subcutaneous (SC) 
fluid pathways from the iLet to the patient (1 for insulin and the other for glucagon). One tube 
connects to the prefilled insulin cartridge and the other tube connects to the fillable (single-use) 
glucagon cartridge. 
In order to provide automatic BG regulation, the iLet and the iPhone-based BP have the ability 
to deliver both insulin and glucagon. However, currently available glucagon formulations have 
limited stability at room temperature, necessitating frequent changes to the glucagon infusion 
set. Therefore, the current trial is designed to test the glucagon analog ZP4207 in the iLet and 
the iPhone-based BP, as this peptide analog of human glucagon is provided in a liquid 
formulation stable at room temperature. 
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The current trial is a first feasibility trial designed to use the first-generation iLet and iLet 
infusion set and the iPhone-based BP to compare ZP4207 with marketed glucagon (Lilly). The 
trial is intended to demonstrate the safety and tolerability of ZP4207 in the iLet and the 
iPhone-based BP and the feasibility of achieving comparable autonomous glycemic control. It 
is not intended to comprehensively demonstrate the definitive efficacy of the BP in extended, 
continuous daily use, but rather to demonstrate its functionality and accuracy in a practical, 
albeit very controlled, clinical setting. The trial is expected to provide practical information that 
will benefit the design of a next-generation iLet and iLet infusion set and help pave the way for 
a more comprehensive outpatient home-use Phase 2 trial and ultimately a pivotal trial where 
comprehensive safety and efficacy through continuous full daily use of the iLet with ZP4207 
will be documented. 
 
The data derived from this trial will permit evaluation of the robustness of the iLet as well as 
the safety and efficacy of ZP4207 when used in conjunction with the iLet and the iPhone-based 
BP. The data obtained will be used to further improve the iLet and will allow BU/MGH to 
expand to larger outpatient trials using the iLet or the iPhone-based BP with ZP4207.  
 
1.2 
Bihormonal Bionic Pancreas System  
The BP is an autonomous, self-learning system that requires only the patient's weight for 
initialization, and then autonomously adapts, modestly or dramatically, as needed, to cope 
with the wide range of insulin requirements of adults, adolescents, and pre-adolescents with 
T1DM. The BP obviates the need for the patient to know, or even appreciate, their insulin 
requirements, and renders obsolete any need for patients or caregivers to know 
carbohydrate-to-insulin ratios, basal rates, or insulin correction factors. 
 
The core technology is a suite of control algorithms that orchestrate the automated dosing of 
insulin and glucagon to regulate BG levels. An insulin controller orchestrates all SC insulin 
dosing. At its centerpiece is a model-predictive control (MPC) algorithm, which bases insulin 
doses on the glucose data and insulin absorption kinetics, compensating for the slow 
absorption rate of SC insulin analogs (peak time in blood of 30-90 min, clearance in 4-8 hr). 
This enables the algorithm to refrain from stacking and overdosing insulin. Furthermore, the 
MPC algorithm automatically adjusts its insulin-dosing aggressiveness continuously and in 
real-time to different insulin needs between individuals and variable needs within the same 
individual. Running in parallel with the MPC algorithm is an algorithm that automatically 
modulates basal insulin delivery over multiple time scales, and another algorithm that 
automatically adapts insulin doses in response to optional meal announcements. Unlike 
current insulin pumps and the insulin-only control algorithms, the adaptive basal insulin 
algorithm obviates the need for the user to set, or even know, his or her “basal-rate profile.” 
Instead, it is capable of automatically adapting to, and compensating for, changes in an 
individual's basal insulin need, such as might occur over a period of hours, days, or weeks 
(e.g., circadian hormonal fluctuations, intercurrent illness, physical activity, or emotional state) 
or as might occur over a period of months or years due to developmental changes 
(e.g., hormonal changes that occur during puberty or menopause). The adaptive meal dose 
controller obviates the need for the user to set, or even know, his or her 
“carbohydrate-to-insulin ratios,” as it makes automatic adjustments based on dosing history 
for similar meal announcements made on previous days, and customizes the dose for each 
individual and for time of day.  
 
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The BP also includes a proportional-derivative algorithm governing SC micro-doses of 
glucagon to help prevent impending hypoglycemia. Glucagon dosing is based on the glucose 
level and rate of descent. It may occur preemptively even if glucose is above range, and it 
includes a feedback term to account for the pending effects of recent glucagon doses.  
 
Taken together, these mathematical algorithms provide a universal framework for a glycemic 
control strategy that requires no quantitative input from, or participation by, the user (besides 
entering body weight to initialize the system), but which automatically adapts insulin and 
glucagon dosing to meet the individual needs of each user. Another challenge met is enabling 
the technology to remain completely autonomous in managing insulin and glucagon delivery 
even when the CGM is offline. Specifically, when the CGM is offline, the BP invokes the 
high-resolution “basal rate profile” that it had recently learned and stored when the CGM was 
online. On the basis of what the system learned and stored about meal announcements when 
the CGM was online, it is able to respond to meal announcements in the same manner when 
the CGM is offline. Finally, it automatically responds to user-entered BG values when the CGM 
is offline by issuing a correction dose of insulin or glucagon based on what it learned about 
the user's insulin and glucagon needs when the CGM was online. Thus, the BP never relies 
on, or burdens the user with, the determination of subjective dosing decisions, which inevitably 
vary in quality and reliability among different users. The BP provides a turnkey solution for 
people with T1DM that comprehensively manages glycemia across a broad range of individual 
needs and across a large spectrum of circumstances and challenges to glycemic control. 
 
A significant challenge for the use of glucagon in a bihormonal BP is the lack of a commercially 
available glucagon formation that is stable and well-suited to infusion over several days in a 
pump reservoir. However, BU/MGH have proceeded with studies using a relatively unstable 
marketed formulation that must be reconstituted from a lyophilized powder on a daily basis. 
This allowed BU/MGH to proceed with studies of the bihormonal system while awaiting the 
production of stable glucagon formulations or stable glucagon analogs. 
 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System 
The BP hardware platform has evolved over the years from a laptop-driven system, which was 
used in all inpatient studies to the first truly mobile wearable iPhone-driven platform, which 
has been used in a number of outpatient studies. Using the iPhone-based BP system, 
>110 outpatient experiments of 5-11 days in duration in each subject have been conducted 
(>800 patient days or >2 patient years of data) across subjects ranging in age between 6 and 
76 years old and in body mass between 21 and 128 kg. The robust adaptation capabilities of 
the BP is evident in the fact that the average total daily dose of insulin among these subjects 
varied by over 13-fold (from 11 to 145 units/day). 
 
In November 2012, Food and Drug Administration (FDA) approval was obtained to conduct 
the first outpatient study testing the BP in adults 21 years or older with T1DM. This study, 
referred to as the Beacon Hill Study, followed a random-order cross-over design in which 
20 adults with T1DM participated in 5 days on the iPhone-based BP and 5 days of usual care 
in which they wore a CGM with blinded display and muted alarms. In the BP arm, subjects 
kept to a 3-square-mile geographic area centered around the Beacon Hill neighborhood in 
Boston. They ate as they chose at local restaurants, and exercised at will with access to 
2 gyms. Analysis was pre-specified to focus on Days 2-5, since glycemic control is more 
representative of BP performance after most of the adaptation by the BP occurs on Day 1 
(Russell, 2014). Results are summarized in Figure 1.  
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In April 2013, FDA approval was obtained to conduct the first outpatient study testing the BP 
in adolescents 12-20 years old with T1DM. This study, referred to as the 2013 Summer Camp 
Study, followed a random-order cross-over design in which 32 adolescents with T1DM 
participated in 5 days on the BP and 5 days of supervised camp care in which they wore a 
CGM with blinded display and muted alarms. Subjects were fully integrated into normal camp 
activities without restrictions on diet or exercise. The study used the same iPhone-based BP 
that was used in the Beacon Hill Study. Results are summarized in Figure 1 (Russell, 2014). 
In April 2014, FDA approval was obtained to conduct the first outpatient study testing the BP 
in pre-adolescents 6-11 years old with T1DM. This study, referred to as the 2014 Summer 
Camp Study, was similar in design to the 2013 Summer Camp Study. Results are summarized 
in Figure 1 (Russell, 2016).  
In April 2014, FDA approval was obtained to conduct the first multi-center study, which was 
also the first home study, to test the BP in adults 18 years or older with T1DM. This study, 
referred to as the Bionic Pancreas Multi-Center Study, followed a random-order cross-over 
design in which 39 adults participated in 11 days on the BP and 11 days of usual care. 
Participants went to work as usual, and lived and slept at home, all without clinical supervision. 
There were no restrictions placed on diet or exercise. The study included 4 medical centers 
(10 subjects per center), which included MGH, the University of Massachusetts Medical 
School, Stanford University, and the University of North Carolina at Chapel Hill. Results are 
summarized in Figure 1.  
All of these studies used marketed glucagon (glucagon for injection, Eli Lilly). Due to its limited 
stability, Lilly glucagon must be reconstituted immediately before use. Animal studies have 
previously shown that despite its limited chemical stability, Lilly glucagon maintains its 
biological activity for up to 7 days in solution. Using this data, an Investigational New Drug 
(IND) exemption was obtained from the FDA for its use in a pump for up to 27 hours. This 
allowed these studies to be performed by asking volunteers to reconstitute a new vial of 
glucagon and fill the glucagon pump at approximately the same time every day. However, 
marketed Lilly glucagon has no path forward for approval for chronic BP use. 
1.4 
ZP4207 
ZP4207 is a peptide analog of human glucagon that is being developed to treat hypoglycemia 
in patients with T1DM and type 2 diabetes mellitus. ZP4207 exhibits improved physical and 
chemical stability in aqueous media and is suitable for liquid formulation. ZP4207 is comprised 
of 29 amino acids and has 7 amino acid substitutions when compared to native glucagon.  
Two clinical Phase 1 trials have been conducted to establish safety and tolerability of ZP4207 
after single and multiple dosing to healthy patients and T1DM patients under insulin-induced 
hypoglycemic conditions. 
The First Human Dose (FHD) trial (ZP4207-14013) was finalized in April 2015. The trial was 
a randomized, double-blinded trial with the objectives to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of ZP4207 as compared to an active 
comparator. Part 1 included a single ascending dose in healthy volunteers in cohorts of 8. In 
each cohort, the patients were randomized 3:1 to ZP4207 (n=6) or Novo Nordisk GlucaGen® 
(n=2). Five cohorts with SC administration (0.01, 0.1, 0.3, 1.0, and 2.0 mg ZP4207 compared 
to 1 mg GlucaGen) and 3 cohorts with intramuscular (IM) administration (0.3, 1.0, and 2.0 mg 
ZP4207 compared to 1 mg GlucaGen) were included. Part 2 included 2 sequence groups of 
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10 hypoglycemic T1DM patients. The patients were treated with fixed single IM doses of 
0.7 mg ZP4207 and 1.0 mg GlucaGen in a sequential cross-over design in a randomized 
treatment order.  
 
The second clinical trial (ZP4207-15007) was a single-center, double-blind, Phase 1b trial 
investigating the safety and tolerability, PK and PD of ZP4207 following repeated 
administration in healthy volunteers compared to placebo. It was finalized in July 2015. Each 
of the 3 cohorts comprised 8 subjects, who received 5 repeated SC doses of ZP4207 or 
placebo in a 3:1 treatment allocation. The first cohort started with the lowest dose of 0.1 mg. 
Cohort 2 and 3 continued with 0.3 and 1.0 mg, respectively. 
 
The Phase 1 results did not give rise to specific safety concerns, beyond those related to the 
pharmacological effect of ZP4207. All adverse events (AEs) recorded in the trials were of mild 
or moderate severity. The most frequent systemic AE related to treatment with ZP4207 was 
nausea, which is a known side-effect following administration of glucagon. The most frequent 
injection site reaction was transient erythema, occurring in all ZP4207, glucagon, and placebo 
treatment groups, irrespective of dose. No anti-drug antibodies (ADA) incidences were 
observed. 
 
The observed PD response, in terms of increased plasma glucose, in insulin-induced 
hypoglycemic patients with T1DM following dosing with 0.7 mg ZP4207 administered IM was 
similar to that observed following IM dosing with 1.0 mg glucagon (GlucaGen, Novo Nordisk). 
An increase in plasma glucose of ≥20 mg/dL from hypoglycemic levels was achieved within 
30 minutes for all patients. 
 
In terms of PK, ZP4207 had a short half-life and high clearance and dose proportionality for 
both maximum plasma concentration and area under the concentration-time curve from 
time 0 to 300 minutes in the dose range 0.1 to 2.0 mg following SC administration. Following 
IM administration, dose proportionality was shown in the investigated dose range of 0.3 to 
2.0 mg. The PK properties of 0.7 mg ZP4207 IM were comparable with those of 1.0 mg 
glucagon (GlucaGen, Novo Nordisk) with IM administration. 
 
1.5 
Risk/Benefit   
While the potential risks are minimal, the findings of this trial may reveal information that can 
substantially improve medical care for persons with diabetes. Therefore, the overall 
risk/benefit for patients participating in this trial is assessed as acceptable. 
 
Potential Risks and Discomforts  
 
Trial patients will be informed by the Investigator of the potential risks of ZP4207 and other 
trial-related procedures before they enter the trial.  
 
In this trial, patients with T1DM will be included to test the safety and efficacy of the BP using 
either the iLet or the iPhone platform when used with ZP4207 versus Lilly glucagon. The 
cross-over design with inclusion of 1 group of 10 T1DM patients into the 2 iLet treatment arms 
and the inclusion of a second group of 10 T1DM patients into the 2 iPhone-based BP treatment 
arms in a randomized order will allow for a direct comparison of the safety and efficacy of the 
2 treatments, based on intra-patient variability only.  
  
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Patients may experience mild discomfort associated with the insertion of the infusion sets and 
sensor into the SC tissues. The risk of discomfort due to insertion of infusion sets and sensors 
is expected to be slightly greater than in their lives outside the trial because more infusion sets 
will be inserted and a CGM sensor will be inserted. Most patients will use only 1 infusion set 
and not all will use a CGM sensor in usual care.  
 
There is a potential risk of hypoglycemia, since recombinant insulin analog will be 
administered. Due to frequent monitoring of glucose and direct supervision by a registered 
nurse (RN) or Doctor of Medicine (MD) at all times, the risk of a hypoglycemic episodes leading 
to significant harm to patients is expected to be substantially lower than their risk during their 
usual therapy.  
 
There is a risk of hyperglycemia. This risk is expected to be less than the risk during the 
patients’ lives outside of the trial based on data from earlier BP trials and the design of this 
trial.  
 
Treatment with ZP4207 and marketed glucagon can result in undesired effects or complaints. 
Undesired effects and complaints such as gastrointestinal side effects including nausea, 
vomiting, and diarrhea are known side effects of glucagon administration at higher dose levels. 
The frequency of nausea associated with the administration of 1 mg of glucagon according to 
the Summary of Product Characteristics (SPC) for Glucagon is described to be between 1/10 
and 1/100. The frequency of vomiting is described to be between 1/100 and 1/1000 
(Novo Nordisk, 2015). Similar gastrointestinal side effects have also been observed to a 
limited degree in the 2 clinical trials conducted with ZP4207, again at higher dose levels. The 
individual doses of ZP4207 and Lilly glucagon delivered by the BP are expected to be 
significantly lower than doses typically associated with nausea. Episodes of low blood 
pressure have also been observed after administration of higher doses of glucagon and 
ZP4207. As with every novel drug substance, new and yet unknown side effects may also 
occur. 
 
There are limited data available to describe the immunogenic potential of glucagon products 
available on the market, but the data available indicate that marketed glucagon only has a 
small immunogenic potential. A Phase 1 trial performed with recombinant human glucagon 
and animal derived glucagon in 75 healthy patients did not show signs of ADA measured 
13 weeks after trial product administration (Eli Lilly, 2005). In the ZP4207 FHD trial, 
ZP4207-14013, no confirmed anti-ZP4207 or anti-glucagon antibodies were detected in any 
of the samples. In addition, the 5 sequential administrations of ZP4207, as applied in trial 
ZP4207-15007, were not associated with the development of antibodies against ZP4207 in 
the 18 subjects enrolled to receive ZP4207. The optimized formulation of ZP4207, as applied 
in the present trial is not expected to change the immunogenic potential of the Investigational 
Medicinal Product (IMP).  
 
In relation to diabetes therapy, development of insulin-antibodies is documented more 
substantially and route of administration has been shown to influence immunogenic potential 
of insulins. However, these antibodies against insulin generally do not have an impact on 
insulin action and are thus not clinically relevant. 
 
In terms of consequence, development of high titer antibodies against ZP4207 could, in theory 
reduce the activity of endogenous glucagon, which again, in theory could influence 
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hypoglycemic episodes. However, most patients with T1DM do not secrete glucagon normally 
in response to hypoglycemia, so they would be less likely to be negatively impacted by 
anti-glucagon antibodies. Limited suppression of glucagon would, however, not be considered 
critical, as low glucose levels can also be corrected by other means, including oral intake of 
glucose and by other endogenous hormones such as oxyntomodulin.  
Overall, ZP4207 is judged to be a low-risk molecule, based upon the available clinical data as 
well as the outcome of the risk-based approach to the immunogenicity assessment made. The 
present trial will include sampling for measurement of antibodies against ZP4207 prior to first 
dosing (Visit 3), at the ADA Assessment Visit (Visit 5), and at the Follow-up Visit (Visit 6). In 
line with regulatory guidance documents, these samples will be appropriately analyzed and 
the results will be included in the overall assessment of the immunogenic potential of ZP4207 
after completion of each trial and as the clinical development program advances. 
Administration of ZP4207 may be associated with a risk of allergic reactions similar to those 
observed for other therapeutic peptides or proteins. Patients with known or suspected allergies 
to the trial products or related products will be excluded from the trial. Mild or moderate allergic 
reactions may include symptoms of rash, fever, flu-like symptoms, nausea, headache, and 
myalgia. Acute generalized hypersensitivity reactions are usually very rare but may include 
symptoms of flushing, sweating, dizziness, change in blood pressure, and difficulties in 
breathing. The risk of acute hypersensitivity reactions is described to be less than 1/10,000 
for native glucagon. No severe acute hypersensitivity reactions have been observed in the 
2 clinical trials conducted with ZP4207.  
Potential Benefits 
Based on experiences from previous trials of the BP and the design of this trial, patients 
enrolled in the trial may benefit from a reduction in risk of hypoglycemia and hyperglycemia 
and a better mean glucose compared to their usual diabetes care during their short trial 
participation.  
The data derived from this trial will allow evaluation of safety and tolerability of ZP4207 in the 
iLet and the iPhone-based BP, and the robustness and effectiveness of the new BP control 
system. The data obtained will be used to further improve the iLet and will allow the expansion 
to larger outpatient trials using the iLet or the iPhone-based BP with ZP4207.  
This trial is a necessary step in preparing the BP with ZP4207 to become available to people 
with T1DM. Wide availability of the BP with ZP4207 could improve the medical care of adults 
and children with T1DM. 
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2 
TRIAL OBJECTIVES  
2.1 
Primary Objective 
The primary objective is to conduct a trial testing the safety and tolerability of the BP using 
either the iLet or the iPhone platform when used with ZP4207 in 20 adult (≥18 years of age) 
patients with T1DM. 
2.2 
Secondary Objectives 
The secondary objectives are to measure glycemic regulation, including hypoglycemia 
exposure (percent of time spent with CGM glucose <60 mg/dL), evaluate BP device reliability, 
and to document the satisfaction of patients with the BP with the goal of optimizing the 
functionality and user interface of the BP. 
3 
TRIAL DESCRIPTION 
3.1 
Summary of Trial Design 
This trial is a single-center, open-label, 2-part, randomized cross-over trial. The trial will enroll 
adult patients with T1DM and will assess the safety and efficacy of the BP using either the iLet 
or the iPhone platform using the glucagon analog ZP4207 versus Lilly glucagon. In Part 1, up 
to 10 patients will participate in two 1-day treatment arms in random order (iPhone-based BP 
using ZP4207 and iPhone-based BP using Lilly glucagon) according to a pre-generated 
randomization scheme. In Part 2, up to 10 new patients will participate in two 1-day treatment 
arms in random order (iLet using ZP4207 and iLet using Lilly glucagon) according to a 
pre-generated randomization scheme. Patients can only participate in 1 part of the trial. An 
interim database lock may occur upon completion of Part 1 of the trial to analyze the 
iPhone-based BP data. The iLet and the iPhone-based BP will also administer insulin (insulin 
lispro, Lilly Humalog) using the same BG control algorithm for all 4 treatment arms. The trial 
will be conducted at a single center, the MGH Diabetes Center in Boston, MA. 
The overall trial design schematic is displayed in Figure 2. 
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Figure 2. 
Trial Design Schematic 
Part 1: 
 
 
Part 2: 
 
Patients can only participate in 1 part of the trial. 
ADA = anti-drug antibodies; BP = bionic pancreas. 
 
3.2 
Indication 
ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid formulation which 
is being studied to improve glycemic control in adults (and children) with T1DM as part of a 
bihormonal BP. 
 
3.3 
Number of Patients 
Up to 40 adult patients with T1DM can be enrolled. The upper bound is based on the 
expectation that some patients will be excluded after the Screening Visit and the possibility 
that some patients may have to be discontinued before completion (due to, for instance, 
inter-current illness or patient withdrawal). It is expected that up to 10 patients will complete 
each part of the trial protocol. 
4 
SELECTION AND WITHDRAWAL OF PATIENTS  
The trial will enroll patients who already manage their T1DM using continuous SC insulin 
infusion pump therapy. This requirement is imposed because multiple daily injection therapy 
involves the use of medium-acting or long-acting basal insulin that would require an extended 
washout period. 
 
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4.1 
Inclusion Criteria  
1. Male and female patients with T1DM for at least 1 year, as defined by the American 
Diabetes Association 
2. Age ≥18 years  
3. Diabetes managed using an insulin pump for ≥6 months 
4. Prescription medication regimen stable for >1 month (except for medications that will 
not affect the safety of the trial and are not expected to affect any outcome of the trial, 
in the judgment of the Investigator) 
5. Informed consent obtained before any trial-related activities (trial-related activities are 
any procedure that would not have been performed during normal management of the 
patient) 
6. Patients in good health according to age (medical history, physical examination, vital 
signs, 12-lead electrocardiograms [ECGs], laboratory assessments), as judged by the 
Investigator 
 
4.2 
Exclusion Criteria  
1. Unable to provide informed consent (e.g., impaired cognition or judgment) 
2. Unable to safely comply with trial procedures and reporting requirements 
(e.g., impairment of vision or dexterity that prevents safe operation of the BP, impaired 
memory, unable to speak and read English) 
3. Participation in another clinical trial of an investigational agent or device concurrently 
or within 1 month (or 5 half-lives) prior to the Screening Visit 
4. Previous exposure to ZP4207 
5. Females of childbearing potential who are pregnant (positive urine human chorionic 
gonadotropin [HCG]), breast feeding, plan to become pregnant in the immediate future, 
or sexually active without using highly effective contraception methods (highly effective 
methods are considered those with a failure rate less than 1% undesired pregnancies 
per year including surgical sterilization, hormonal intrauterine devices [coil], oral 
hormonal contraceptives, sexual abstinence, or a surgically sterilized partner) or 
postmenopausal 
women 
amenorrheic 
for 
less 
than 
1 year 
with 
serum 
follicle-stimulating hormone (FSH) level ≤40 IU/L and not using highly effective 
contraceptive methods during the trial and until 1 month after last dosing in the trial 
6. Male who is sexually active and not surgically sterilized who or whose partner(s) is not 
using highly effective contraceptive methods (highly effective contraceptive measures 
include surgical sterilization, hormonal intrauterine devices [coil], oral hormonal 
contraceptives, each in combination with spermicide-coated condoms), or who is not 
willing to refrain from sexual intercourse from the first dosing until 1 month after last 
dosing in the trial 
7. Current alcohol abuse (intake averaging >3 drinks daily in last 30 days) or use within 
the last 6 months of controlled substances without a prescription (other than marijuana)  
8. New onset clinically significant illness within 4 weeks prior to screening, as judged by 
the Investigator 
9. Unwilling or unable to refrain on the treatment visits from: 
a. Acetaminophen in any form 
b. Use of drugs that may dull the sensorium, reduce sensitivity to symptoms of 
hypoglycemia, or hinder decision making during the period of participation in 
the trial (use of beta blockers will be allowed as long as the dose is stable and 
the patient does not meet the criteria for hypoglycemia unawareness while 
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taking that stable dose, but use of benzodiazepines or narcotics, even if by 
prescription, may be excluded according to the judgment of the Investigator) 
10. History of liver disease that is expected to interfere with the anti-hypoglycemia action
of glucagon (e.g., liver failure or cirrhosis). Other liver disease (i.e., active hepatitis,
steatosis, active biliary disease, any tumor of the liver, hemochromatosis, glycogen
storage disease) may exclude the patient if it causes significant compromise to liver
function or may do so in an unpredictable fashion.
11. Aspartate 
aminotransferase >2 
× 
upper limit of 
normal (ULN), alanine
aminotransferase >2 × ULN, or bilirubin >1.5 × ULN on screening laboratories
12. Renal failure on dialysis or estimated glomerular filtration rate <30 mL/min/1.73 m2 on
screening laboratories
13. Hemoglobin <12 gm/dL for men and <11 gm/dL for women
14. Personal history of cystic fibrosis, pancreatitis, pancreatic tumor, or any other
pancreatic disease besides T1DM
15. Any known history of coronary artery disease including, but not limited to, history of
myocardial infarction, stress test showing ischemia, history of angina, or history of
intervention such as coronary artery bypass grafting, percutaneous coronary
intervention, or enzymatic lysis of a presumed coronary occlusion)
16. Congestive heart failure with New York Heart Association Functional Classification III
or IV
17. History of transient ischemic attack or stroke in the last 12 months
18. Seizure disorder, history of any non-hypoglycemic seizure within the last 2 years, or
ongoing treatment with anticonvulsants
19. History of hypoglycemic seizures (grand-mal) or coma in the last 12 months
20. History of hypoglycemic unawareness in the last 12 months
21. History of pheochromocytoma: fractionated metanephrines will be tested in patients
with history increasing the risk for a catecholamine secreting tumor:
a.
Episodic or treatment refractory (requiring 4 or more medications to achieve
normotension) hypertension
b.
Paroxysms of tachycardia, pallor, or headache
c.
Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or
von Hippel-Lindau disease
22. History of adrenal disease or tumor
23. Hypertension with systolic blood pressure (SBP) ≥160 mm Hg or diastolic blood
pressure (DBP) ≥100 mm Hg despite treatment
24. Hypotension (SBP <90 mm Hg or DBP <60 mm Hg), either sitting or standing, or
orthostatic hypotension (decrease in SBP >20 mm Hg or decrease in DBP >10 mm Hg
within 3 minutes of standing from a seated position)
25. Untreated or inadequately treated mental illness (indicators would include symptoms
such as psychosis, hallucinations, mania, and any psychiatric hospitalization in the last
year), or treatment with anti-psychotic medications that are known to affect glucose
regulation
26. Electrically powered implants (e.g., cochlear implants, neurostimulators) that might be
susceptible to radio frequency interference
27. History of adverse reaction to glucagon (including allergy) besides nausea and
vomiting
28. History of severe hypersensitivity to milk proteins or lactose
29. Established history of allergy or severe reaction to adhesive or tape that must be used
in the trial
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according to a pre-generated randomization scheme. Up to 2 patients may participate in the 
trial per day. The order of the treatment visits will be randomized in blocks of 2 patients. 
6 
TRIAL TREATMENT 
6.1 
Investigational Medicinal Products 
Insulin: The trial involves SC administration of insulin lispro (Humalog, Lilly), which is 
commercially available by prescription and is indicated for patients with T1DM, but not for use 
in a BP. 
Glucagon: The trial also involves SC administration of Lilly glucagon in 1 iLet arm and 
1 iPhone-based BP arm. Lilly glucagon is commercially available by prescription and is 
indicated for patients with T1DM in severe hypoglycemia, but not for use in a BP. 
ZP4207: The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, 
in the other iLet arm and the other iPhone-based BP arm. ZP4207 will be made available by 
Zealand Pharma A/S, Denmark as liquid formulation in prefilled syringes of 0.6 mL. 
6.2 
Storage and Drug Accountability of IMPs 
All IMPs will be stored and handled in accordance with the Sponsor’s instructions and/or the 
product labeling at the Investigator’s site, e.g., refrigerated (+2ºC to +8ºC) and should not be 
exposed to excessive heat, direct sunlight and never be frozen. 
All used, partly used, and unused vials or prefilled syringes must be kept by the Investigator 
and stored between +2ºC and +8ºC (unused) or at room temperature (partly used and used). 
Used and unused pre-filled syringes must be stored separately.  
The Investigator must ensure the availability of proper storage conditions and record and 
evaluate the temperature. Temperature of the refrigerator used for drug storage is monitored 
continuously, an alarm system is established. The Investigator must inform the monitor 
immediately if any IMP has been stored outside specified conditions (e.g., outside temperature 
storage). Investigational Medicinal Product that has been stored improperly must not be 
dispensed to any patient before it has been re-evaluated and approved for further use. The 
Investigator must take appropriate action to ensure correct storage. 
For the IMP, the Investigator must keep an accurate record of all IMPs received and the 
products used for each patient in a Drug Accountability Record. Storage locations, batch 
numbers, and expiry dates are also documented in this form. 
The drug accountability must be performed in a timely manner by the monitor. 
6.3 
Dispensing and Return of IMPs 
No IMPs may be dispensed to any person not enrolled in the trial. 
Upon completion of the trial, the Sponsor will be responsible for destruction or storage of IMPs 
(used, partially used, or unused). These duties can be delegated to a contract research 
organization (CRO) and must be documented in the trial files. 
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6.4 
Doses 
The iLet and the iPhone-based BP can administer isolated insulin-glucagon doses once every 
5 minutes. A single automated bolus of insulin will not exceed 3 units per 5-minute dose (30 µl 
of U-100 insulin) in both systems, and a single meal-priming dose, in response to a meal 
announcement made by the user, will not exceed 12 units (120 µl of U-100 insulin). A single 
bolus of glucagon will not exceed 80 µg (80 µl of 1 mg/mL Lilly glucagon or 1 mg/mL ZP4207). 
In prior studies, typical doses of glucagon were in the range of 2.5-40 µg per dose. The iLet 
and the iPhone-based BP are capable of administering as little as ~0.5 µl (0.05 units of U-100 
insulin or 0.5 µg of 1 mg/mL ZP4207). 
 
It is expected that the mean total daily doses of glucagon/ZP4207 will be <1.0 mg daily as in 
previous studies. The mean daily glucagon dose in a previous 11-day outpatient trial was 
0.5 mg/day (range 0.2-0.9 mg/day). Currently, single doses of up to 2 mg ZP4207 have been 
administered in clinical trials. The recommended dose of marketed glucagon for adult patients 
suffering from severe hypoglycemia is 1 mg as a single injection. Mean glucagon levels in 
previous inpatient studies have been above the normal fasting range for glucagon only 1% of 
the time. Therefore, the glucagon exposure of patients is expected to be modest. 
 
6.5 
iPhone-based Bionic Pancreas 
Infusion Set: Patients will wear 2 FDA-approved commercially available infusion sets, 1 for 
insulin infusion and 1 for glucagon infusion. Infusion sets that are compatible with the Tandem 
t:slim infusion pump (luer lock connection) will be provided. 
 
Continuous Glucose Monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to 
the controller. The sensor is powered by the battery within the transmitter that clips to the 
sensor and the whole assembly is held to the skin with an adhesive patch and communicates 
wirelessly with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM 
signal), it will be replaced promptly.  
 
Bionic Pancreas Control Unit: The control unit consists of a stock iPhone 4S and a Dexcom 
G4 Platinum receiver connected with a custom hardware interface and placed back-to-back 
in a custom enclosure. The G4 receiver converts the raw wireless signal from the transmitter 
into an estimated BG signal that is sent via a hardwired connection to the iPhone.  
 
 
The iPhone runs iOS 6 in “Guided Access” mode, where the only app accessible to the patient 
is the Beta Bionics app, which runs the control algorithm. The home screen, where typical user 
options reside, is password protected. Access to other functions on the iPhone (primarily the 
Settings options) is separately password protected and only accessible to the study staff. This 
prevents accidental activation of other apps that could interfere with the function of the BP. 
The control algorithm app has a graphical user interface (GUI) that displays the current CGM 
glucose, a graphical history of the CGM glucose, and doses of insulin and glucagon delivered 
by the control algorithm. The GUI can also be used to input meal announcements, designating 
the size of the meal as larger than typical, typical in size, smaller than typical, or just a bite, 
and the type of meal as breakfast, lunch, or dinner. This will trigger a partial meal-priming 
bolus the size of which will adapt during the course of the trial to meet a target of 75% of the 
insulin needs for that size and type of meal.  
 
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The target glucose level will be programmed to 100 mg/dL by the study engineers prior to the 
start of each experiment. This will be locked for each arm of the study; the patient will be 
unable to accidentally change or tamper with this setting.  
The GUI can be used to manage meal boluses and correction boluses during periods when 
the CGM is offline, such as the period after a sensor is replaced and before the new sensor 
has been calibrated. During these times the control algorithm will determine and direct the 
administration of insulin basal rates based on the patient's weight. The controller will also 
administer insulin and/or glucagon as appropriate in response to any entered BG values, just 
as if they were CGM values. 
The GUI also displays visual alarms associated with an audio signal if communication is 
dropped between the CGM transmitter and the BP control unit or between the control unit and 
the 2 insulin pumps. 
The iPhone communicates wirelessly via the Bluetooth Low Energy (BTLE) protocol with 
2 Tandem t:slim insulin pumps to deliver insulin and glucagon. 
Tandem t:slim Pumps: These pumps are FDA-approved insulin pumps with reservoirs 
capable of holding 300 units (3 mL) of insulin or 3 mL of glucagon or ZP4207 solution. The 
pumps have a mechanical dosing resolution of 1/120 (0.00833) unit and can deliver liquids at 
a maximal rate of ~33 µl per minute (2 mL per hour). They are slave to the BP control unit and 
are controlled wirelessly via the BTLE protocol by the iPhone 4S. 
6.6 
iLet Bionic Pancreas  
Infusion Set: A novel, dual cannula infusion set has been designed specifically for use with 
the iLet. Patients will wear dual channel tubing that will be attached to 2 infusion sets with 
1 steel cannula each, 1 for insulin infusion and the other for glucagon infusion. The tubing and 
infusion sets will have undergone sterilization prior to being delivered in a sealed pouch. The 
steel cannulae will be inserted in the abdominal SC tissue. 
Continuous Glucose Monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to 
the controller. The sensor is powered by the battery within the transmitter that clips to the 
sensor and the whole assembly is held to the skin with an adhesive patch and communicates 
wirelessly with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM 
signal), it will be replaced promptly.  
Bionic Pancreas Control Unit: The iLet is being built according to Class III medical device 
standards, adheres to a comprehensive and robust quality system, and is fully compliant with 
International Organization for Standardization (ISO) 13485 standards and document control 
practices. The iLet is a fully-integrated dual-hormone BP system that integrates the CGM 
technology (currently the Dexcom G4 Share system) as well as 2 independent motor-drivetrain 
pumping assemblies, which independently actuate the delivery of insulin and glucagon from 
pre-filled cartridges that are separately loaded into the iLet housing. Each drivetrain assembly 
utilizes a lead screw, which is driven by a precision micromotor, a gear case assembly, and a 
motor controller unit, in a manner similar to what is commonly found in most insulin infusion 
pumps on the market today. The iLet has dosing accuracy that is comparable to 
FDA-approved insulin pumps currently on the market. The iLet has a built-in BTLE radio that 
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also allows automatic communication with the paired CGM, as well as the Nova StatStrip® 
Xpress BG meter (Nova Biomedical). The iLet does not contain a cellular nor a WiFi radio, 
and does not accept input data from another mobile device (e.g., smartphone), other than the 
paired CGM and BG meter(s). 
 
The mathematical control algorithms (which are the same as those used in the iPhone-based 
BP), the CGM glucose engine (Dexcom), and the native user interface software, are all 
interconnected through controller framework software and reside as embedded systems on 
printed circuit boards contained within the device housing. The touchscreen-enabled, 
menu-driven user interface and onboard processor provide a comprehensive and standalone 
platform, which allows the iLet to operate independently of smartphones or other devices and 
without the need for internet support during routine operation. The graphical user interface of 
the iLet has the same user options and capabilities of the iPhone BP, including having its 
home screen password protected and its settings options only accessible to trial staff via a 
separate password. 
 
6.7 
Other Trial Devices  
YSI 2300 STAT Plus™ (Yellow Springs Instruments): The YSI 2300 STAT Plus is an 
FDA-approved glucose analyzer. Blood glucose measurements using the YSI 2300 STAT 
Plus will be obtained off of the intravenous (IV) line during both treatment visits.   
 
Nova Biomedical StatStrip Xpress Glucose Meter: The Nova StatStrip Xpress glucose 
meter is an FDA-approved glucose meter that is commercially available. Blood glucose 
measurements for CGM calibration will be obtained with the Nova StatStrip Xpress during both 
treatment visits if the YSI 2300 STAT Plus fails and via fingerstick with the Nova StatStrip 
Xpress during any periods when IV blood samples are not available for any reason or the IV 
fails. 
 
Exercise Bike: The trial will utilize a stationary exercise bike (ergometer) for the in-clinic 
exercise at the treatment visits. This bike will be stored at the Diabetes Research Center when 
not in use. 
 
6.8 
Concomitant Medications 
6.8.1 
Permitted Medications and/or Procedures  
Patients may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference with 
CGM sensing. All concomitant medications, including over-the-counter medications, should 
be recorded. 
 
Use of beta blockers will be allowed as long as the dose is stable and the patient does not 
meet the criteria for hypoglycemia unawareness while taking that stable dose. 
 
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911. 
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6.8.2 
Excluded Medications and/or Procedures 
During the trial, patients will not use any recreational drugs or drugs of abuse. The need to 
take prescription drugs that dull the sensorium, reduce sensitivity to symptoms of 
hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion from the 
trial or discontinuation of participation, a decision that will be made by the Investigator. 
Use of benzodiazepines or narcotics, even if by prescription, may be excluded according to 
the judgment of the Investigator. Use of oral anti-diabetic medications (e.g., thiazolidinediones, 
biguanides, sulfonylureas, glitinides, DPP-4 inhibitors, SGLT-2 inhibitors) will also be 
excluded. 
7 
TRIAL PROCEDURES  
7.1 
Informed Consent 
After potential patients have had time to review the consent document, and prior to any 
trial-related activities, they will meet with a trial MD or designee who will explain the trial, 
answer any questions, and administer informed consent. In the event that a volunteer is a 
patient of 1 of the trial MDs, another staff MD or designee will answer questions and administer 
consent. The patients will be fully informed of their responsibilities and their rights while 
participating in the trial as well as of the possible risks and potential benefits of participation in 
the trial. They will have the opportunity to discuss all questions and ample time to consider 
participation. 
Trial-related activities are any procedures that would not have been performed during normal 
management of the patient. Patients who wish to participate in the trial will be asked to 
personally date and sign an informed consent form (ICF). Likewise, the Investigator must also 
personally date and sign the ICF. All patients will be provided with a copy of their own signed 
and dated ICF. 
Trial staff will answer any questions that the patients may have during their participation. They 
will share any new information in a timely manner that may be relevant to the patient's 
willingness to continue participating in the trial. The patients may choose to discontinue their 
participation at any time.  
7.2 
Screening Visit (Visit 1) 
All patients will have a Screening Visit to confirm eligibility. The patient will be interviewed and 
the electronic Case Report Form (eCRF) will be completed by trial staff to establish whether 
the patient is eligible. 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits per the 
medical judgment of the Investigator. 
Once all of the results have been returned, a trial MD will review the eCRF to determine patient 
eligibility. If a patient is not eligible to continue in the trial, the results of abnormal tests will be 
reported to the patient and to a health care provider of their choosing. 
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7.2.1 
Data Collected at Screening 
•
Age, sex, race, and ethnicity
•
Date of last menstrual period in female patients
•
Medical, surgical, and social history, allergies, and review of systems relevant to
inclusion and exclusion criteria, including:
o
Date of diabetes diagnosis
o
Duration of insulin pump use and type of insulin used in pump
o
Type/model of insulin pump
o
Insulin regimen (basal rate, sensitivity factor, and carbohydrate ratio)
o
Average total daily dose of insulin in the last 30 days as available (from pump
history)
o
Usage of CGM, if any (type of CGM, days per month worn, usage of data,
whether insulin is dosed based on CGM alone, alarm settings)
•
Concomitant illness (any illness present at screening)
•
Concomitant medications (prescription and non-prescription) and date of last change
in medication regimen
•
Height, weight, physical examination, and vital signs including body temperature and
blood pressure
•
Orthostatic vital signs (heart rate and blood pressure) in the seated position and within
3 minutes of standing
•
12-lead ECG
•
Hemoglobin A1c
•
Chemistry and hematology samples (see Appendix B)
•
Urine HCG pregnancy test for women of childbearing potential
•
FSH level for postmenopausal women amenorrheic for less than 1 year
•
Fractionated plasma metanephrines (if indicated by history)
7.3 
Training Visit (Visit 2) 
A Training Visit will take place before the first treatment visit. Patients will be trained in the 
insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. Trial staff 
will verify that the patients have understood the material and are competent to participate 
safely in the trial. Concomitant medications will also be reviewed. 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits per the 
medical judgment of the Investigator. The goals of diabetes management for patients during 
the fasting period are to avoid hypoglycemia, to treat hypoglycemia if it occurs, and to arrive 
at the treatment visit in the morning with a BG between 80 and 250 mg/dL. If insulin pump 
basal rates are properly configured, patients should be able to fast from 12:00 AM until the 
time of arrival for the visit without a high likelihood that they will become hypoglycemic or 
severely hyperglycemic. Patients will be asked whether they believe that they can safely fast 
from 12:00 AM until their arrival time at approximately 7:00 AM without adjusting their basal 
rates. If they have concerns, a trial physician will consult with them regarding pump basal rate 
adjustments. In all cases, subjects will be instructed to self-treat with carbohydrates according 
to the 15/15 rule (15 grams of carbohydrates, repeated in 15 minutes if necessary) during the 
overnight fasting period and at any time prior to their arrival at the trial site for the treatment 
visits. 
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7.4 
Treatment Visits (Visit 3 and Visit 4) 
• 
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 
30 days after screening (Visit 1). 
• 
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum 
of 3 weeks between Visit 3 and Visit 4. 
• 
Up to 2 patients may participate per day.  
• 
In Part 1, each patient will participate in 2 treatment visits: 1 with the iPhone-based BP 
using ZP4207 and 1 with the iPhone-based BP using Lilly glucagon in a randomized 
order. 
• 
In Part 2, each patient will participate in 2 treatment visits: 1 with the iLet using ZP4207 
and 1 with the iLet using Lilly glucagon in a randomized order. 
• 
The night before the treatment visit, patients will place a Dexcom G4 CGM sensor in 
the abdominal skin and calibrate the sensor when prompted using the provided Nova 
StatStrip Xpress meter. Patients will be instructed to call if they encounter any difficulty 
with their CGM.  
• 
Patients will be responsible for their own medications other than insulin during the trial. 
Any medical advice needed by the patients during their participation that is not directly 
related to BG control should be obtained from them in their usual manner. Patients 
may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference 
with CGM sensing. If patients experience urgent or emergent medical concerns 
outside the scope of diabetes care and their primary care physicians, they will be taken 
to the MGH walk-in clinic or emergency room, or if necessary call 911. 
• 
During the trial, patients will not use any recreational drugs or drugs of abuse. The 
need to take prescription drugs that dull the sensorium, reduce sensitivity to symptoms 
of hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion 
from the trial or discontinuation of participation, a decision that will be made by the 
Investigator.  
• 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits 
per the medical judgment of the Investigator.  
• 
Patients will not tamper with the BP, including changing any settings. 
• 
Patients may not remove the BP during the trial unless the BP failed or they are 
withdrawing from the trial. 
• 
The exact time of each procedure and assessment will be documented. 
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7.4.1 
Visit Procedures  
•
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the
BP having fasted since 12:00 AM the night before (treatment with simple carbohydrate
of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled
within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the
visit window. If BG is <50 mg/dL, the patient will be treated with simple carbohydrate
according to the 15/15 rule (15 grams of carbohydrates, repeated in 15 minutes if
necessary). The visit will not need to be rescheduled unless the patient experiences a
severe hypoglycemic event and requires treatment with glucagon or IV dextrose. If the
visit needs to be rescheduled due to hypoglycemia or hyperglycemia, trial staff will
assist the patient with insulin or medication adjustments to address glycemic control.
The patient will be instructed to contact trial staff later in the day if his or her BG remains
uncontrolled.
•
Upon arrival to the visit, the patient’s weight and vital signs including body temperature
and blood pressure will be documented.
•
Orthostatic vital signs (heart rate and blood pressure) will be measured in the seated
position and within 3 minutes of standing.
•
Patient reports of symptoms, any other complaints, and AEs will be reviewed.
•
Concomitant medications will be recorded.
•
Chemistry and hematology samples will be collected at visit start (see Appendix B).
•
ADA samples will be collected before the start of dosing (Visit 3 only).
•
A 12-lead ECG will be performed.
•
A urine HCG pregnancy test will be performed in female patients of childbearing
potential. If the test is positive, the patient will be informed of the result and the visit
will be ended.
•
Patients will complete a baseline survey about their attitudes and experience with their
usual diabetes care.
•
An IV catheter will be placed for blood sampling.
•
Trial staff will assist the patient to calibrate their CGM, review the trial procedures again
and assist with the setup of the BP system, including inserting and priming infusion
sets.
•
The control algorithm will be initialized only with the patient’s weight. Diagnostics will
be performed to ensure that the CGM device is appropriately calibrated and that all of
the components of the BP systems are in working order.
•
The basal rate of the patient’s own insulin infusion pump will be changed to be 2-fold
higher than weighted mean of the basal rate during the trial period. This is intended to
increase the usage of glucagon during the treatment visit.
•
The patients will continue to wear their own infusion pump infusing at the temporary
2-fold basal rate throughout the visit until the start of the structured exercise period, in
addition to the BP.
•
The staff will start the BP as close as possible to a minute divisible by 5 minutes
(i.e., on a 5-minute mark). The starting time will be considered Hour 0.
•
Additional calibrations will be performed at any of the BG checks throughout the day if
the CGM value does not meet the ISO standard (<15 mg/dL difference for BG values
<75 mg/dL; <20% absolute difference for BG values >75 mg/dL) at the time of the BG
measurement AND it is a good time to calibrate (the CGM trend arrow is flat and there
has been no carbohydrate intake in the last 30 minutes or glucagon boluses in the last
15 minutes).
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•
Blood samples will be taken from the IV at least hourly and processed for plasma
ZP4207/glucagon. If BG is <150 mg/dL, more frequent samples for plasma
ZP4207/glucagon may be drawn at the discretion of the Investigator. The actual time
of sampling will be recorded in the eCRF.
•
Plasma glucose samples will be taken from the IV at least hourly in parallel with
ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT Plus.
If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes.
If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then
sampling will be every 10 minutes. The actual time of sampling will be recorded in the
eCRF.
•
Patients will be asked to rate any nausea and/or infusion site pain on 10 cm visual
analog scales (VAS) at the beginning of the visit once the infusion sites have been
placed but no drug has yet been administered, then approximately at the top of every
hour during the visit, and at the end of the visit. Trial staff will also evaluate their infusion
sites to document any erythema or edema at the same times. If moderate or severe
pain is reported or swelling or redness occurs at the infusion site, the infusion site will
be replaced in a different location. If moderate or severe pain, swelling, or redness
continues at the old site for more than 30 minutes after the infusion site is removed, or
if moderate or severe pain, swelling, or redness occurs at the new site, all infusion
sites will be removed and the patient will be discontinued from the study. Any such
symptoms will be followed until resolution.
•
From the start of closed loop control until approximately Hour 3, the patients will
continue to fast.
•
Between approximately Hour 3 and Hour 4, patients will be provided with a lunch meal
of their choice in the Diabetes Research Center from a menu of choices from nearby
restaurants. They will be asked to choose a meal that is a “typical meal” for them. The
content of their meal will not be restricted in any way, with the exception that the
number of carbohydrates should be in the “typical” range for them at lunch, and that
they must eat the same meal at the same time during both visits.
•
At approximately 15 minutes before the meal, patients will administer a bolus for the
meal with their own insulin pump based on the carbohydrate count for the meal.
•
After lunch is completed, the patients will not be allowed any carbohydrate intake
(non-caloric drinks will be permitted) until the trial is completed (except as necessary
to treat hypoglycemia), to allow the BP to control the post-prandial BG without further
interruption.
•
Between approximately Hour 6 and Hour 7, the patients will start a period of structured
exercise.
•
At the start of the exercise period, patients will restore their normal basal insulin profile
so that they will not have elevated insulin levels at the end of the study period when
they are to transition back to their usual care.
•
Patients will exercise on a stationary bike with a heart rate from 120-140 beats per
minute for a total of 4,000 heart beats (approximately 30 minutes). Patients will rate
their exercise intensity using the Borg scale every 5 minutes, with the target intensity
level between 12 and 14. Heart rate will be measured every 5 minutes.
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•
BG measurements will be obtained off of the IV line every 10 minutes. If BG is
<80 mg/dL, BG measurements will be obtained off of the IV line every 5 minutes.
o
Carbohydrates will be given for any BG <50 mg/dL according to the following
protocol: Dextrose (g) = BSA (m2)/[1.7 m2 (women) or 1.9 m2 (men)] *15 g.
o
Repeat treatments will be given at 15-minute intervals as long as BG remains
<50 mg/dL.
•
If there is an interruption in the Dexcom CGM output, trial staff will assist the patient in
recovering CGM data streaming. If this requires replacement of the CGM sensor, BGs
will be checked every 10 minutes (every 5 minutes if BG is <80 mg/dL) using blood
from the IV until the CGM is able to be calibrated again. These BGs will be entered
into the BP, which will treat them as CGM values and dose insulin and/or glucagon
appropriately.
•
If there is a complete failure of the BP operation, patients will take over their own BG
control using their personal insulin pump until the BP can be brought back online. If BP
control cannot be promptly resumed (e.g., within 30 minutes), the patient may be asked
to repeat that trial day once.
•
Patients may choose to withdraw from the trial at any time. If they withdraw from the
trial, they should alert a provider immediately.
•
Just prior to the end of the study visit, vital signs including body temperature and blood
pressure will be obtained and a 12-lead ECG will be performed. Orthostatic vital signs
(heart rate and blood pressure) will be measured in the seated position and within
3 minutes of standing. If patients have hypotension or orthostatic hypotension,
discharge will be delayed until their blood pressure is normal and stable.
•
After approximately Hour 8, but not earlier than at least 60 minutes after end of
exercise, the BP will be stopped and the patient will continue with their personal insulin
pump.
•
If the patient experiences seizure or unconsciousness, persistent nausea or vomiting,
diabetic ketoacidosis, persistent hyperglycemia with ketonemia, hemodynamic
changes such as hypotension, or other medically significant findings, a longer
observation period at the trial site may be necessary until the patient is considered
stable for discharge. If the Investigator or trial staff determines that the patient requires
further observation or treatment, the patient may be transferred to the emergency room
for additional monitoring and/or medical care. At discharge, patients will be provided
with any necessary instructions concerning personal insulin pump usage, food intake,
and driving arrangements.
•
The maximum amount of blood loss per study visit will be approximately 230 mL. The
total blood loss for the entire study will be up to 460 mL.
•
Patients will answer questionnaires (see Appendix C).
•
Chemistry and hematology samples will be collected at visit end (see Appendix B).
•
The BP and glucose meters will be collected and downloaded.
•
A trial MD will review the last several hours of insulin and glucagon dosing and assist
the patient in resuming their usual diabetes care. A longer observation period at the
trial site may be necessary. Patients will be instructed to call trial staff with any
questions, issues, or concerns.
7.4.2 
Data Collected During the Treatment Visits 
•
CGM glucose every 5 minutes from the Dexcom G4 Platinum CGM
•
All BG measurements taken
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•
Insulin total dose by the BP and the patient’s own insulin pump
•
Glucagon total dose
•
Timing and content of the meal eaten and carbohydrate amount
•
Timing of meal announcement and size of meal announced
•
Timing and glucose values at calibrations
•
Timing and amount of carbohydrates taken for hypoglycemia
•
Data from a questionnaire about attitudes and expectations regarding the BP before
and after each treatment arm (see Appendix C)
•
Time patients were not under BP control for any reason
•
List of technical faults associated with the BP including cause and resolution
•
ZP4207/glucagon sampling will be collected at least hourly. If BG is <150 mg/dL, more
frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the
Investigator.
•
Plasma glucose sampling will be collected at least hourly in parallel with
ZP4207/glucagon exposure sampling. If BG is <150 mg/dL, then sampling will be every
30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is
<80 mg/dL, then sampling will be every 10 minutes.
•
Nausea and infusion site pain on a VAS at visit start (after insertion and before any
drug administration), hourly, and at visit end
•
Infusion site reaction according to the Draize scale at visit start (after insertion and
before any drug administration), hourly, and at visit end
•
Patient reports of symptoms, any other complaints, and AEs
•
Vital signs including body temperature and blood pressure (at visit start and visit end)
and weight
•
Orthostatic vital signs (heart rate and blood pressure) in the seated position and within
3 minutes of standing
•
Concomitant medications
•
Chemistry and hematology samples (see Appendix B) at visit start and visit end
•
ADA (Visit 3 only)
•
12-lead ECG at visit start and visit end
•
Urine HCG pregnancy test for women of childbearing potential
7.4.3 
Response to Hypoglycemia 
•
Patients are encouraged to check their BG for any symptoms of hypoglycemia.
•
Patients will be permitted to take 15 grams of carbohydrates for any BG value
<60 mg/dL. Trial staff will ensure proper functioning of the BP, infusion set, and insulin
pump, and will encourage the patient to wait for the BP to treat the low blood sugar for
as long as they feel comfortable.
•
Patients will be required to take 15 grams of carbohydrates for any BG value
<50 mg/dL. After treatment of hypoglycemia, a follow-up measurement will be taken
15 minutes later. Repeated measurements will be taken every 15 minutes until the
BG is >60 mg/dL. Treatment will be repeated if subsequent BG values are still
<50 mg/dL. All carbohydrate treatments for hypoglycemia will be documented by trial
staff (amount and time).
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• 
Trial staff will check the infusion site, BP, and insulin pump for normal operation any 
time hypoglycemia occurs. If there is any suspicion of infusion set malfunction, the site 
should be replaced. Trial staff will check the BP for any malfunction and correct any 
problems that are found. 
• 
If no correctable fault is found, but there is doubt regarding the correct function of the 
BP system, an entirely new backup BP system may be started. 
• 
If a patient experiences a seizure or unconsciousness associated with hypoglycemia, 
his or her participation in the trial will be discontinued.  
7.4.4 
Response to Hyperglycemia  
• 
Trial staff will check the infusion site, BP, and insulin pump for normal operation any 
time BG is >300 mg/dL. If there is any suspicion of infusion set malfunction, the site 
should be replaced. Trial staff will check the BP for any malfunction and correct any 
problems that are found. If the BG remains >300 mg/dL for 2 hours despite 
troubleshooting, blood ketones will be measured. If the blood ketone result is 
>1.5 mmol/L, the visit will be stopped and rescheduled. The patient will be provided 
with insulin and a syringe to give an injection based on their correction factor. 
• 
If a patient experiences diabetic ketoacidosis, his or her participation in the trial will be 
discontinued. 
• 
If no correctable fault is found, but there is doubt regarding the correct function of the 
BP system, the treatment visit may be stopped and the visit rescheduled. 
7.4.5 
Response to Nausea/Vomiting 
If significant nausea (e.g., that prevents the patient from eating normally) or any vomiting 
occurs, trial staff will notify the Investigator. Trial staff will assist the patient in troubleshooting, 
such as checking BG and the calibration of the CGM (excessive glucagon dosing may occur 
if the CGM is reading lower than the true BG). If a patient experiences persistent nausea and 
vomiting thought to be related to glucagon dosing, his or her participation in the trial will be 
discontinued. 
7.4.6 
Response to Other Medical Needs  
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911.  
7.4.7 
Monitoring of Bionic Pancreas Performance  
Bionic pancreas inventors and developers 
, 
, and/or an 
engineer trained by them will be readily available by phone for consultation for the trial staff at 
all times during the course of the trial.  
7.4.8 
Supervision by Trial Staff  
A trial MD will be on call at all times during the course of the trial. An RN or MD will be with 
the trial patients in the Diabetes Research Center at all times. 
 
7.5 
Anti-drug Antibodies Assessment Visit (Visit 5) 
Patients will return for an ADA Assessment Visit 10 days ±3 days following the last day of 
dosing (Visit 4) for ADA sampling and a review of AEs and concomitant medications. 
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7.6 
Follow-up Visit (Visit 6) 
Patients will return for a Follow-up Visit 25 days ±4 days following the last day of dosing 
(Visit 4), for chemistry, hematology, and ADA sampling, and a review of AEs and 
concomitant medications.  
8 
ENDPOINTS  
8.1 
Primary Endpoint  
The primary endpoint is the safety and tolerability of ZP4207 in the BP using either the iLet 
or the iPhone platform as assessed by: 
• 
Number and type of AEs 
• 
Clinical laboratory measurements 
• 
Vital signs 
• 
12-lead ECG 
• 
Local tolerability and infusion site reactions as measured with the Draize scale 
• 
Immunogenicity as measured by ADA 
• 
Pain as measured on a 10 cm VAS 
• 
Nausea as measured on a 10 cm VAS 
 
8.2 
Secondary Endpoints 
The secondary endpoints include measurements of BP function as well as glycemic and 
non-glycemic measurements. 
8.2.1 
Bionic Pancreas Function  
This endpoint data will be generated from the BP data during each treatment visit: 
• 
Average percent insulin dose amounts calculated by the BP control algorithm that are 
successfully delivered by the pump 
• 
Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts successfully issued to the pump by the BP control 
algorithm that are successfully delivered by the pump (calculated doses are not issued 
unless the pump is accessible and its delivery channel is available) 
o Average percent insulin dose amounts successfully issued to the pump by the 
BP control algorithm that are successfully delivered by the pump 
o Average percent glucagon/ZP4207 dose amounts successfully issued to the 
pump by the BP control algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts calculated by the BP algorithm that are successfully 
issued to the pump by the BP (calculated doses are not issued unless the pump is 
accessible and its delivery channel is available) 
o Average percent insulin dose amounts calculated by the BP control algorithm 
that are successfully issued by the BP 
o Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully issued by the BP 
• 
Average percent of 5-minute steps during which the BP is functioning nominally in all 
respects based on real-time CGM data (new CGM glucose reading captured, dose 
calculated, and dose issued to pumps)  
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•
Average percent of 5-minute steps during which the BP is functioning nominally with
or without a new CGM glucose reading captured (dose calculated and dose issued to
pumps). If a CGM signal is not available, the dose calculated may be based on weight
or historical basal rates.
•
CGM reliability index, calculated as percent of possible values actually recorded by
CGM
•
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter
download
•
List of technical faults associated with the BP including cause and resolution
8.2.2 
Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit: 
•
Fraction of time spent within each of the following glucose ranges:
o
<50 mg/dL
o
<60 mg/dL
o
<70 mg/dL
o
70-120 mg/dL
o
70-140 mg/dL
o
70-180 mg/dL
o
>180 mg/dL
o
>250 mg/dL
o
>300 mg/dL
•
Number of severe hypoglycemic events (patients unable to self-treat, requiring the
assistance of another person)
•
Number of episodes of symptomatic hypoglycemia
•
Number of carbohydrate interventions for hypoglycemia
•
Total grams of carbohydrates taken for hypoglycemia
•
Mean CGM glucose
8.2.3 
Non-glycemic 
•
Glucagon/ZP4207 total delivery per kg of body mass
•
Insulin total delivery per kg of body mass
•
Number of unscheduled infusion set replacements
•
Number of unscheduled CGM sensor changes
9 
LABORATORY ASSESSMENTS 
Descriptions of sample handling and sample processing, storage, and shipment at the site will 
be included in the laboratory manual. 
The responsible laboratories are listed in the address list. 
9.1 
Safety Laboratory Assessments 
Chemistry and hematology samples will be collected at specified time points. See Appendix A 
for the schedule of procedures and Appendix B for a list of clinical laboratory analytes. 
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9.2 
Pharmacodynamic Assessments (Plasma Glucose) 
At Visit 3 and Visit 4, plasma glucose samples will be taken from the IV at least hourly in 
parallel with ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT 
Plus. If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for 
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is 
<100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will 
be every 10 minutes. The actual time of sampling will be recorded in the eCRF. 
9.3 
Exposure Assessments (ZP4207 and Glucagon) 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the 
discretion of the Investigator. The actual time of sampling will be recorded in the eCRF. 
Bioanalytical Reports will be prepared. 
9.4 
Anti-drug Antibodies Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken at Visit 3, the ADA Assessment Visit (Visit 5), and the Follow-up Visit 
(Visit 6). Any patient that tests positive for ADA will be monitored until the ADA levels return 
to baseline. 
Bioanalytical Reports will be prepared. 
10 
SAFETY REPORTING 
10.1 
Adverse Events 
An AE is any untoward medical occurrence in a trial patient administered an IMP and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be 
any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not considered related to 
the IMP. Patients should be instructed to report any AE they experience to the Investigator. 
Note: This includes events from the first trial-related activity from Visit 3.  
AEs for ZP4207 include: 
•
A clinically significant worsening of a concomitant illness
•
A clinical laboratory abnormality which is clinically significant, i.e., any abnormality that
suggests a disease and/or organ toxicity and is of a severity that requires active
management. Active management includes active treatment or further investigations,
for example, change of medicine dose or more frequent follow-up due to the
abnormality.
•
Hypoglycemic episodes  
•
Injection site reactions
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The following should not be recorded as AEs, if recorded prior to randomization (on the 
Screening Form or the eCRF): 
•
Pre-planned procedure, unless the condition for which the procedure was planned has
worsened from the first trial-related activity from Visit 3. 
•
Pre-existing conditions found as a result of screening procedures (pre-existing
conditions should be reported as medical history or concomitant illness). 
For known (listed) AEs for Glucagon and Humalog, please refer to SPC for Glucagon and 
Humalog. 
10.1.1 
Follow-up of Adverse Events 
All AEs that are ongoing at the end of the patient’s participation in the trial will be followed-up 
until the event is resolved or reaches a satisfactory outcome as deemed by the Investigator. 
Follow-up actions for all serious adverse events (SAEs) will be performed according to 
appropriate clinical care practices and may depend on the nature of the event. These will be 
determined after internal review and/or Sponsor review. The follow-up information should only 
include new (updated and/or additional) information that reflects the situation at the time of the 
Investigator’s signature. 
Follow-up information on (S)AEs will be updated using the (S)AE Form. If a non-serious event 
becomes serious during the follow-up, the AE Form and SAE Form must be used and reporting 
timelines follow those of an SAE. 
The Investigator must forward follow-up information on SAEs, and if previously non-serious 
AEs become SAEs, to the Sponsor. 
10.1.2 
Precautions 
Normal precautions taken for a human trial will be taken during this trial. Qualified and 
well-trained physicians and medical staff will instruct the patients. During a patient’s 
participation in the trial, the Investigator should ensure that adequate medical care is provided 
to the patient for any AEs, including clinically significant laboratory values related to the trial. 
The Investigator should inform the patient when medical care is needed for intercurrent 
illnesses of which the Investigator becomes aware.  
For further information on safety precautions for ZP4207, Lilly glucagon, and Lilly Humalog, 
please refer to the current version of the Investigator’s Brochure (IB) for ZP4207 (Zealand 
Pharma A/S, 2015, or any updates hereof), and the SPC for Glucagon (Eli Lilly, 2012) and 
Humalog (Eli Lilly, 2015), respectively. 
10.1.3 
Assessment of Adverse Events by the Investigator 
Intensity of an Adverse Event 
The maximum intensity (severity) of all AEs must be assessed by the Investigator and 
documented. Severity should be graded when the AE outcome is known: 
•
Mild: A type of AE that is usually transient and may require only minimal treatment or
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
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•
Moderate: A type of AE that is usually alleviated with additional specific therapeutic
intervention. The event interferes with usual activities of daily living, causing discomfort
but poses no significant or permanent risk of harm to the patient.
•
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects
clinical status, or may require intensive therapeutic intervention.
A “severe” reaction does not necessarily deem the AE as “serious,” and an SAE may not be 
“severe” in nature. 
Causality Relationship to IMP 
Insulin (insulin lispro, Lilly Humalog), glucagon (glucagon for injection, Eli Lilly), and ZP4207 
are all regarded as IMP. 
The causality of each AE should be assessed by the Investigator according to the following 
classification: 
•
Related: Good reason and sufficient documentation to assume a causal relationship.
•
Not related: No relationship to trial product can be established.
Outcome of an Adverse Event 
The outcome of all AEs must be assessed by the Investigator and documented by his/her 
staff. The following definitions should be used: 
•
Recovered/resolved: The patient has fully recovered, or by medical or surgical
treatment the condition has returned to the level observed at the first trial-related 
activity from Visit 3. 
•
Recovering/resolving: The condition is improving and the patient is expected to recover
from the event. This term is only applicable if the patient has completed the trial.
•
Recovered/resolved with sequelae: The patient has recovered from the condition, but
with lasting effect due to a disease, injury, treatment, or procedure. If a sequela meets
an SAE criterion, the AE must be reported as an SAE.
•
Not recovered/not resolved: The condition of the patient has not improved and the
symptoms are unchanged, or the outcome is not known.
•
Fatal: This term is only applicable if the patient died from a condition related to the
reported AE. Outcomes of other reported AEs in a patient before he/she died should
be assessed as “recovered/resolved,” “recovering/resolving,” “recovered/resolved with
sequelae,” or “not recovered/not resolved.” An AE with a fatal outcome must be
reported as an SAE.
•
Unknown: This term is only applicable if the patient is lost to follow-up.
10.2 
Serious Adverse Events   
An SAE is any untoward medical occurrence that at any dose: 
•
Results in death
•
Is life-threatening
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability or incapacity
•
Is a congenital anomaly or birth defect
•
Medically important
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Medical judgement must be exercised in deciding whether an AE is believed to be “medically 
important.” Medically important events may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require intervention to prevent 
1 of the other outcomes listed in the definition above. 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is an AE fulfilling 1 of the criteria of seriousness and being assessed as related to 
an IMP, the nature or severity of which is not consistent with the applicable reference 
document (e.g., ZP4207 IB or package leaflet/SPC for an approved product). 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety, any life-threatening problem or 
death caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the application; or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. 
 
10.3 
Adverse Event Reporting – Procedures for Investigators  
The Principal Investigator and co-investigators will review any AEs and report any SAEs to 
the Sponsor as soon as possible and within 24 hours of obtaining knowledge of the event. The 
Principal Investigator and co-investigators will promptly report AEs to the Partner’s Institutional 
Review Board (IRB) and to the BU IRB (unless oversight is ceded by the BU IRB to the 
Partners IRB), in accordance with local requirements.  
 
Ed Damiano is the Sponsor of the Investigational Device Exception for the BP and Zealand 
Pharma A/S is the Sponsor of the IND for ZP4207.  
 
Reports of AEs will be submitted to the FDA in compliance with the terms of the Code of 
Federal Regulations. 
 
All events meeting the definition of an AE must be collected and reported from the first 
trial-related activity from Visit 3 until the end of the post-treatment follow-up period. At each 
contact with the site (visit or telephone, excluding safety visits, where the patient is not seeing 
the Investigator or staff [e.g., visits to the laboratory], the patient must be asked about AEs. 
All AEs, either observed by the Investigator or reported by the patient, must be recorded by 
the Investigator and evaluated. 
 
The Investigator should record the diagnosis, if possible. If no diagnosis can be made, the 
Investigator should record each sign and symptom as individual AEs. 
All AEs must be recorded by the Investigator. One single AE Form must be used per AE from 
start to resolution. For SAEs, the SAE Form must also be completed.  
 
AE information should include the following: 
• 
Patient identification number on all pages 
• 
Date and time of treatment start 
• 
Date and time of onset and date of outcome 
• 
Date and time of Investigator’s first information on the (S)AE 
• 
Seriousness 
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10.5 
Hypoglycemia 
Hypoglycemia will be regarded as an AE and will be recorded and documented on an AE 
Form. For the purposes of AE reporting, the following definitions of hypoglycemia will be used: 
• 
Symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia 
are accompanied by a BG concentration ≤70 mg/dL 
• 
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of 
hypoglycemia but with a BG concentration ≤50 mg/dL 
• 
Severe hypoglycemia: an event requiring assistance of another person to actively 
administer carbohydrates, glucagon, or take other corrective actions 
 
10.6 
Safety Monitoring 
10.6.1 
Data and Safety Monitoring Board 
An external DSMB will oversee the conduct of the trial, as set forth in the DSMB Charter. 
Additionally, the DSMB will be informed in the event of any serious and unexpected AEs. The 
DSMB will be informed if there are any changes to the trial protocol that could significantly 
impact the safety or scientific validity of the trial. A final DSMB meeting will convene after the 
completion of the trial. 
 
The participation of individual patients will be discontinued if they experience: 
• 
Seizure or unconsciousness associated with hypoglycemia and associated with 
participation in the trial  
• 
Persistent nausea and vomiting thought to be related to glucagon dosing associated 
with participation in the trial 
• 
Hospitalization associated with participation in the trial 
• 
Pregnancy 
• 
Diabetic ketoacidosis 
 
If more than 1 patient must be withdrawn from the trial for these reasons, the trial will stop and 
a vote of the DSMB will be required to restart it. All AEs that are serious and unexpected but 
related will be reported to the DSMB within 5 working days. 
 
Note that patients may discontinue participation at any time. Patients may be removed from 
the trial for other reasons, for instance, failure to comply with trial procedures or intercurrent 
illness that is unrelated to the BP but that precludes safe participation. Discontinuation of 
participation for these reasons will not contribute to a decision to discontinue the trial.  
10.6.2 
Zealand Pharma Safety Committee 
The internal Zealand Pharma Safety Committee is constituted to perform ongoing safety 
surveillance of clinical trials within ZP4207, including this trial. 
 
If safety signals are observed either based on reported SAEs, periodic review of laboratory 
parameters, planned review of all AEs reported between the safety committee meetings, or 
on notification of significant findings, the Safety Committee will take appropriate measures to 
safeguard the patients. 
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11 
STATISTICS 
For all analysis, the 2 treatment arms from Part 1 (iPhone-based BP) will be compared, and 
the 2 treatment arms from Part 2 (iLet) will be compared. The analysis of Part 1 will be 
completely separate from the analysis of Part 2. 
 
11.1 
Analysis Populations  
The following analysis sets are defined in accordance with the ICH-E9 guidance: 
 
The Full Analysis Set is based on the intention-to-treat principle and includes all randomized 
patients. In exceptional cases, patients from the Full Analysis Set may be excluded (will be 
decided in the database review [DBR] meeting). In such cases, the exclusion will be justified 
and documented. Patients will contribute to the evaluation “as randomized.” 
 
The Per-Protocol Set includes all patients of the Full Analysis Set who completed the trial 
without any major protocol violations. Patients in the Per-Protocol Set will contribute to the 
evaluation “as treated.” This analysis will only be used if it is different than the Full Analysis 
Set. 
 
The Safety Analysis Set includes all patients receiving at least 1 dose of the IMP. Patients in 
the Safety Analysis Set will contribute to the evaluation “as treated.”  
 
Analyses of efficacy endpoints will be based on the Full Analysis Set (and the Per-Protocol 
Set if necessary). This decision will be made in the DBR meeting. The analysis of the safety 
endpoints will be based on the Safety Analysis Set.  
 
Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. At this time, it will be 
determined if patients and/or data should be excluded from the analysis. Furthermore, outliers 
will be identified by data review according to ICH-E9. 
 
Obviously erroneous data points may be excluded from the analyses or re-analyzed 
(e.g., serum concentrations). The decision to re-analyze or exclude data points from the 
statistical analysis is the joint responsibility of the Sponsor, the Principal Investigator, and the 
Trial Statistician. 
 
The patients or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to database release. The documentation 
will be stored together with the remaining trial documentation. The patients and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report. 
 
11.2 
Statistical Methods  
Medpace will be responsible for the statistical analysis. The statistical planning and conduct 
of analyses of the data from this trial will follow the principles defined in relevant ICH guidelines 
and Medpace’s biostatistical standard operating procedures (SOPs). A general description of 
the statistical methods to be used is given in this section, specific details will be provided in 
the Statistical Analysis Plan (SAP), which will be prepared before database lock. All statistical 
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analyses will be performed using SAS® (SAS Institute Inc., Cary, North Carolina, USA), 
version 9.3 or later.  
11.2.1 
Analysis of Safety 
The following variables will be evaluated according to treatment for safety purposes: 
Adverse Events 
All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). Individual AEs will be presented in a listing including relationship to trial 
product/device, severity, and treatment period at onset. If more than 20 treatment-emergent 
AEs (AEs with onset after [first] dosing at Visit 3 until the Follow-up Visit 6) are registered, a 
summary table including number of AEs, number of patients with at least 1 AE, and percentage 
of exposed patients with at least 1 AE will be made by system organ class and treatment 
period at onset. 
Local Tolerability 
Local tolerability at the injection site will be summarized using descriptive statistics as 
appropriate. 
Laboratory Safety Assessments 
Laboratory assessments will be summarized. A listing of abnormal values will be provided. 
Physical Examination 
A frequency table will show the number and percentage of physical examination results. 
Vital Signs 
Vital signs will be summarized using descriptive statistics. 
12-lead ECG 
The Investigator’s evaluations of 12-lead ECGs will be summarized and abnormal individual 
evaluations will be listed together with the Investigator’s comments. Changes in 12-lead ECG 
between measurements will be recorded as AEs if the Investigator judges them to be clinically 
significant.  
11.2.2 
Analysis of Efficacy 
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis, any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. Further details will be included in the 
SAP. 
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The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow.  
11.2.3 
Interim Analysis 
An interim database lock may occur upon completion of Part 1 of the trial to analyze the 
iPhone-based BP data. 
11.2.4 
Sample Size Determination 
No formal sample size calculations were made. It is expected that between 20 and 24 patients 
will be randomized in the trial. The sample size is based on a clinical rather than statistical 
rationale. The sample size is considered adequate to address the primary trial objective of 
exploring the safety of ZP4207 when used in the BP and with reference to Lilly glucagon used 
in the BP. 
12 
DATA MANAGEMENT AND RECORD KEEPING 
Data Management is the responsibility of Medpace. The complete Data Management process 
will be described in detail and agreed on in the Data Management Plan for this trial. 
12.1 
Data Handling 
Case Report Forms 
Electronic Case Report Forms will be used in this trial. The Data Management Department of 
Medpace will provide the eCRFs. All further information regarding the eCRFs and the data 
flow will be described and agreed on in the Data Management Plan. 
Device-Related Data 
During the trial, CGM data, calibration data, insulin dosing data, and glucagon dosing data will 
be automatically stored in the BP device (from which it will be downloaded at intervals), 
combined in a single database that will be compared against the primary data files for integrity, 
and ultimately transferred to Medpace.  
12.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
12.3 
Data Entry 
Data must be recorded using the electronic data capture (EDC) system as the trial is in 
progress. The patient questionnaires will be transcribed into the EDC system by site 
personnel. All site personnel must log into the system using their secure user name and 
password in order to enter, review, or correct trial data. These procedures must comply with 
Title 21 of the Code of Federal Regulations (21 CFR Part 11) and other appropriate 
international regulations. All passwords will be strictly confidential. 
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12.4 
Medical Information Coding 
Adverse events and medical history will be coded using the latest version of MedDRA. Prior 
and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. 
12.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, 
will be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
12.6 
Record Keeping 
Medpace will be responsible for hosting the TMF. Records of patients, source documents, 
monitoring visit logs, eCRFs, inventory of trial product, regulatory documents, and other 
Sponsor correspondence pertaining to the trial must be kept in the appropriate trial files at the 
site. Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
evaluation and reconstruction of the clinical trial. Source data are contained in source 
documents (original records or certified copies). These records will be retained in a secure file 
for the period as set forth in the Clinical Trial Agreement. Prior to transfer or destruction of 
these records, the Sponsor must be notified in writing and be given the opportunity to further 
store such records. 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
13.1 
Ethical Conduct of the Trial 
The trial will be conducted according to Medpace, MGH, and/or the Sponsor’s written 
instructions (SOPs, working instructions, or process descriptions). Content and definitions of 
the written instructions are based on the Declaration of Helsinki and the ICH GCP.  
13.2 
Institutional Review Board  
Written favorable opinion must be obtained from the responsible IRB prior to commencement 
of the trial. Clinical trial submission and reporting requirements before, during, and after 
completion of the trial will be performed in accordance with national law and local regulations. 
All amendments that affect patient safety or the trial integrity (substantial amendments) must 
not be implemented before favorable opinion has been obtained, unless necessary to 
eliminate hazards to the patients. Non-substantial amendments do not require favorable 
opinion by the IRB, but the respective IRB will be notified according to local requirements.  
The Sponsor and Investigator must approve any amendment in writing before its 
implementation. 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
IRB. The records should be filed in the Sponsor’s Trial Master File (TMF). 
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13.3 
Informed Consent  
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirement(s) and adhere to the ICH GCP guideline and the 
requirements in the Declaration of Helsinki. 
 
Prior to any trial-related activity, the Investigator must give the patient oral and written 
information in a form that the patient can read and understand about all aspects of the trial 
that are relevant to the patient’s decision to participate. The patient will be given ample time 
to decide whether or not to participate in the trial. 
 
The patient must be informed that his/her personal trial-related data will be used in accordance 
with the local data protection law. The level of disclosure must also be explained to the patient. 
 
The patient must be informed that his/her medical records may be examined by authorized 
monitors or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
 
A voluntary, personally signed and dated ICF must be obtained from the patient prior to any 
trial-related activity. The ICF must also be signed and dated by the physician or designee who 
conducted the informed consent procedure. A signed copy of the ICF and any additional 
patient information must be given to each patient.  
 
The responsibility for taking informed consent must remain with that of a research physician 
or designee. If information becomes available that may be relevant to the patient’s willingness 
to continue participating in the trial, the Investigator must inform the patient in a timely manner, 
and a revised written informed consent must be obtained. 
 
Should a protocol amendment become necessary, the ICF may need to be revised to reflect 
the changes to the protocol. It is the responsibility of the Sponsor to ensure that an amended 
consent form is reviewed and has received favorable opinion from IRB, and the Investigator 
must ensure that the amended consent form is signed by all patients subsequently entered 
into the trial and those currently in the trial, if affected by the amendment. 
 
13.4 
Trial Monitoring Requirements  
The monitoring procedures for this trial are described in detail in the Monitoring Manual. The 
objectives of the monitoring procedures are to ensure that (i) the safety and rights of the trial 
patients are respected, (ii) that accurate, valid, and complete data are collected, and (iii) that 
the trial is conducted in accordance with the trial protocol, the principles of GCP, and local 
legislation, including drug accountability. 
 
The monitor must be given direct access to the investigational site files and source documents 
(original documents, data, and records). Direct access includes permission to examine, 
analyze, verify, and reproduce any record(s) and report(s) that are important to evaluation of 
the clinical trial. 
 
Key tasks of the monitor include verifying the presence of informed consent, the adherence to 
the inclusion/exclusion criteria, the documentation of SAEs, and the recording of all safety and 
efficacy variables. The monitor will also confirm the completeness of patient records, the 
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adherence to the protocol, ICH GCP, and the progress in patient enrollment and perform drug 
accountability.  
 
Because no information that could reveal the identity of patients may ever be removed from 
the trial site, the monitor will visit the site at regular intervals to perform these monitoring tasks. 
Other contact between the Investigator and monitors will be maintained as required through 
telephone calls and e-mail. The Investigator and/or key members of staff involved in the trial 
must be available to assist the monitors during all visits.  
 
Site Initiation Visit 
During the Site Initiation Visit (SIV) the CRO, Sponsor, and/or monitors will go through 
information on the IMP, the protocol, the eCRFs, and other key aspects of the trial with the 
Investigator and the key members of staff involved in the trial. The topics of the SIV are 
documented in a SIV report made available to the Investigator. Documentation on the SIV 
(e.g., power point presentation) should be filed by both Investigator and Sponsor. 
 
13.5 
Disclosure of Data 
Data generated by this trial must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal 
physician or other appropriate medical personnel responsible for their welfare. 
 
Patient medical information obtained during the trial is confidential and disclosure to third 
parties other than those noted above is prohibited. 
 
13.6 
Retention of Records  
Massachusetts General Hospital will maintain the patient’s medical file according to local 
regulations. MGH will archive the documentation pertaining to the trial in an archive after 
completion or discontinuation of the trial if not otherwise notified. MGH should not destroy any 
documents without prior permission from the Sponsor. 
 
The documentation includes all the raw data generated during the clinical trial, the 
investigational site files, and a copy of the clinical trial report. The documents will be retained 
for a period of at least 15 years at archives by MGH, or its sub-contractor. After this period, 
the Sponsor will be contacted and their advice sought on the return or further retention of the 
trial records. 
 
The Sponsor will maintain the documentation pertaining to the trial in accordance with national 
regulations. 
 
13.7 
Publication Policy  
The Principal Investigator of the trial will review and sign the clinical trial report. A summary of 
the final clinical trial report will be submitted to the IRB and Competent Authority. 
  
According to the Declaration of Helsinki Investigators and Sponsors “have ethical obligations 
with regard to the publication and dissemination of the results of research.” The trial design 
and results may be published as 1 or more original research manuscripts/abstracts and 
presented at a scientific meeting. The Investigator and Sponsor reserve the right to review any 
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proposed presentation of the results of this trial before they are submitted for publication. 
Authorship on any publication(s) resulting from this clinical trial will be assigned according to 
the recommendations of the International Committee of Medicinal Journal Editors. 
 
Participating patients will not be identified by name in any published reports about the clinical 
trial. 
 
The Sponsor is responsible for trial registration at ClinicalTrials.gov (www.clinicaltrials.gov) 
according to the requirements from the FDA. 
  
13.8 
Legal Aspects  
An implicit or explicit approval must be obtained from the Competent Authority prior to 
commencement of the trial. Clinical trial submission and reporting requirements before, during, 
and after completion of the trial will be performed in accordance with national law and local 
regulations. 
 
An implicit or explicit approval will also be mandatory before implementation of substantial 
changes. Non-substantial amendments do not require approval from the Competent Authority 
but will be notified according to local requirements. 
 
The Sponsor and Investigator must approve the amendment in writing before its 
implementation. 
 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
Competent Authority. The records should be filed in the Sponsor’s TMF. 
  
Audits and Inspections  
In the event of an audit, representatives of the Sponsor or designee, or national and 
international regulatory authorities may request access to all trial records for inspection and 
copying. Such access must be stated in the ICF signed by the patient. 
 
13.9 
Sponsor Discontinuation Criteria  
The Sponsor, Investigator, or a pertinent regulatory authority may decide to stop the trial or 
part of the trial at any time but agreement on procedures to be followed must be obtained. 
 
Conditions that may warrant termination of the clinical trial include, but are not limited to: 
• 
Safety or administrative reasons 
• 
The discovery of an unexpected, relevant, or unacceptable risk to the patients enrolled 
in the clinical trial 
• 
A decision of the Sponsor to suspend or discontinue investigation of the IMP 
 
If the trial is prematurely terminated or suspended, the Investigator should promptly inform the 
patients and assure appropriate therapy and follow-up. Furthermore, the Sponsor should 
promptly inform the IRB and provide a detailed written explanation. The pertinent regulatory 
authorities should be informed according to national regulations. 
 
If after the termination of the trial the risk/benefit analysis has changed, the new evaluation 
should be provided to the IRB in case it will have an impact on the planned follow-up of the 
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patients who have participated in the trial. Necessary actions needed to protect the patients 
should be described. 
13.10 
Patient Compensation 
Financial compensation will be provided to all patients who complete the Screening Visit. 
Patients will be paid $25 for completing the Screening Visit whether or not they are eligible to 
participate in the trial. Patients will be compensated $25 for completing the Training Visit. 
Patients will be compensated $100 for completing each of the 2 treatment visits, $25 for 
completing the ADA Assessment Visit, and $25 for completing the Follow-up Visit. Thus, the 
total compensation for a patient who completes the trial would be $300. Patients who are 
unable to complete the trial or choose to stop participation will receive prorated compensation 
for each visit. In addition to the monetary compensation, the cost of the patients’ lunch meals 
during their participation in the trial, as well as the patients’ parking at each visit, will be covered 
by trial funds.  
14 
TRIAL ADMINISTRATIVE INFORMATION 
14.1 
Protocol Amendments  
Any amendments to the trial protocol will be communicated to the Investigators by Medpace 
or the Sponsor. All protocol amendments will undergo the same review and approval process 
as the original protocol. A protocol amendment may be implemented after it has been 
approved by the IRB, unless immediate implementation of the change is necessary for patient 
safety. In this case, the situation must be documented and reported to the IRB within 5 working 
days. 
14.2 
Address List 
14.2.1 
Sponsor 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Telephone: +45 88 77 36 00 
Facsimile: +45 88 77 38 98 
14.2.2 
Supplier of Device 
, PhD 
Beta Bionics, Inc. 
Business Innovation Center, Photonics Center 
8 Saint Mary’s Street, Suite 936 
Boston, Massachusetts 02215-2421 
United States 
Telephone: 
 
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APPENDIX A: SCHEDULE OF PROCEDURES – PARTS 1 AND 2 
Trial Visit 
Visit 1 [1]
Screening 
Visit 2
Training 
Visit 3 [2] [3]
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3]
[5] 
(2nd Treatment 
Visit) 
Visit 5
ADA 
Assessment 
Visit [6] 
Visit 6
Follow-Up 
[7] 
Informed consent 
X 
Assess/confirm elig bility 
X 
X 
Demographics 
X
Medical, surgical, and social history; allergies  
X 
Concomitant illness 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Height, weight, physical examination, and vital signs 
including body temperature and blood pressure [8] 
X 
X [9] 
X [9] 
12-lead ECG 
X 
X [10] 
X [10] 
Urine HCG pregnancy test and menstrual history [11]   
X 
X 
X 
FSH [12] 
X 
Screening labs – HbA1c, optional fractionated 
metanephrines [13] 
X 
Safety lab sampling including chemistry and hematology 
X 
X [10] 
X [10] 
X 
Training on devices [14] 
X 
Monitored BP use 
X 
X
Plasma glucose sampling [15] 
X 
X 
ZP4207/glucagon exposure sampling [16] 
X 
X 
Nausea and infusion site pain VAS and infusion site 
reaction Draize scale (visit start [17], hourly, & visit end) 
X 
X 
Standardized lunch [18] 
X 
X 
In-clinic exercise [19] 
X 
X 
Questionnaires (pre & post BP) 
X 
X 
ADA 
X [20] 
X 
X 
Adverse event review 
X 
X 
X 
X 
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1.
Once the patient has been enrolled and eligibility has been established, the order of the treatment visits will be randomized in blocks of 2 patients.
2.
In Part 1, each patient will participate in 2 treatment visits: 1 with the iPhone-based BP using ZP4207 and 1 with the iPhone-based BP using Lilly glucagon in a
randomized order. In Part 2, each patient will participate in 2 treatment visits: 1 with the iLet using ZP4207 and 1 with the iLet using Lilly glucagon in a randomized
order. Up to 2 patients may participate in the trial per day.
3.
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal skin and calibrate the sensor when prompted using the provided Nova
StatStrip Xpress meter. Patients will be asked to arrive at he visit at least 1 hour in advance of the start of the BP having fasted since 12:00 AM the night before
(treatment with simple carbohydrate of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled within the visit window. If BG
is >250 mg/dL, the visit will be rescheduled within the visit window. If BG is <50 mg/dL, the patient will be treated with simple carbohydrate according to the 15/15 rule
(15 grams of carbohydrates, repeated in 15 minutes if necessary). The visit will not need to be rescheduled unless the patient experiences a severe hypoglycemic
event and requires treatment with glucagon or intravenous dextrose.
4.
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 30 days after screening (Visit 1).
5.
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum of 3 weeks between Visit 3 and Visit 4.
6.
Visit 5 will take place 10 days ±3 days from Visit 4.
7.
Visit 6 will take place 25 days ±4 days from Visit 4.
8.
Height and physical examination will be measured at Visit 1 only.
9.
Vital signs including body temperature and blood pressure will be obtained at visit start and visit end. Blood pressure and heart rate will be measured in the seated
position and within 3 minutes of standing.
10. At visit start and visit end.
11. Urine HCG pregnancy test only for women of childbearing potential. The date of the last menstrual period in female patients will be obtained at Visit 1 only.
12. Test for FSH level only for postmenopausal women amenorrheic for less than 1 year.
13. If indicated by history.
14. Patients will be trained in the insertion and calibration of the Dexcom G4 sensor, diabetes management (e g., basal insulin rate adjustment by insulin pump) during
fasting prior to and between the treatment visits, and trial policies and procedures.
15. Collected at least hourly. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG
is <80 mg/dL, then sampling will be every 10 minutes.
16. Collected at least hourly. If BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the Investigator.
17. Once the infusion sites have been placed but no drug has yet been administered.
18. Between approximately Hour 3 and Hour 4.
19. Between approximately Hour 6 and Hour 7.
20. Before the start of dosing.
ADA = anti-drug antibodies; BG = blood glucose; BP = bionic pancreas; CGM = continuous glucose monitor; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
HbA1c = hemoglobin A1c; HCG = human chorionic gonadotropin; VAS = visual analog scale. 
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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Chemistry 
Alanine aminotransferase 
Aspartate aminotransferase 
Alkaline phosphatase 
Total protein 
Albumin 
Total and direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Creatinine 
Estimated glomerular filtration rate 
Blood urea nitrogen 
Uric acid
Bicarbonate 
Sodium 
Potassium 
Calcium 
Chloride 
Phosphorus 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell count 
White blood cell count and differential 
Platelets 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Pregnancy Test 
A urine HCG pregnancy test will be performed at screening, Visit 3, and Visit 4 only for 
women of childbearing potential. 
Anti-drug Antibodies Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken prior to first dosing (Visit 3), at the ADA Assessment Visit (Visit 5), 
and at the Follow-up Visit (Visit 6). 
ZP4207/Glucagon Exposure Sampling 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at 
the discretion of the Investigator. 
Screening Visit Only 
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year 
Optional fractionated plasma metanephrines (if indicated by history) 
Hemoglobin A1c 
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APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES  
Diabetes Treatment Satisfaction Questionnaire – Status (DTSQs)  
The DTSQs measures patient satisfaction with diabetes treatment. It consists of a 6 item scale 
for assessing treatment satisfaction and two additional items assessing perceived frequency 
of hyperglycemia and hypoglycemia. The DTSQs is meant for adults and older children. 
Dr. Clare Bradley has produced a version that is appropriate for bionic pancreas studies for 
this use, along with a version for younger children. It is administered before the intervention. 
The DTSQs is valid and reliable. Administration time is less than 5 minutes. 
 
Diabetes Treatment Satisfaction Questionnaire – Change (DTSQc) 
Although the DTSQ is responsive to treatment changes, ceiling effects are often seen with this 
instrument, where maximum or close-to-maximum scores at baseline provide little opportunity 
for registering improvement. The DTSQc contains the same items as the DTSQs version but 
asks patients to consider their satisfaction with their current treatment compared with their 
previous treatment. The DTSQc is meant for adults and older children. Dr. Clare Bradley has 
produced a version that is appropriate for bionic pancreas studies for our use, along with a 
version for younger children. It is administered during and at the end of the intervention. The 
DTSQc is valid and reliable. Administration time is less than 5 minutes. 
 
T1-Diabetes Distress Scale (T1-DDS) 
The T1-DDS is a 28-item survey that assesses seven sources of diabetes distress for type 1 
adults. It captures feelings of powerlessness; management distress; hypoglycemia distress; 
negative social perceptions by others; eating distress; physician (health care) distress; and 
friend/family distress. Items are scored on a 6-point scale from not a problem to a very serious 
problem. It is administered before, during, and at the end of the intervention. The scale is valid 
and reliable, and has been shown to be sensitive to change over time. Administration time is 
5 minutes. 
 
Problem Areas in Diabetes Survey (PAID) 
There are three versions of the PAID: Teen (PAID-T), Parent (PAID-P), and Child (PAID-C) 
versions. This measure of diabetes-specific emotional distress in youth with diabetes and their 
parents is 26 items. A total score is generated. It is administered before, during, and at the 
end of the intervention. The PAID-T and PAID-P are valid and reliable. Psychometric analysis 
of the PAID-C is in progress. Administration time is 5 minutes. 
 
Hypoglycemia Fear Survey (HFS) 
There are three versions of the HFS, Adult (HFS), Youth (HFS-Y) and Parent (HFS-P). The 
HFS measures several dimensions of fear of hypoglycemia among adults with type 1 diabetes. 
It consists of 23 items and produces two sub-scale scores; a Behavior sub-scale that 
measures behaviors involved in avoidance and/or over-treatment of hypoglycemia and a 
Worry sub-scale that measures anxiety and fear surrounding hypoglycemia. The HFS-Y 
consists of 25 items and the HFS-P consists of 26 items; both produce sub-scale scores 
similar to the Adult HFS. It is administered before, during, and at the end of the intervention. 
All versions of the HFS are valid and reliable. Administration time is 5-10 minutes. 
 
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Impact of Daily Diabetes Demands (IDDD) 
There are four versions of the IDDD; Adult (IDDD-A), Youth (IDDD-Y), Parent (IDDD-P), and 
Significant Other (IDDD-SO). This instrument measures the burden related to the demands of 
the daily diabetes regimen and is 22 items. A total score is generated. It is administered before, 
during, and at the end of the intervention. Psychometric analysis of the IDDD-Y is in progress 
using the data from the second Bionic Pancreas Camp Study in pre-adolescent children, and 
of the IDDD-A is in progress using data from the Bionic Pancreas Multicenter Study in adults. 
Administration time is 5 minutes. 
Bionic Pancreas User Opinion Survey (BPUOS) 
There are four versions of the BPUOS; Adult (BPUOS-A), Youth (BPUOS-Y), Parent 
(BPUOS-P), and Significant Other (BPUOS-SO). This measure assessing both the benefits 
from, and difficulties with, use of the bionic pancreas, and consists of 38 items. A total score 
is generated. It is administered during and at the end of the intervention. Psychometric 
analysis of the BPUOS-Y is in progress using the data from the second Bionic Pancreas Camp 
Study in pre-adolescent children, and of the BPUOS -A is in progress using data from the 
Bionic Pancreas Multicenter Study in adults. Administration time is 10 minutes. 
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12 September 2016 
1
 
SUMMARY OF CHANGES DOCUMENT 
PROTOCOL NUMBER ZP4207-16051 
AMENDMENT NUMBER 5.0 
 
PROTOCOL TITLE: The Bionic Pancreas Feasibility Trial Testing the Bionic Pancreas with 
ZP4207 
AMENDMENT DATE: 09 September 2016 
SUMMARY AND JUSTIFICATION OF CHANGES: 
This amendment was developed to include additional anti-drug antibodies (ADA) sampling at 
10 days ±3 days following the last day of dosing (Visit 4). Visit 5 has been changed from a 
phone call 7 days ±3 days following the last day of dosing (Visit 4) to an ADA Assessment Visit 
at the trial site 10 days ±3 days following the last day of dosing (Visit 4). In addition, language 
has been added that any patient that tests positive for ADA will be monitored until the ADA 
levels return to baseline. The schedule of procedures was updated to reflect the changes 
specified in this document. Other minor edits were made throughout the protocol to provide 
greater clarity and consistency. 
SUMMARY OF CHANGES: 
The amended protocol sections and the details of the changes are summarized in the following 
sections. Revisions to the protocol are presented as strikethrough (ie, subject) for text that was 
removed and bold (ie, subject) for text that was added. 
 
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2
Section 1.5, Risk/Benefit, Page 21 
Original Text: 
Overall, ZP4207 is judged to be a low-risk molecule, based upon the available clinical data as 
well as the outcome of the risk-based approach to the immunogenicity assessment made. The 
present trial will include sampling for measurement of antibodies against ZP4207 prior to first 
dosing (Visit 3) and at the Follow-up Visit. In line with regulatory guidance documents, these 
samples will be appropriately analyzed and the results will be included in the overall 
assessment of the immunogenic potential of ZP4207 after completion of each trial and as the 
clinical development program advances. 
New Text: 
Overall, ZP4207 is judged to be a low-risk molecule, based upon the available clinical data as 
well as the outcome of the risk-based approach to the immunogenicity assessment made. The 
present trial will include sampling for measurement of antibodies against ZP4207 prior to first 
dosing (Visit 3), at the ADA Assessment Visit (Visit 5), and at the Follow-up Visit (Visit 6). In 
line with regulatory guidance documents, these samples will be appropriately analyzed and the 
results will be included in the overall assessment of the immunogenic potential of ZP4207 after 
completion of each trial and as the clinical development program advances. 
Section 7.5, Anti-drug Antibodies Assessment Visit (Visit 5), Page 38 
Original Text: 
7.5 
Phone Call (Visit 5) 
A phone call will be conducted 7 days ±3 days following the last day of dosing (Visit 4) to review 
AEs and concomitant medications. 
New Text: 
7.5 
Phone Call Anti-drug Antibodies Assessment Visit (Visit 5) 
A phone call Patients will be conducted return for an ADA Assessment Visit 7 10 days 
±3 days following the last day of dosing (Visit 4) to for ADA sampling and a review of AEs 
and concomitant medications. 
Section 9.4, Anti-drug Antibodies Assessments, Page 40 
Original Text: 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken at Visit 3 and the Follow-up Visit 6. 
New Text: 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken at Visit 3, the ADA Assessment Visit (Visit 5), and the Follow-up Visit 
(Visit 6). Any patient that tests positive for ADA will be monitored until the ADA levels 
return to baseline. 
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Section 13.10, Patient Compensation, Page 54 
Original Text: 
Patients will be compensated $100 for completing each of the 2 treatment visits, $25 for 
completing the phone call, and $25 for completing the Follow-up Visit. Thus, the total 
compensation for a patient who completes the trial would be $300. Patients who are unable to 
complete the trial or choose to stop participation will receive prorated compensation for each 
visit. In addition to the monetary compensation, the cost of the patients’ lunch meals during 
their participation in the trial, as well as the patients’ parking at each visit, will be covered by 
trial funds. 
New Text: 
Patients will be compensated $100 for completing each of the 2 treatment visits, $25 for 
completing the phone call ADA Assessment Visit, and $25 for completing the Follow-up Visit. 
Thus, the total compensation for a patient who completes the trial would be $300. Patients who 
are unable to complete the trial or choose to stop participation will receive prorated 
compensation for each visit. In addition to the monetary compensation, the cost of the patients’ 
lunch meals during their participation in the trial, as well as the patients’ parking at each visit, 
will be covered by trial funds. 
Appendix B, Clinical Laboratory Analytes, Page 60 
Original Text: 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken prior to first dosing (Visit 3) and at the Follow-up Visit (Visit 6). 
New Text: 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken prior to first dosing (Visit 3), at the ADA Assessment Visit (Visit 5), 
and at the Follow-up Visit (Visit 6). 
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Appendix A, Schedule of Procedures – Parts 1 and 2, Page 58-59 
Original Text: 
APPENDIX A: SCHEDULE OF PROCEDURES – PARTS 1 AND 2 
Trial Visit 
Visit 1 [1] 
Screening 
Visit 2 
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5] 
(2nd Treatment 
Visit) 
Visit 5 
Phone Call [6] 
Visit 6 
Follow-Up [7] 
Informed consent 
X 
 
 
 
 
 
Assess/confirm eligibility 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical, surgical, and social history; 
allergies  
X 
 
 
 
 
 
Concomitant illness 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Height, weight, physical examination, 
and vital signs including body 
temperature and blood pressure [8] 
X 
 
X [9] 
X [9] 
 
 
12-lead ECG 
X 
 
X [10] 
X [10] 
 
 
Urine HCG pregnancy test and 
menstrual history [11]   
X 
 
X 
X 
 
 
FSH [12] 
X 
 
 
 
 
 
Screening labs – HbA1c, optional 
fractionated metanephrines [13] 
X 
 
 
 
 
 
Safety lab sampling including 
chemistry and hematology 
X 
 
X [10] 
X [10] 
 
X 
Training on devices [14] 
 
X 
 
 
 
 
Monitored BP use 
 
 
X 
X 
 
 
Plasma glucose sampling [15] 
 
 
X 
X 
 
 
ZP4207/glucagon exposure sampling 
[16] 
 
 
X 
X 
 
 
Nausea and infusion site pain VAS 
and infusion site reaction Draize scale 
(visit start [17], hourly, & visit end) 
 
 
X 
X 
 
 
 
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Summary of Changes, Amendment 5.0, ZP4207-16051 
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12 September 2016 
5
Trial Visit 
Visit 1 [1] 
Screening 
Visit 2 
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5] 
(2nd Treatment 
Visit) 
Visit 5 
Phone Call [6] 
Visit 6 
Follow-Up [7] 
Standardized lunch [18] 
X 
X 
In-clinic exercise [19] 
X 
X 
Questionnaires (pre & post BP) 
X 
X 
ADA 
X [20] 
X 
Adverse event review 
X 
X 
X 
X 
1.
Once the patient has been enrolled and eligibility has been established, the order of the treatment visits will be randomized in blocks of 2 pa ients.
2.
In Part 1, each patient will participate in 2 treatment visits: 1 with the iPhone-based BP using ZP4207 and 1 with the iPhone-based BP using Lilly glucagon in a randomized
order. In Part 2, each patient will participate in 2 treatment visits: 1 with he iLet using ZP4207 and 1 with the iLet using Lilly glucagon in a randomized order. Up to 2 patients
may participate in the trial per day.
3.
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal skin and calibrate the sensor when prompted using the provided Nova StatStrip
Xpress meter. Pa ients will be asked to arrive at the visit at least 1 hour in advance of the start of he BP having fasted since 12:00 AM the night before (treatment with simple
carbohydrate of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled within the visit window. If BG is >250 mg/dL, the visit will be
rescheduled within the visit window. If BG is <50 mg/dL, treatment with simple carbohydrate is allowed. If the pa ient experiences persistent hypoglycemia, the visit will be
rescheduled within the visit window.
4.
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more han 30 days after screening (Visit 1).
5.
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum of 3 weeks between Visit 3 and Visit 4.
6.
Visit 5 will take place 7 days ±3 days from Visit 4.
7.
Visit 6 will take place 25 days ±4 days from Visit 4.
8.
Height and physical examination will be measured at Visit 1 only.
9.
Vital signs including body temperature and blood pressure will be obtained at visit start and visit end.
10.
At visit start and visit end.
11.
Urine HCG pregnancy test only for women of childbearing poten ial. The date of the last menstrual period in female patients will be obtained at Visit 1 only.
12.
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year.
13.
If indicated by history.
14.
Patients will be trained in the insertion and calibration of the Dexcom G4 sensor, diabetes management (e.g., basal insulin rate adjustment by insulin pump) during fas ing
prior to and between the treatment visits, and trial policies and procedures.
15.
Collected at least hourly. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, hen
sampling will be every 10 minutes.
16.
Collected at least hourly. If BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the Investigator.
17.
Once the infusion sites have been placed but no drug has yet been administered.
18.
Between approximately Hour 3 and Hour 4.
19.
Between approximately Hour 6 and Hour 7.
20.
Before the start of dosing.
ADA = anti-drug antibodies; BG = blood glucose; BP = bionic pancreas; CGM = continuous glucose monitor; ECG = electrocardiogram; FSH = follicle-stimula ing hormone; 
HbA1c = hemoglobin A1c; HCG = human chorionic gonadotropin; VAS = visual analog scale. 
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12 September 2016 
6
New Text: 
APPENDIX A: SCHEDULE OF PROCEDURES – PARTS 1 AND 2 
Trial Visit 
Visit 1 [1] 
Screening 
Visit 2 
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5] 
(2nd Treatment 
Visit) 
Visit 5 
Phone Call 
ADA 
Assessment 
Visit [6] 
Visit 6 
Follow-Up [7] 
Informed consent 
X 
Assess/confirm eligibility 
X 
X 
Demographics 
X 
Medical, surgical, and social history; 
allergies  
X 
Concomitant illness 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Height, weight, physical examination, 
and vital signs including body 
temperature and blood pressure [8] 
X 
X [9] 
X [9] 
12-lead ECG 
X 
X [10] 
X [10] 
Urine HCG pregnancy test and 
menstrual history [11]   
X 
X 
X 
FSH [12] 
X 
Screening labs – HbA1c, optional 
fractionated metanephrines [13] 
X 
Safety lab sampling including 
chemistry and hematology 
X 
X [10] 
X [10] 
X 
Training on devices [14] 
X 
Monitored BP use 
X 
X 
Plasma glucose sampling [15] 
X 
X 
ZP4207/glucagon exposure sampling 
[16] 
X 
X 
Nausea and infusion site pain VAS 
and infusion site reaction Draize scale 
(visit start [17], hourly, & visit end) 
X 
X 
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Trial Visit 
Visit 1 [1] 
Screening 
Visit 2 
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5] 
(2nd Treatment 
Visit) 
Visit 5 
Phone Call 
ADA 
Assessment 
Visit [6] 
Visit 6 
Follow-Up [7] 
Standardized lunch [18] 
 
 
X 
X 
 
 
In-clinic exercise [19] 
 
 
X 
X 
 
 
Questionnaires (pre & post BP) 
 
 
X 
X 
 
 
ADA 
 
 
X [20] 
 
X 
X 
Adverse event review 
 
 
X 
X 
X 
X 
1. 
Once the patient has been enrolled and eligibility has been established, the order of the treatment visits will be randomized in blocks of 2 patients. 
2. 
In Part 1, each patient will participate in 2 treatment visits: 1 with the iPhone-based BP using ZP4207 and 1 with the iPhone-based BP using Lilly glucagon in a randomized 
order. In Part 2, each patient will participate in 2 treatment visits: 1 with the iLet using ZP4207 and 1 with the iLet using Lilly glucagon in a randomized order. Up to 2 patients 
may participate in the trial per day. 
3. 
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal skin and calibrate the sensor when prompted using the provided Nova StatStrip 
Xpress meter. Pa ients will be asked to arrive at the visit at least 1 hour in advance of the start of he BP having fasted since 12:00 AM the night before (treatment with simple 
carbohydrate of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled within the visit window. If BG is >250 mg/dL, the visit will be 
rescheduled within the visit window. If BG is <50 mg/dL, treatment with simple carbohydrate is allowed. If he patient experiences persistent hypoglycemia, the visit will be 
rescheduled within the visit window. 
4. 
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 30 days after screening (Visit 1). 
5. 
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum of 3 weeks between Visit 3 and Visit 4. 
6. 
Visit 5 will take place 7 10 days ±3 days from Visit 4.  
7. 
Visit 6 will take place 25 days ±4 days from Visit 4. 
8. 
Height and physical examination will be measured at Visit 1 only. 
9. 
Vital signs including body temperature and blood pressure will be obtained at visit start and visit end. 
10. At visit start and visit end. 
11. Urine HCG pregnancy test only for women of childbearing poten ial. The date of the last menstrual period in female patients will be obtained at Visit 1 only. 
12. Test for FSH level only for postmenopausal women amenorrheic for less than 1 year. 
13. If indicated by history. 
14. Patients will be trained in the insertion and calibration of the Dexcom G4 sensor, diabetes management (e.g., basal insulin rate adjustment by insulin pump) during fasting 
prior to and between the treatment visits, and trial policies and procedures. 
15. Collected at least hourly. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then 
sampling will be every 10 minutes. 
16. Collected at least hourly. If BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the Investigator. 
17. Once the infusion sites have been placed but no drug has yet been administered. 
18. Between approximately Hour 3 and Hour 4. 
19. Between approximately Hour 6 and Hour 7. 
20. Before the start of dosing. 
ADA = anti-drug antibodies; BG = blood glucose; BP = bionic pancreas; CGM = continuous glucose monitor; ECG = electrocardiogram; FSH = follicle-stimula ing hormone; 
HbA1c = hemoglobin A1c; HCG = human chorionic gonadotropin; VAS = visual analog scale. 
 
 
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Clinical Trial Protocol 
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Date: 09 September 2016 
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SYNOPSIS 
TITLE: The Bionic Pancreas Feasibility Trial Testing the Bionic Pancreas with ZP4207 
PROTOCOL NUMBER: ZP4207-16051 
INVESTIGATIONAL PRODUCT: ZP4207 
PHASE: 2 
INDICATION: ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid 
formulation which is being studied to improve glycemic control in adults (and children) with 
type 1 diabetes mellitus (T1DM) as part of a bihormonal bionic pancreas (BP). 
OBJECTIVES: 
Primary: The primary objective is to conduct a trial testing the safety and tolerability of the BP 
using either the iLet or the iPhone platform when used with ZP4207 in 20 adult (≥18 years of 
age) patients with T1DM. 
Secondary: The secondary objectives are to measure glycemic regulation, including 
hypoglycemia exposure (percent of time spent with continuous glucose monitor [CGM] 
glucose <60 mg/dL), evaluate BP device reliability, and to document the satisfaction of 
patients with the BP with the goal of optimizing the functionality and user interface of the BP. 
POPULATION: Up to 40 adult (≥18 years of age) patients who already manage their T1DM 
using continuous subcutaneous (SC) insulin infusion pump therapy can be enrolled. It is 
expected that up to 10 patients will complete each part of the trial protocol. 
TRIAL DESIGN: This trial is a single-center, open-label, 2-part, randomized cross-over trial. 
The trial will enroll adult patients with T1DM and will assess the safety and efficacy of the BP 
using either the iLet or the iPhone platform using the glucagon analog ZP4207 versus Lilly 
glucagon. In Part 1, up to 10 patients will participate in two 1-day treatment arms in random 
order (iPhone-based BP using ZP4207 and iPhone-based BP using Lilly glucagon) according 
to a pre-generated randomization scheme. In Part 2, up to 10 new patients will participate in 
two 1-day treatment arms in random order (iLet using ZP4207 and iLet using Lilly glucagon) 
according to a pre-generated randomization scheme. Patients can only participate in 1 part of 
the trial. An interim database lock may occur upon completion of Part 1 of the trial to analyze 
the iPhone-based BP data. The iLet and the iPhone-based BP will also administer insulin 
(insulin lispro, Lilly Humalog) using the same blood glucose (BG) control algorithm for all 
4 treatment arms. The trial will be conducted at a single center, the Massachusetts General 
Hospital Diabetes Center in Boston, MA. 
TRIAL TREATMENT: The trial involves SC administration of insulin lispro (Humalog, Lilly), 
which is commercially available by prescription and is indicated for patients with T1DM, but 
not for use in a BP. 
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The trial also involves SC administration of Lilly glucagon in 1 iLet arm and 1 iPhone-based 
BP arm. Lilly glucagon is commercially available by prescription and is indicated for patients 
with T1DM in severe hypoglycemia, but not for use in a BP. 
The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, in the 
other iLet arm and the other iPhone-based BP arm. ZP4207 will be made available by Zealand 
Pharma A/S, Denmark as liquid formulation in prefilled syringes of 0.6 mL. 
PRIMARY ENDPOINT: 
The primary endpoint is the safety and tolerability of ZP4207 in the BP using either the iLet or 
the iPhone platform as assessed by: 
•
Number and type of adverse events (AEs)
•
Clinical laboratory measurements
•
Vital signs
•
12-lead electrocardiogram (ECG)
•
Local tolerability and infusion site reactions as measured with the Draize scale
•
Immunogenicity as measured by anti-drug antibodies
•
Pain as measured on a 10 cm visual analog scale (VAS)
•
Nausea as measured on a 10 cm VAS
SECONDARY ENDPOINTS: 
The secondary endpoints include measurements of BP function as well as glycemic and 
non-glycemic measurements. 
Bionic Pancreas Function 
This endpoint data will be generated from the BP data during each treatment visit: 
•
Average percent insulin dose amounts calculated by the BP control algorithm that are
successfully delivered by the pump
•
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully delivered by the pump
•
Average percent dose amounts successfully issued to the pump by the BP control
algorithm that are successfully delivered by the pump (calculated doses are not issued
unless the pump is accessible and its delivery channel is available)
o
Average percent insulin dose amounts successfully issued to the pump by the
BP control algorithm that are successfully delivered by the pump
o
Average percent glucagon/ZP4207 dose amounts successfully issued to the
pump by the BP control algorithm that are successfully delivered by the pump
•
Average percent dose amounts calculated by the BP algorithm that are successfully
issued to the pump by the BP (calculated doses are not issued unless the pump is
accessible and its delivery channel is available)
o
Average percent insulin dose amounts calculated by the BP control algorithm
that are successfully issued by the BP
o
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully issued by the BP
•
Average percent of 5-minute steps during which the BP is functioning nominally in all
respects based on real-time CGM data (new CGM glucose reading captured, dose
calculated, and dose issued to pumps)
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•
Average percent of 5-minute steps during which the BP is functioning nominally with
or without a new CGM glucose reading captured (dose calculated and dose issued to
pumps). If a CGM signal is not available, the dose calculated may be based on weight
or historical basal rates.
•
CGM reliability index, calculated as percent of possible values actually recorded by
CGM
•
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter
download
•
List of technical faults associated with the BP including cause and resolution
Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit: 
•
Fraction of time spent within each of the following glucose ranges:
o
<50 mg/dL
o
<60 mg/dL
o
<70 mg/dL
o
70-120 mg/dL
o
70-140 mg/dL
o
70-180 mg/dL
o
>180 mg/dL
o
>250 mg/dL
o
>300 mg/dL
•
Number of severe hypoglycemic events (patients unable to self-treat, requiring the
assistance of another person)
•
Number of episodes of symptomatic hypoglycemia
•
Number of carbohydrate interventions for hypoglycemia
•
Total grams of carbohydrates taken for hypoglycemia
•
Mean CGM glucose
Non-glycemic 
•
Glucagon/ZP4207 total delivery per kg of body mass
•
Insulin total delivery per kg of body mass
•
Number of unscheduled infusion set replacements
•
Number of unscheduled CGM sensor changes
EVALUATION OF TRIAL DATA: The following variables will be evaluated according to 
treatment for safety purposes: AEs, local tolerability, laboratory safety assessments, physical 
examination, vital signs, and 12-lead ECGs.  
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
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A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow. 
  
SPONSOR: 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Tel: +45 88 77 36 00 
Fax: +45 88 77 38 98 
 
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Clinical Trial Protocol 
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Date: 09 September 2016 
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TABLE OF CONTENTS 
SIGNATURE PAGE ............................................................................................................. 2 
INVESTIGATOR AGREEMENT .......................................................................................... 3 
SYNOPSIS ........................................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................... 8 
LIST OF FIGURES ............................................................................................................ 11 
LIST OF ABBREVIATIONS .............................................................................................. 12 
1 
INTRODUCTION AND BACKGROUND INFORMATION ...................................... 14 
1.1 
Background and Rationale ..................................................................................... 14 
1.2 
Bihormonal Bionic Pancreas System ..................................................................... 15 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System ........................ 16 
1.4 
ZP4207 ................................................................................................................... 18 
1.5 
Risk/Benefit ............................................................................................................ 19 
2 
TRIAL OBJECTIVES .............................................................................................. 22 
2.1 
Primary Objective ................................................................................................... 22 
2.2 
Secondary Objectives ............................................................................................. 22 
3 
TRIAL DESCRIPTION ............................................................................................ 22 
3.1 
Summary of Trial Design ........................................................................................ 22 
3.2 
Indication ................................................................................................................ 23 
3.3 
Number of Patients ................................................................................................. 23 
4 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................ 23 
4.1 
Inclusion Criteria ..................................................................................................... 24 
4.2 
Exclusion Criteria .................................................................................................... 24 
4.3 
Target Population ................................................................................................... 26 
4.4 
Withdrawal Criteria ................................................................................................. 26 
5 
ASSIGNMENT TO TREATMENT GROUPS........................................................... 26 
6 
TRIAL TREATMENT .............................................................................................. 27 
6.1 
Investigational Medicinal Products ......................................................................... 27 
6.2 
Storage and Drug Accountability of IMPs ............................................................... 27 
6.3 
Dispensing and Return of IMPs .............................................................................. 27 
6.4 
Doses ..................................................................................................................... 28 
6.5 
iPhone-based Bionic Pancreas .............................................................................. 28 
6.6 
iLet Bionic Pancreas ............................................................................................... 29 
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6.7 
Other Trial Devices ................................................................................................. 30 
6.8 
Concomitant Medications ....................................................................................... 30 
6.8.1 
Permitted Medications and/or Procedures ...................................................... 30 
6.8.2 
Excluded Medications and/or Procedures ....................................................... 31 
7 
TRIAL PROCEDURES ........................................................................................... 31 
7.1 
Informed Consent ................................................................................................... 31 
7.2 
Screening Visit (Visit 1) .......................................................................................... 31 
7.2.1 
Data Collected at Screening ............................................................................ 32 
7.3 
Training Visit (Visit 2) .............................................................................................. 32 
7.4 
Treatment Visits (Visit 3 and Visit 4) ....................................................................... 32 
7.4.1 
Visit Procedures .............................................................................................. 33 
7.4.2 
Data Collected During the Treatment Visits .................................................... 36 
7.4.3 
Response to Hypoglycemia ............................................................................. 37 
7.4.4 
Response to Hyperglycemia ........................................................................... 37 
7.4.5 
Response to Nausea/Vomiting ........................................................................ 37 
7.4.6 
Response to Other Medical Needs ................................................................. 38 
7.4.7 
Monitoring of Bionic Pancreas Performance ................................................... 38 
7.4.8 
Supervision by Trial Staff ................................................................................ 38 
7.5 
Anti-drug Antibodies Assessment Visit (Visit 5) ...................................................... 38 
7.6 
Follow-up Visit (Visit 6) ........................................................................................... 38 
8 
ENDPOINTS ........................................................................................................... 38 
8.1 
Primary Endpoint .................................................................................................... 38 
8.2 
Secondary Endpoints ............................................................................................. 38 
8.2.1 
Bionic Pancreas Function ................................................................................ 39 
8.2.2 
Glycemic .......................................................................................................... 39 
8.2.3 
Non-glycemic ................................................................................................... 40 
9 
LABORATORY ASSESSMENTS ........................................................................... 40 
9.1 
Safety Laboratory Assessments ............................................................................. 40 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) .............................................. 40 
9.3 
Exposure Assessments (ZP4207 and Glucagon) ................................................... 40 
9.4 
Anti-drug Antibodies Assessments ......................................................................... 40 
10 
SAFETY REPORTING ............................................................................................ 41 
10.1 
Adverse Events ...................................................................................................... 41 
10.1.1 
Follow-up of Adverse Events ........................................................................... 41 
10.1.2 
Precautions ..................................................................................................... 42 
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10.1.3 
Assessment of Adverse Events by the Investigator ........................................ 42 
10.2 
Serious Adverse Events ......................................................................................... 43 
10.3 
Adverse Event Reporting – Procedures for Investigators ....................................... 43 
10.4 
Pregnancy Reporting .............................................................................................. 45 
10.5 
Hypoglycemia ......................................................................................................... 46 
10.6 
Safety Monitoring .................................................................................................... 46 
10.6.1 
Data and Safety Monitoring Board .................................................................. 46 
10.6.2 
Zealand Pharma Safety Committee ................................................................ 47 
11 
STATISTICS ........................................................................................................... 47 
11.1 
Analysis Populations .............................................................................................. 47 
11.2 
Statistical Methods ................................................................................................. 48 
11.2.1 
Analysis of Safety ............................................................................................ 48 
11.2.2 
Analysis of Efficacy ......................................................................................... 49 
11.2.3 
Interim Analysis ............................................................................................... 49 
11.2.4 
Sample Size Determination ............................................................................. 49 
12 
DATA MANAGEMENT AND RECORD KEEPING ................................................ 49 
12.1 
Data Handling ......................................................................................................... 49 
12.2 
Computer Systems ................................................................................................. 50 
12.3 
Data Entry ............................................................................................................... 50 
12.4 
Medical Information Coding .................................................................................... 50 
12.5 
Data Validation ....................................................................................................... 50 
12.6 
Record Keeping ...................................................................................................... 50 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ........................... 50 
13.1 
Ethical Conduct of the Trial .................................................................................... 50 
13.2 
Institutional Review Board ...................................................................................... 51 
13.3 
Informed Consent ................................................................................................... 51 
13.4 
Trial Monitoring Requirements ............................................................................... 52 
13.5 
Disclosure of Data .................................................................................................. 52 
13.6 
Retention of Records .............................................................................................. 52 
13.7 
Publication Policy ................................................................................................... 53 
13.8 
Legal Aspects ......................................................................................................... 53 
13.9 
Sponsor Discontinuation Criteria ............................................................................ 54 
13.10 
Patient Compensation ......................................................................................... 54 
14 
TRIAL ADMINISTRATIVE INFORMATION ............................................................ 54 
14.1 
Protocol Amendments ............................................................................................ 54 
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14.2 
Address List ............................................................................................................ 55 
14.2.1 
Sponsor ........................................................................................................... 55 
14.2.2 
Supplier of Device ........................................................................................... 55 
14.2.3 
Principal Investigator (Site) ............................................................................. 55 
14.2.4 
Contract Research Organization (Including Monitoring) ................................. 55 
14.2.5 
Medical Monitoring .......................................................................................... 55 
14.2.6 
Pharmacovigilance .......................................................................................... 56 
14.2.7 
Central Laboratory (Safety Laboratory and Plasma Glucose) ......................... 56 
14.2.8 
Special Laboratory (ZP4207 Exposure and ADA Analyses) ........................... 56 
14.2.9 
Special Laboratory (Glucagon Exposure) ....................................................... 56 
15 
REFERENCES ........................................................................................................ 57 
APPENDIX A: SCHEDULE OF PROCEDURES – PARTS 1 AND 2 ................................ 58 
APPENDIX B: CLINICAL LABORATORY ANALYTES ................................................... 60 
APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES ....................................... 61 
LIST OF FIGURES 
Figure 1. 
Outpatient Results Summarizing the Distribution of Mean CGM Glucose 
Levels and Hypoglycemia in the BP and Control Arms ............................. 17 
Figure 2. 
Trial Design Schematic ................................................................................. 23 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
BG 
Blood glucose 
BP 
Bionic pancreas 
BTLE 
Bluetooth Low Energy 
BU 
Boston University 
CFR 
Code of Federal Regulations 
CGM 
Continuous glucose monitor 
CRO 
Contract research organization 
DBR 
Database review 
DPP-4 
Dipeptidyl peptidase-4 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FHD 
First Human Dose 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GUI 
Graphical user interface 
HCG 
Human chorionic gonadotropin 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IV 
Intravenous 
MD 
Doctor of Medicine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH 
Massachusetts General Hospital 
MPC 
Model-predictive control 
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Abbreviation 
Definition 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
RN 
Registered nurse 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SGLT-2 
Sodium-glucose co-transporter-2 
SIV 
Site Initiation Visit 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 diabetes mellitus 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background and Rationale 
To date, clinical trials conducted by Boston University (BU) and Massachusetts General 
Hospital (MGH) in patients with type 1 diabetes mellitus (T1DM) have demonstrated the 
practicality of a wearable automated bionic pancreas (BP) control system for robust glucose 
regulation using a continuous glucose monitor (CGM) to provide the input to the control 
system. Despite current technical limitations in CGMs and infusion pumps, the trials by 
BU/MGH have shown that a bihormonal BP is capable of achieving safe and effective blood 
glucose (BG) control automatically, with minimal hypoglycemia during 11 continuous days in 
the face of unrestrained meals and exercise and with trivial patient input (optional 
announcement of meals).  
 
The BP provides automatic BG regulation and reduces hypoglycemic episodes. Additionally, 
the system spares the wearer the relentless tasks of carbohydrate counting, frequent BG 
monitoring, estimating the effects of specific meals and exercise activity on BG levels, and 
manual drug administration, which are inexact, demanding, aggravating, and require 
continuous diligence and vigilance. The degree of glycemic control achieved by the BP is 
predicted to dramatically reduce the deleterious and debilitating complications of T1DM. 
 
In its last tested embodiment, the BP consisted of a Dexcom G4 CGM, and an iPhone that are 
hardwired together, with the iPhone running the control algorithm and communicating via 
Bluetooth with 2 Tandem t:slim pumps to dose insulin and glucagon. The connections are 
repeatedly lost among these 4 components throughout the day, an issue that has the potential 
to adversely impact BG control, whether due to missed CGM values or missed doses. In 
addition, the troubleshooting required to repair these recurring disconnections can be 
burdensome to the user. Integrating these components into a single device would establish 
seamless connectivity among them, which would eliminate the need for such troubleshooting. 
This would lead to smoother device operation with fewer interruptions, which would enhance 
its user friendliness, optimize its BG control potential, and further improve the quality of life of 
its users.  
 
The BU Investigators have recently designed, built, and tested a proprietary first-generation 
of such a fully integrated BP system, referred to as the iLet and the iLet infusion set. The iLet 
is a dual-chamber infusion system that currently incorporates the Dexcom G4 CGM 
technology, a custom user interface with touchscreen display, and all of the mathematical 
dosing algorithms that were tested in and validated using the iPhone-based BP in outpatient 
studies over the past 3 years. The iLet infusion set provides 2 independent subcutaneous (SC) 
fluid pathways from the iLet to the patient (1 for insulin and the other for glucagon). One tube 
connects to the prefilled insulin cartridge and the other tube connects to the fillable (single-use) 
glucagon cartridge. 
 
In order to provide automatic BG regulation, the iLet and the iPhone-based BP have the ability 
to deliver both insulin and glucagon. However, currently available glucagon formulations have 
limited stability at room temperature, necessitating frequent changes to the glucagon infusion 
set. Therefore, the current trial is designed to test the glucagon analog ZP4207 in the iLet and 
the iPhone-based BP, as this peptide analog of human glucagon is provided in a liquid 
formulation stable at room temperature. 
 
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The current trial is a first feasibility trial designed to use the first-generation iLet and iLet 
infusion set and the iPhone-based BP to compare ZP4207 with marketed glucagon (Lilly). The 
trial is intended to demonstrate the safety and tolerability of ZP4207 in the iLet and the 
iPhone-based BP and the feasibility of achieving comparable autonomous glycemic control. It 
is not intended to comprehensively demonstrate the definitive efficacy of the BP in extended, 
continuous daily use, but rather to demonstrate its functionality and accuracy in a practical, 
albeit very controlled, clinical setting. The trial is expected to provide practical information that 
will benefit the design of a next-generation iLet and iLet infusion set and help pave the way for 
a more comprehensive outpatient home-use Phase 2 trial and ultimately a pivotal trial where 
comprehensive safety and efficacy through continuous full daily use of the iLet with ZP4207 
will be documented. 
 
The data derived from this trial will permit evaluation of the robustness of the iLet as well as 
the safety and efficacy of ZP4207 when used in conjunction with the iLet and the iPhone-based 
BP. The data obtained will be used to further improve the iLet and will allow BU/MGH to 
expand to larger outpatient trials using the iLet or the iPhone-based BP with ZP4207.  
 
1.2 
Bihormonal Bionic Pancreas System  
The BP is an autonomous, self-learning system that requires only the patient's weight for 
initialization, and then autonomously adapts, modestly or dramatically, as needed, to cope 
with the wide range of insulin requirements of adults, adolescents, and pre-adolescents with 
T1DM. The BP obviates the need for the patient to know, or even appreciate, their insulin 
requirements, and renders obsolete any need for patients or caregivers to know 
carbohydrate-to-insulin ratios, basal rates, or insulin correction factors. 
 
The core technology is a suite of control algorithms that orchestrate the automated dosing of 
insulin and glucagon to regulate BG levels. An insulin controller orchestrates all SC insulin 
dosing. At its centerpiece is a model-predictive control (MPC) algorithm, which bases insulin 
doses on the glucose data and insulin absorption kinetics, compensating for the slow 
absorption rate of SC insulin analogs (peak time in blood of 30-90 min, clearance in 4-8 hr). 
This enables the algorithm to refrain from stacking and overdosing insulin. Furthermore, the 
MPC algorithm automatically adjusts its insulin-dosing aggressiveness continuously and in 
real-time to different insulin needs between individuals and variable needs within the same 
individual. Running in parallel with the MPC algorithm is an algorithm that automatically 
modulates basal insulin delivery over multiple time scales, and another algorithm that 
automatically adapts insulin doses in response to optional meal announcements. Unlike 
current insulin pumps and the insulin-only control algorithms, the adaptive basal insulin 
algorithm obviates the need for the user to set, or even know, his or her “basal-rate profile.” 
Instead, it is capable of automatically adapting to, and compensating for, changes in an 
individual's basal insulin need, such as might occur over a period of hours, days, or weeks 
(e.g., circadian hormonal fluctuations, intercurrent illness, physical activity, or emotional state) 
or as might occur over a period of months or years due to developmental changes 
(e.g., hormonal changes that occur during puberty or menopause). The adaptive meal dose 
controller obviates the need for the user to set, or even know, his or her 
“carbohydrate-to-insulin ratios,” as it makes automatic adjustments based on dosing history 
for similar meal announcements made on previous days, and customizes the dose for each 
individual and for time of day.  
 
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The BP also includes a proportional-derivative algorithm governing SC micro-doses of 
glucagon to help prevent impending hypoglycemia. Glucagon dosing is based on the glucose 
level and rate of descent. It may occur preemptively even if glucose is above range, and it 
includes a feedback term to account for the pending effects of recent glucagon doses.  
Taken together, these mathematical algorithms provide a universal framework for a glycemic 
control strategy that requires no quantitative input from, or participation by, the user (besides 
entering body weight to initialize the system), but which automatically adapts insulin and 
glucagon dosing to meet the individual needs of each user. Another challenge met is enabling 
the technology to remain completely autonomous in managing insulin and glucagon delivery 
even when the CGM is offline. Specifically, when the CGM is offline, the BP invokes the 
high-resolution “basal rate profile” that it had recently learned and stored when the CGM was 
online. On the basis of what the system learned and stored about meal announcements when 
the CGM was online, it is able to respond to meal announcements in the same manner when 
the CGM is offline. Finally, it automatically responds to user-entered BG values when the CGM 
is offline by issuing a correction dose of insulin or glucagon based on what it learned about 
the user's insulin and glucagon needs when the CGM was online. Thus, the BP never relies 
on, or burdens the user with, the determination of subjective dosing decisions, which inevitably 
vary in quality and reliability among different users. The BP provides a turnkey solution for 
people with T1DM that comprehensively manages glycemia across a broad range of individual 
needs and across a large spectrum of circumstances and challenges to glycemic control. 
A significant challenge for the use of glucagon in a bihormonal BP is the lack of a commercially 
available glucagon formation that is stable and well-suited to infusion over several days in a 
pump reservoir. However, BU/MGH have proceeded with studies using a relatively unstable 
marketed formulation that must be reconstituted from a lyophilized powder on a daily basis. 
This allowed BU/MGH to proceed with studies of the bihormonal system while awaiting the 
production of stable glucagon formulations or stable glucagon analogs. 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System 
The BP hardware platform has evolved over the years from a laptop-driven system, which was 
used in all inpatient studies to the first truly mobile wearable iPhone-driven platform, which 
has been used in a number of outpatient studies. Using the iPhone-based BP system, 
>110 outpatient experiments of 5-11 days in duration in each subject have been conducted 
(>800 patient days or >2 patient years of data) across subjects ranging in age between 6 and 
76 years old and in body mass between 21 and 128 kg. The robust adaptation capabilities of 
the BP is evident in the fact that the average total daily dose of insulin among these subjects 
varied by over 13-fold (from 11 to 145 units/day). 
In November 2012, Food and Drug Administration (FDA) approval was obtained to conduct 
the first outpatient study testing the BP in adults 21 years or older with T1DM. This study, 
referred to as the Beacon Hill Study, followed a random-order cross-over design in which 
20 adults with T1DM participated in 5 days on the iPhone-based BP and 5 days of usual care 
in which they wore a CGM with blinded display and muted alarms. In the BP arm, subjects 
kept to a 3-square-mile geographic area centered around the Beacon Hill neighborhood in 
Boston. They ate as they chose at local restaurants, and exercised at will with access to 
2 gyms. Analysis was pre-specified to focus on Days 2-5, since glycemic control is more 
representative of BP performance after most of the adaptation by the BP occurs on Day 1 
(Russell, 2014). Results are summarized in Figure 1.  
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In April 2013, FDA approval was obtained to conduct the first outpatient study testing the BP 
in adolescents 12-20 years old with T1DM. This study, referred to as the 2013 Summer Camp 
Study, followed a random-order cross-over design in which 32 adolescents with T1DM 
participated in 5 days on the BP and 5 days of supervised camp care in which they wore a 
CGM with blinded display and muted alarms. Subjects were fully integrated into normal camp 
activities without restrictions on diet or exercise. The study used the same iPhone-based BP 
that was used in the Beacon Hill Study. Results are summarized in Figure 1 (Russell, 2014). 
In April 2014, FDA approval was obtained to conduct the first outpatient study testing the BP 
in pre-adolescents 6-11 years old with T1DM. This study, referred to as the 2014 Summer 
Camp Study, was similar in design to the 2013 Summer Camp Study. Results are summarized 
in Figure 1 (Russell, 2016).  
 
In April 2014, FDA approval was obtained to conduct the first multi-center study, which was 
also the first home study, to test the BP in adults 18 years or older with T1DM. This study, 
referred to as the Bionic Pancreas Multi-Center Study, followed a random-order cross-over 
design in which 39 adults participated in 11 days on the BP and 11 days of usual care. 
Participants went to work as usual, and lived and slept at home, all without clinical supervision. 
There were no restrictions placed on diet or exercise. The study included 4 medical centers 
(10 subjects per center), which included MGH, the University of Massachusetts Medical 
School, Stanford University, and the University of North Carolina at Chapel Hill. Results are 
summarized in Figure 1.  
 
All of these studies used marketed glucagon (glucagon for injection, Eli Lilly). Due to its limited 
stability, Lilly glucagon must be reconstituted immediately before use. Animal studies have 
previously shown that despite its limited chemical stability, Lilly glucagon maintains its 
biological activity for up to 7 days in solution. Using this data, an Investigational New Drug 
(IND) exemption was obtained from the FDA for its use in a pump for up to 27 hours. This 
allowed these studies to be performed by asking volunteers to reconstitute a new vial of 
glucagon and fill the glucagon pump at approximately the same time every day. However, 
marketed Lilly glucagon has no path forward for approval for chronic BP use. 
 
1.4 
ZP4207 
ZP4207 is a peptide analog of human glucagon that is being developed to treat hypoglycemia 
in patients with T1DM and type 2 diabetes mellitus. ZP4207 exhibits improved physical and 
chemical stability in aqueous media and is suitable for liquid formulation. ZP4207 is comprised 
of 29 amino acids and has 7 amino acid substitutions when compared to native glucagon.  
 
Two clinical Phase 1 trials have been conducted to establish safety and tolerability of ZP4207 
after single and multiple dosing to healthy patients and T1DM patients under insulin-induced 
hypoglycemic conditions. 
 
The First Human Dose (FHD) trial (ZP4207-14013) was finalized in April 2015. The trial was 
a randomized, double-blinded trial with the objectives to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of ZP4207 as compared to an active 
comparator. Part 1 included a single ascending dose in healthy volunteers in cohorts of 8. In 
each cohort, the patients were randomized 3:1 to ZP4207 (n=6) or Novo Nordisk GlucaGen® 
(n=2). Five cohorts with SC administration (0.01, 0.1, 0.3, 1.0, and 2.0 mg ZP4207 compared 
to 1 mg GlucaGen) and 3 cohorts with intramuscular (IM) administration (0.3, 1.0, and 2.0 mg 
ZP4207 compared to 1 mg GlucaGen) were included. Part 2 included 2 sequence groups of 
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10 hypoglycemic T1DM patients. The patients were treated with fixed single IM doses of 
0.7 mg ZP4207 and 1.0 mg GlucaGen in a sequential cross-over design in a randomized 
treatment order.  
The second clinical trial (ZP4207-15007) was a single-center, double-blind, Phase 1b trial 
investigating the safety and tolerability, PK and PD of ZP4207 following repeated 
administration in healthy volunteers compared to placebo. It was finalized in July 2015. Each 
of the 3 cohorts comprised 8 subjects, who received 5 repeated SC doses of ZP4207 or 
placebo in a 3:1 treatment allocation. The first cohort started with the lowest dose of 0.1 mg. 
Cohort 2 and 3 continued with 0.3 and 1.0 mg, respectively. 
The Phase 1 results did not give rise to specific safety concerns, beyond those related to the 
pharmacological effect of ZP4207. All adverse events (AEs) recorded in the trials were of mild 
or moderate severity. The most frequent systemic AE related to treatment with ZP4207 was 
nausea, which is a known side-effect following administration of glucagon. The most frequent 
injection site reaction was transient erythema, occurring in all ZP4207, glucagon, and placebo 
treatment groups, irrespective of dose. No anti-drug antibodies (ADA) incidences were 
observed. 
The observed PD response, in terms of increased plasma glucose, in insulin-induced 
hypoglycemic patients with T1DM following dosing with 0.7 mg ZP4207 administered IM was 
similar to that observed following IM dosing with 1.0 mg glucagon (GlucaGen, Novo Nordisk). 
An increase in plasma glucose of ≥20 mg/dL from hypoglycemic levels was achieved within 
30 minutes for all patients. 
In terms of PK, ZP4207 had a short half-life and high clearance and dose proportionality for 
both maximum plasma concentration and area under the concentration-time curve from 
time 0 to 300 minutes in the dose range 0.1 to 2.0 mg following SC administration. Following 
IM administration, dose proportionality was shown in the investigated dose range of 0.3 to 
2.0 mg. The PK properties of 0.7 mg ZP4207 IM were comparable with those of 1.0 mg 
glucagon (GlucaGen, Novo Nordisk) with IM administration. 
1.5 
Risk/Benefit 
While the potential risks are minimal, the findings of this trial may reveal information that can 
substantially improve medical care for persons with diabetes. Therefore, the overall 
risk/benefit for patients participating in this trial is assessed as acceptable. 
Potential Risks and Discomforts  
Trial patients will be informed by the Investigator of the potential risks of ZP4207 and other 
trial-related procedures before they enter the trial.  
In this trial, patients with T1DM will be included to test the safety and efficacy of the BP using 
either the iLet or the iPhone platform when used with ZP4207 versus Lilly glucagon. The 
cross-over design with inclusion of 1 group of 10 T1DM patients into the 2 iLet treatment arms 
and the inclusion of a second group of 10 T1DM patients into the 2 iPhone-based BP treatment 
arms in a randomized order will allow for a direct comparison of the safety and efficacy of the 
2 treatments, based on intra-patient variability only.  
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Patients may experience mild discomfort associated with the insertion of the infusion sets and 
sensor into the SC tissues. The risk of discomfort due to insertion of infusion sets and sensors 
is expected to be slightly greater than in their lives outside the trial because more infusion sets 
will be inserted and a CGM sensor will be inserted. Most patients will use only 1 infusion set 
and not all will use a CGM sensor in usual care.  
 
There is a potential risk of hypoglycemia, since recombinant insulin analog will be 
administered. Due to frequent monitoring of glucose and direct supervision by a registered 
nurse (RN) or Doctor of Medicine (MD) at all times, the risk of a hypoglycemic episodes leading 
to significant harm to patients is expected to be substantially lower than their risk during their 
usual therapy.  
 
There is a risk of hyperglycemia. This risk is expected to be less than the risk during the 
patients’ lives outside of the trial based on data from earlier BP trials and the design of this 
trial.  
 
Treatment with ZP4207 and marketed glucagon can result in undesired effects or complaints. 
Undesired effects and complaints such as gastrointestinal side effects including nausea, 
vomiting, and diarrhea are known side effects of glucagon administration at higher dose levels. 
The frequency of nausea associated with the administration of 1 mg of glucagon according to 
the Summary of Product Characteristics (SPC) for Glucagon is described to be between 1/10 
and 1/100. The frequency of vomiting is described to be between 1/100 and 1/1000 
(Novo Nordisk, 2015). Similar gastrointestinal side effects have also been observed to a 
limited degree in the 2 clinical trials conducted with ZP4207, again at higher dose levels. The 
individual doses of ZP4207 and Lilly glucagon delivered by the BP are expected to be 
significantly lower than doses typically associated with nausea. Episodes of low blood 
pressure have also been observed after administration of higher doses of glucagon and 
ZP4207. As with every novel drug substance, new and yet unknown side effects may also 
occur. 
 
There are limited data available to describe the immunogenic potential of glucagon products 
available on the market, but the data available indicate that marketed glucagon only has a 
small immunogenic potential. A Phase 1 trial performed with recombinant human glucagon 
and animal derived glucagon in 75 healthy patients did not show signs of ADA measured 
13 weeks after trial product administration (Eli Lilly, 2005). In the ZP4207 FHD trial, 
ZP4207-14013, no confirmed anti-ZP4207 or anti-glucagon antibodies were detected in any 
of the samples. In addition, the 5 sequential administrations of ZP4207, as applied in trial 
ZP4207-15007, were not associated with the development of antibodies against ZP4207 in 
the 18 subjects enrolled to receive ZP4207. The optimized formulation of ZP4207, as applied 
in the present trial is not expected to change the immunogenic potential of the Investigational 
Medicinal Product (IMP).  
 
In relation to diabetes therapy, development of insulin-antibodies is documented more 
substantially and route of administration has been shown to influence immunogenic potential 
of insulins. However, these antibodies against insulin generally do not have an impact on 
insulin action and are thus not clinically relevant. 
 
In terms of consequence, development of high titer antibodies against ZP4207 could, in theory 
reduce the activity of endogenous glucagon, which again, in theory could influence 
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hypoglycemic episodes. However, most patients with T1DM do not secrete glucagon normally 
in response to hypoglycemia, so they would be less likely to be negatively impacted by 
anti-glucagon antibodies. Limited suppression of glucagon would, however, not be considered 
critical, as low glucose levels can also be corrected by other means, including oral intake of 
glucose and by other endogenous hormones such as oxyntomodulin.  
 
Overall, ZP4207 is judged to be a low-risk molecule, based upon the available clinical data as 
well as the outcome of the risk-based approach to the immunogenicity assessment made. The 
present trial will include sampling for measurement of antibodies against ZP4207 prior to first 
dosing (Visit 3), at the ADA Assessment Visit (Visit 5), and at the Follow-up Visit (Visit 6). In 
line with regulatory guidance documents, these samples will be appropriately analyzed and 
the results will be included in the overall assessment of the immunogenic potential of ZP4207 
after completion of each trial and as the clinical development program advances. 
 
Administration of ZP4207 may be associated with a risk of allergic reactions similar to those 
observed for other therapeutic peptides or proteins. Patients with known or suspected allergies 
to the trial products or related products will be excluded from the trial. Mild or moderate allergic 
reactions may include symptoms of rash, fever, flu-like symptoms, nausea, headache, and 
myalgia. Acute generalized hypersensitivity reactions are usually very rare but may include 
symptoms of flushing, sweating, dizziness, change in blood pressure, and difficulties in 
breathing. The risk of acute hypersensitivity reactions is described to be less than 1/10,000 
for native glucagon. No severe acute hypersensitivity reactions have been observed in the 
2 clinical trials conducted with ZP4207.  
 
Potential Benefits 
 
Based on experiences from previous trials of the BP and the design of this trial, patients 
enrolled in the trial may benefit from a reduction in risk of hypoglycemia and hyperglycemia 
and a better mean glucose compared to their usual diabetes care during their short trial 
participation.  
 
The data derived from this trial will allow evaluation of safety and tolerability of ZP4207 in the 
iLet and the iPhone-based BP, and the robustness and effectiveness of the new BP control 
system. The data obtained will be used to further improve the iLet and will allow the expansion 
to larger outpatient trials using the iLet or the iPhone-based BP with ZP4207.  
 
This trial is a necessary step in preparing the BP with ZP4207 to become available to people 
with T1DM. Wide availability of the BP with ZP4207 could improve the medical care of adults 
and children with T1DM. 
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2 
TRIAL OBJECTIVES  
2.1 
Primary Objective  
The primary objective is to conduct a trial testing the safety and tolerability of the BP using 
either the iLet or the iPhone platform when used with ZP4207 in 20 adult (≥18 years of age) 
patients with T1DM. 
 
2.2 
Secondary Objectives  
The secondary objectives are to measure glycemic regulation, including hypoglycemia 
exposure (percent of time spent with CGM glucose <60 mg/dL), evaluate BP device reliability, 
and to document the satisfaction of patients with the BP with the goal of optimizing the 
functionality and user interface of the BP. 
3 
TRIAL DESCRIPTION  
3.1 
Summary of Trial Design  
This trial is a single-center, open-label, 2-part, randomized cross-over trial. The trial will enroll 
adult patients with T1DM and will assess the safety and efficacy of the BP using either the iLet 
or the iPhone platform using the glucagon analog ZP4207 versus Lilly glucagon. In Part 1, up 
to 10 patients will participate in two 1-day treatment arms in random order (iPhone-based BP 
using ZP4207 and iPhone-based BP using Lilly glucagon) according to a pre-generated 
randomization scheme. In Part 2, up to 10 new patients will participate in two 1-day treatment 
arms in random order (iLet using ZP4207 and iLet using Lilly glucagon) according to a 
pre-generated randomization scheme. Patients can only participate in 1 part of the trial. An 
interim database lock may occur upon completion of Part 1 of the trial to analyze the 
iPhone-based BP data. The iLet and the iPhone-based BP will also administer insulin (insulin 
lispro, Lilly Humalog) using the same BG control algorithm for all 4 treatment arms. The trial 
will be conducted at a single center, the MGH Diabetes Center in Boston, MA. 
 
The overall trial design schematic is displayed in Figure 2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 2. 
Trial Design Schematic 
Part 1: 
Part 2: 
Patients can only participate in 1 part of the trial. 
ADA = anti-drug antibodies; BP = bionic pancreas. 
3.2 
Indication 
ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid formulation which 
is being studied to improve glycemic control in adults (and children) with T1DM as part of a 
bihormonal BP. 
3.3 
Number of Patients 
Up to 40 adult patients with T1DM can be enrolled. The upper bound is based on the 
expectation that some patients will be excluded after the Screening Visit and the possibility 
that some patients may have to be discontinued before completion (due to, for instance, 
inter-current illness or patient withdrawal). It is expected that up to 10 patients will complete 
each part of the trial protocol. 
4 
SELECTION AND WITHDRAWAL OF PATIENTS 
The trial will enroll patients who already manage their T1DM using continuous SC insulin 
infusion pump therapy. This requirement is imposed because multiple daily injection therapy 
involves the use of medium-acting or long-acting basal insulin that would require an extended 
washout period. 
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4.1 
Inclusion Criteria  
1. Male and female patients with T1DM for at least 1 year, as defined by the American 
Diabetes Association 
2. Age ≥18 years  
3. Diabetes managed using an insulin pump for ≥6 months 
4. Prescription medication regimen stable for >1 month (except for medications that will 
not affect the safety of the trial and are not expected to affect any outcome of the trial, 
in the judgment of the Investigator) 
5. Informed consent obtained before any trial-related activities (trial-related activities are 
any procedure that would not have been performed during normal management of the 
patient) 
6. Patients in good health according to age (medical history, physical examination, vital 
signs, 12-lead electrocardiograms [ECGs], laboratory assessments), as judged by the 
Investigator 
 
4.2 
Exclusion Criteria  
1. Unable to provide informed consent (e.g., impaired cognition or judgment) 
2. Unable to safely comply with trial procedures and reporting requirements 
(e.g., impairment of vision or dexterity that prevents safe operation of the BP, impaired 
memory, unable to speak and read English) 
3. Participation in another clinical trial of an investigational agent or device concurrently 
or within 1 month (or 5 half-lives) prior to the Screening Visit 
4. Previous exposure to ZP4207 
5. Females of childbearing potential who are pregnant (positive urine human chorionic 
gonadotropin [HCG]), breast feeding, plan to become pregnant in the immediate future, 
or sexually active without using highly effective contraception methods (highly effective 
methods are considered those with a failure rate less than 1% undesired pregnancies 
per year including surgical sterilization, hormonal intrauterine devices [coil], oral 
hormonal contraceptives, sexual abstinence, or a surgically sterilized partner) or 
postmenopausal 
women 
amenorrheic 
for 
less 
than 
1 year 
with 
serum 
follicle-stimulating hormone (FSH) level ≤40 IU/L and not using highly effective 
contraceptive methods during the trial and until 1 month after last dosing in the trial 
6. Male who is sexually active and not surgically sterilized who or whose partner(s) is not 
using highly effective contraceptive methods (highly effective contraceptive measures 
include surgical sterilization, hormonal intrauterine devices [coil], oral hormonal 
contraceptives, each in combination with spermicide-coated condoms), or who is not 
willing to refrain from sexual intercourse from the first dosing until 1 month after last 
dosing in the trial 
7. Current alcohol abuse (intake averaging >3 drinks daily in last 30 days) or use within 
the last 6 months of controlled substances without a prescription (other than marijuana)  
8. New onset clinically significant illness within 4 weeks prior to screening, as judged by 
the Investigator 
9. Unwilling or unable to refrain on the treatment visits from: 
a. Acetaminophen in any form 
b. Use of drugs that may dull the sensorium, reduce sensitivity to symptoms of 
hypoglycemia, or hinder decision making during the period of participation in 
the trial (use of beta blockers will be allowed as long as the dose is stable and 
the patient does not meet the criteria for hypoglycemia unawareness while 
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taking that stable dose, but use of benzodiazepines or narcotics, even if by 
prescription, may be excluded according to the judgment of the Investigator) 
10. History of liver disease that is expected to interfere with the anti-hypoglycemia action
of glucagon (e.g., liver failure or cirrhosis). Other liver disease (i.e., active hepatitis,
steatosis, active biliary disease, any tumor of the liver, hemochromatosis, glycogen
storage disease) may exclude the patient if it causes significant compromise to liver
function or may do so in an unpredictable fashion.
11. Aspartate 
aminotransferase >2 
× 
upper limit of 
normal (ULN), alanine
aminotransferase >2 × ULN, or bilirubin >1.5 × ULN on screening laboratories
12. Renal failure on dialysis or estimated glomerular filtration rate <30 mL/min/1.73 m2 on
screening laboratories
13. Hemoglobin <12 gm/dL for men and <11 gm/dL for women
14. Personal history of cystic fibrosis, pancreatitis, pancreatic tumor, or any other
pancreatic disease besides T1DM
15. Any known history of coronary artery disease including, but not limited to, history of
myocardial infarction, stress test showing ischemia, history of angina, or history of
intervention such as coronary artery bypass grafting, percutaneous coronary
intervention, or enzymatic lysis of a presumed coronary occlusion)
16. Congestive heart failure with New York Heart Association Functional Classification III
or IV
17. History of transient ischemic attack or stroke in the last 12 months
18. Seizure disorder, history of any non-hypoglycemic seizure within the last 2 years, or
ongoing treatment with anticonvulsants
19. History of hypoglycemic seizures (grand-mal) or coma in the last 12 months
20. History of hypoglycemic unawareness in the last 12 months
21. History of pheochromocytoma: fractionated metanephrines will be tested in patients
with history increasing the risk for a catecholamine secreting tumor:
a.
Episodic or treatment refractory (requiring 4 or more medications to achieve
normotension) hypertension
b.
Paroxysms of tachycardia, pallor, or headache
c.
Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or
von Hippel-Lindau disease
22. History of adrenal disease or tumor
23. Hypertension with systolic blood pressure ≥160 mm Hg or diastolic blood pressure
≥100 mm Hg despite treatment
24. Untreated or inadequately treated mental illness (indicators would include symptoms
such as psychosis, hallucinations, mania, and any psychiatric hospitalization in the last
year), or treatment with anti-psychotic medications that are known to affect glucose
regulation
25. Electrically powered implants (e.g., cochlear implants, neurostimulators) that might be
susceptible to radio frequency interference
26. History of adverse reaction to glucagon (including allergy) besides nausea and
vomiting
27. History of severe hypersensitivity to milk proteins or lactose
28. Established history of allergy or severe reaction to adhesive or tape that must be used
in the trial
29. Use of oral anti-diabetic medications (e.g., thiazolidinediones, biguanides,
sulfonylureas, glitinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose
co-transporter-2 [SGLT-2] inhibitors)
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30. Inadequate venous access as determined by trial nurse or physician at time of 
screening 
31. Any factors that, in the opinion of the Investigator, would interfere with trial endpoints 
or the safe completion of the trial  
 
4.3 
Target Population  
Patients who meet all of the inclusion and none of the exclusion criteria will be considered as 
candidates for this trial. Individuals who have previously inquired about participation in 
BU/MGH trials and have asked to have their contact information kept on file will be contacted. 
In addition, advertisements for the trial may be posted at the MGH Diabetes Center and other 
places, and may be distributed in the weekly broadcast e-mail of research studies seeking 
volunteers. A letter may be sent to adult endocrinologists in the Boston metropolitan as well 
as selected nearby endocrinologists informing them of the trial and asking them to refer any 
eligible patients who might be interested. Information will be posted about the trial along with 
contact 
information 
on 
the 
BU/MGH 
website 
www.bionicpancreas.org 
and 
on 
www.clinicaltrials.gov. 
  
4.4 
Withdrawal Criteria  
The participation of individual patients will be discontinued if they experience: 
• 
Seizure or unconsciousness associated with hypoglycemia and associated with 
participation in the trial  
• 
Persistent nausea and vomiting thought to be related to glucagon dosing associated 
with participation in the trial 
• 
Hospitalization associated with participation in the trial 
• 
Pregnancy 
• 
Diabetic ketoacidosis 
 
If more than 1 patient must be withdrawn from the trial for these reasons, the trial will stop and 
a vote of the Data and Safety Monitoring Board (DSMB) will be required to restart it. All AEs 
that are serious and unexpected but related will be reported to the DSMB within 5 working 
days. 
Note that patients may discontinue participation at any time. Patients may be removed from 
the trial for other reasons, for instance, failure to comply with trial procedures or intercurrent 
illness that is unrelated to the BP but that precludes safe participation. Discontinuation of 
participation for these reasons will not contribute to a decision to discontinue the trial.  
5 
ASSIGNMENT TO TREATMENT GROUPS 
This trial is an open-label, 2-part, randomized cross-over trial. Patients who have completed 
the Screening Visit and meet all of the inclusion and none of exclusion criteria will be enrolled 
into the trial. In Part 1, up to 10 patients will participate in two 1-day treatment arms in random 
order (iPhone-based BP using ZP4207 and iPhone-based BP using Lilly glucagon) according 
to a pre-generated randomization scheme. In Part 2, up to 10 new patients will participate in 
two 1-day treatment arms in random order (iLet using ZP4207 and iLet using Lilly glucagon) 
according to a pre-generated randomization scheme. Up to 2 patients may participate in the 
trial per day. The order of the treatment visits will be randomized in blocks of 2 patients. 
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6 
TRIAL TREATMENT 
6.1 
Investigational Medicinal Products 
Insulin: The trial involves SC administration of insulin lispro (Humalog, Lilly), which is 
commercially available by prescription and is indicated for patients with T1DM, but not for use 
in a BP. 
 
Glucagon: The trial also involves SC administration of Lilly glucagon in 1 iLet arm and 
1 iPhone-based BP arm. Lilly glucagon is commercially available by prescription and is 
indicated for patients with T1DM in severe hypoglycemia, but not for use in a BP. 
  
ZP4207: The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, 
in the other iLet arm and the other iPhone-based BP arm. ZP4207 will be made available by 
Zealand Pharma A/S, Denmark as liquid formulation in prefilled syringes of 0.6 mL. 
 
6.2 
Storage and Drug Accountability of IMPs 
All IMPs will be stored and handled in accordance with the Sponsor’s instructions and/or the 
product labeling at the Investigator’s site, e.g., refrigerated (+2ºC to +8ºC) and should not be 
exposed to excessive heat, direct sunlight and never be frozen. 
 
All used, partly used, and unused vials or prefilled syringes must be kept by the Investigator 
and stored between +2ºC and +8ºC (unused) or at room temperature (partly used and used). 
Used and unused pre-filled syringes must be stored separately.  
 
The Investigator must ensure the availability of proper storage conditions and record and 
evaluate the temperature. Temperature of the refrigerator used for drug storage is monitored 
continuously, an alarm system is established. The Investigator must inform the monitor 
immediately if any IMP has been stored outside specified conditions (e.g., outside temperature 
storage). Investigational Medicinal Product that has been stored improperly must not be 
dispensed to any patient before it has been re-evaluated and approved for further use. The 
Investigator must take appropriate action to ensure correct storage. 
  
For the IMP, the Investigator must keep an accurate record of all IMPs received and the 
products used for each patient in a Drug Accountability Record. Storage locations, batch 
numbers, and expiry dates are also documented in this form. 
 
The drug accountability must be performed in a timely manner by the monitor.  
 
6.3 
Dispensing and Return of IMPs 
No IMPs may be dispensed to any person not enrolled in the trial. 
 
Upon completion of the trial, the Sponsor will be responsible for destruction or storage of IMPs 
(used, partially used, or unused). These duties can be delegated to a contract research 
organization (CRO) and must be documented in the trial files. 
 
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6.4 
Doses 
The iLet and the iPhone-based BP can administer isolated insulin-glucagon doses once every 
5 minutes. A single automated bolus of insulin will not exceed 3 units per 5-minute dose (30 µl 
of U-100 insulin) in both systems, and a single meal-priming dose, in response to a meal 
announcement made by the user, will not exceed 12 units (120 µl of U-100 insulin). A single 
bolus of glucagon will not exceed 80 µg (80 µl of 1 mg/mL Lilly glucagon or 1 mg/mL ZP4207). 
In prior studies, typical doses of glucagon were in the range of 2.5-40 µg per dose. The iLet 
and the iPhone-based BP are capable of administering as little as ~0.5 µl (0.05 units of U-100 
insulin or 0.5 µg of 1 mg/mL ZP4207). 
It is expected that the mean total daily doses of glucagon/ZP4207 will be <1.0 mg daily as in 
previous studies. The mean daily glucagon dose in a previous 11-day outpatient trial was 
0.5 mg/day (range 0.2-0.9 mg/day). Currently, single doses of up to 2 mg ZP4207 have been 
administered in clinical trials. The recommended dose of marketed glucagon for adult patients 
suffering from severe hypoglycemia is 1 mg as a single injection. Mean glucagon levels in 
previous inpatient studies have been above the normal fasting range for glucagon only 1% of 
the time. Therefore, the glucagon exposure of patients is expected to be modest. 
6.5 
iPhone-based Bionic Pancreas 
Infusion Set: Patients will wear 2 FDA-approved commercially available infusion sets, 1 for 
insulin infusion and 1 for glucagon infusion. Infusion sets that are compatible with the Tandem 
t:slim infusion pump (luer lock connection) will be provided. 
Continuous Glucose Monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to 
the controller. The sensor is powered by the battery within the transmitter that clips to the 
sensor and the whole assembly is held to the skin with an adhesive patch and communicates 
wirelessly with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM 
signal), it will be replaced promptly.  
Bionic Pancreas Control Unit: The control unit consists of a stock iPhone 4S and a Dexcom 
G4 Platinum receiver connected with a custom hardware interface and placed back-to-back 
in a custom enclosure. The G4 receiver converts the raw wireless signal from the transmitter 
into an estimated BG signal that is sent via a hardwired connection to the iPhone.  
The iPhone runs iOS 6 in “Guided Access” mode, where the only app accessible to the patient 
is the Beta Bionics app, which runs the control algorithm. The home screen, where typical user 
options reside, is password protected. Access to other functions on the iPhone (primarily the 
Settings options) is separately password protected and only accessible to the study staff. This 
prevents accidental activation of other apps that could interfere with the function of the BP. 
The control algorithm app has a graphical user interface (GUI) that displays the current CGM 
glucose, a graphical history of the CGM glucose, and doses of insulin and glucagon delivered 
by the control algorithm. The GUI can also be used to input meal announcements, designating 
the size of the meal as larger than typical, typical in size, smaller than typical, or just a bite, 
and the type of meal as breakfast, lunch, or dinner. This will trigger a partial meal-priming 
bolus the size of which will adapt during the course of the trial to meet a target of 75% of the 
insulin needs for that size and type of meal.  
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The target glucose level will be programmed to 100 mg/dL by the study engineers prior to the 
start of each experiment. This will be locked for each arm of the study; the patient will be 
unable to accidentally change or tamper with this setting.  
The GUI can be used to manage meal boluses and correction boluses during periods when 
the CGM is offline, such as the period after a sensor is replaced and before the new sensor 
has been calibrated. During these times the control algorithm will determine and direct the 
administration of insulin basal rates based on the patient's weight. The controller will also 
administer insulin and/or glucagon as appropriate in response to any entered BG values, just 
as if they were CGM values. 
The GUI also displays visual alarms associated with an audio signal if communication is 
dropped between the CGM transmitter and the BP control unit or between the control unit and 
the 2 insulin pumps. 
The iPhone communicates wirelessly via the Bluetooth Low Energy (BTLE) protocol with 
2 Tandem t:slim insulin pumps to deliver insulin and glucagon. 
Tandem t:slim Pumps: These pumps are FDA-approved insulin pumps with reservoirs 
capable of holding 300 units (3 mL) of insulin or 3 mL of glucagon or ZP4207 solution. The 
pumps have a mechanical dosing resolution of 1/120 (0.00833) unit and can deliver liquids at 
a maximal rate of ~33 µl per minute (2 mL per hour). They are slave to the BP control unit and 
are controlled wirelessly via the BTLE protocol by the iPhone 4S. 
6.6 
iLet Bionic Pancreas  
Infusion Set: A novel, dual cannula infusion set has been designed specifically for use with 
the iLet. Patients will wear dual channel tubing that will be attached to 2 infusion sets with 
1 steel cannula each, 1 for insulin infusion and the other for glucagon infusion. The tubing and 
infusion sets will have undergone sterilization prior to being delivered in a sealed pouch. The 
steel cannulae will be inserted in the abdominal SC tissue. 
Continuous Glucose Monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to 
the controller. The sensor is powered by the battery within the transmitter that clips to the 
sensor and the whole assembly is held to the skin with an adhesive patch and communicates 
wirelessly with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM 
signal), it will be replaced promptly.  
Bionic Pancreas Control Unit: The iLet is being built according to Class III medical device 
standards, adheres to a comprehensive and robust quality system, and is fully compliant with 
International Organization for Standardization (ISO) 13485 standards and document control 
practices. The iLet is a fully-integrated dual-hormone BP system that integrates the CGM 
technology (currently the Dexcom G4 Share system) as well as 2 independent motor-drivetrain 
pumping assemblies, which independently actuate the delivery of insulin and glucagon from 
pre-filled cartridges that are separately loaded into the iLet housing. Each drivetrain assembly 
utilizes a lead screw, which is driven by a precision micromotor, a gear case assembly, and a 
motor controller unit, in a manner similar to what is commonly found in most insulin infusion 
pumps on the market today. The iLet has dosing accuracy that is comparable to 
FDA-approved insulin pumps currently on the market. The iLet has a built-in BTLE radio that 
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also allows automatic communication with the paired CGM, as well as the Nova StatStrip® 
Xpress BG meter (Nova Biomedical). The iLet does not contain a cellular nor a WiFi radio, 
and does not accept input data from another mobile device (e.g., smartphone), other than the 
paired CGM and BG meter(s). 
 
The mathematical control algorithms (which are the same as those used in the iPhone-based 
BP), the CGM glucose engine (Dexcom), and the native user interface software, are all 
interconnected through controller framework software and reside as embedded systems on 
printed circuit boards contained within the device housing. The touchscreen-enabled, 
menu-driven user interface and onboard processor provide a comprehensive and standalone 
platform, which allows the iLet to operate independently of smartphones or other devices and 
without the need for internet support during routine operation. The graphical user interface of 
the iLet has the same user options and capabilities of the iPhone BP, including having its 
home screen password protected and its settings options only accessible to trial staff via a 
separate password. 
 
6.7 
Other Trial Devices  
YSI 2300 STAT Plus™ (Yellow Springs Instruments): The YSI 2300 STAT Plus is an 
FDA-approved glucose analyzer. Blood glucose measurements using the YSI 2300 STAT 
Plus will be obtained off of the intravenous (IV) line during both treatment visits.   
 
Nova Biomedical StatStrip Xpress Glucose Meter: The Nova StatStrip Xpress glucose 
meter is an FDA-approved glucose meter that is commercially available. Blood glucose 
measurements for CGM calibration will be obtained with the Nova StatStrip Xpress during both 
treatment visits if the YSI 2300 STAT Plus fails and via fingerstick with the Nova StatStrip 
Xpress during any periods when IV blood samples are not available for any reason or the IV 
fails. 
 
Exercise Bike: The trial will utilize a stationary exercise bike (ergometer) for the in-clinic 
exercise at the treatment visits. This bike will be stored at the Diabetes Research Center when 
not in use. 
 
6.8 
Concomitant Medications 
6.8.1 
Permitted Medications and/or Procedures  
Patients may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference with 
CGM sensing. All concomitant medications, including over-the-counter medications, should 
be recorded. 
 
Use of beta blockers will be allowed as long as the dose is stable and the patient does not 
meet the criteria for hypoglycemia unawareness while taking that stable dose. 
 
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911. 
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6.8.2 
Excluded Medications and/or Procedures  
During the trial, patients will not use any recreational drugs or drugs of abuse. The need to 
take prescription drugs that dull the sensorium, reduce sensitivity to symptoms of 
hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion from the 
trial or discontinuation of participation, a decision that will be made by the Investigator. 
 
Use of benzodiazepines or narcotics, even if by prescription, may be excluded according to 
the judgment of the Investigator. Use of oral anti-diabetic medications (e.g., thiazolidinediones, 
biguanides, sulfonylureas, glitinides, DPP-4 inhibitors, SGLT-2 inhibitors) will also be 
excluded. 
7 
TRIAL PROCEDURES  
7.1 
Informed Consent  
After potential patients have had time to review the consent document, and prior to any 
trial-related activities, they will meet with a trial MD or designee who will explain the trial, 
answer any questions, and administer informed consent. In the event that a volunteer is a 
patient of 1 of the trial MDs, another staff MD or designee will answer questions and administer 
consent. The patients will be fully informed of their responsibilities and their rights while 
participating in the trial as well as of the possible risks and potential benefits of participation in 
the trial. They will have the opportunity to discuss all questions and ample time to consider 
participation. 
 
Trial-related activities are any procedures that would not have been performed during normal 
management of the patient. Patients who wish to participate in the trial will be asked to 
personally date and sign an informed consent form (ICF). Likewise, the Investigator must also 
personally date and sign the ICF. All patients will be provided with a copy of their own signed 
and dated ICF. 
 
Trial staff will answer any questions that the patients may have during their participation. They 
will share any new information in a timely manner that may be relevant to the patient's 
willingness to continue participating in the trial. The patients may choose to discontinue their 
participation at any time.  
 
7.2 
Screening Visit (Visit 1) 
All patients will have a Screening Visit to confirm eligibility. The patient will be interviewed and 
the electronic Case Report Form (eCRF) will be completed by trial staff to establish whether 
the patient is eligible. 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits per the 
medical judgment of the Investigator. 
 
Once all of the results have been returned, a trial MD will review the eCRF to determine patient 
eligibility. If a patient is not eligible to continue in the trial, the results of abnormal tests will be 
reported to the patient and to a health care provider of their choosing. 
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7.2.1 
Data Collected at Screening 
• 
Age, sex, race, and ethnicity 
• 
Date of last menstrual period in female patients  
• 
Medical, surgical, and social history, allergies, and review of systems relevant to 
inclusion and exclusion criteria, including: 
o Date of diabetes diagnosis 
o Duration of insulin pump use and type of insulin used in pump 
o Type/model of insulin pump 
o Insulin regimen (basal rate, sensitivity factor, and carbohydrate ratio) 
o Average total daily dose of insulin in the last 30 days as available (from pump 
history) 
o Usage of CGM, if any (type of CGM, days per month worn, usage of data, 
whether insulin is dosed based on CGM alone, alarm settings) 
• 
Concomitant illness (any illness present at screening) 
• 
Concomitant medications (prescription and non-prescription) and date of last change 
in medication regimen  
• 
Height, weight, physical examination, and vital signs including body temperature and 
blood pressure 
• 
12-lead ECG 
• 
Hemoglobin A1c 
• 
Chemistry and hematology samples (see Appendix B) 
• 
Urine HCG pregnancy test for women of childbearing potential 
• 
FSH level for postmenopausal women amenorrheic for less than 1 year 
• 
Fractionated plasma metanephrines (if indicated by history) 
 
7.3 
Training Visit (Visit 2) 
A Training Visit will take place before the first treatment visit. Patients will be trained in the 
insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. Trial staff 
will verify that the patients have understood the material and are competent to participate 
safely in the trial. Patients will be instructed concerning diabetes management (e.g., basal 
insulin rate adjustment by insulin pump) during fasting prior to and between the treatment 
visits per the medical judgment of the Investigator. Concomitant medications will also be 
reviewed. 
 
7.4 
Treatment Visits (Visit 3 and Visit 4) 
• 
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 
30 days after screening (Visit 1). 
• 
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum 
of 3 weeks between Visit 3 and Visit 4. 
• 
Up to 2 patients may participate per day.  
• 
In Part 1, each patient will participate in 2 treatment visits: 1 with the iPhone-based BP 
using ZP4207 and 1 with the iPhone-based BP using Lilly glucagon in a randomized 
order. 
• 
In Part 2, each patient will participate in 2 treatment visits: 1 with the iLet using ZP4207 
and 1 with the iLet using Lilly glucagon in a randomized order. 
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• 
The night before the treatment visit, patients will place a Dexcom G4 CGM sensor in 
the abdominal skin and calibrate the sensor when prompted using the provided Nova 
StatStrip Xpress meter. Patients will be instructed to call if they encounter any difficulty 
with their CGM.  
• 
Patients will be responsible for their own medications other than insulin during the trial. 
Any medical advice needed by the patients during their participation that is not directly 
related to BG control should be obtained from them in their usual manner. Patients 
may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference 
with CGM sensing. If patients experience urgent or emergent medical concerns 
outside the scope of diabetes care and their primary care physicians, they will be taken 
to the MGH walk-in clinic or emergency room, or if necessary call 911. 
• 
During the trial, patients will not use any recreational drugs or drugs of abuse. The 
need to take prescription drugs that dull the sensorium, reduce sensitivity to symptoms 
of hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion 
from the trial or discontinuation of participation, a decision that will be made by the 
Investigator.  
• 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits 
per the medical judgment of the Investigator. 
• 
Patients will not tamper with the BP, including changing any settings. 
• 
Patients may not remove the BP during the trial unless the BP failed or they are 
withdrawing from the trial. 
• 
The exact time of each procedure and assessment will be documented. 
7.4.1 
Visit Procedures  
• 
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the 
BP having fasted since 12:00 AM the night before (treatment with simple carbohydrate 
of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled 
within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the 
visit window. If BG is <50 mg/dL, treatment with simple carbohydrate is allowed. If the 
patient experiences persistent hypoglycemia, the visit will be rescheduled within the 
visit window. If the visit needs to be rescheduled due to hypoglycemia or 
hyperglycemia, trial staff will assist the patient with insulin or medication adjustments 
to address glycemic control. The patient will be instructed to contact trial staff later in 
the day if his or her BG remains uncontrolled. 
• 
Upon arrival to the visit, the patient’s weight and vital signs including body temperature 
and blood pressure will be documented. 
• 
Patient reports of symptoms, any other complaints, and AEs will be reviewed. 
• 
Concomitant medications will be recorded. 
• 
Chemistry and hematology samples will be collected at visit start (see Appendix B). 
• 
ADA samples will be collected before the start of dosing (Visit 3 only).  
• 
A 12-lead ECG will be performed. 
• 
A urine HCG pregnancy test will be performed in female patients of childbearing 
potential. If the test is positive, the patient will be informed of the result and the visit 
will be ended. 
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• 
Patients will complete a baseline survey about their attitudes and experience with their 
usual diabetes care. 
• 
An IV catheter will be placed for blood sampling. 
• 
Trial staff will assist the patient to calibrate their CGM, review the trial procedures again 
and assist with the setup of the BP system, including inserting and priming infusion 
sets. 
• 
The control algorithm will be initialized only with the patient’s weight. Diagnostics will 
be performed to ensure that the CGM device is appropriately calibrated and that all of 
the components of the BP systems are in working order. 
• 
The basal rate of the patient’s own insulin infusion pump will be changed to be 2-fold 
higher than weighted mean of the basal rate during the trial period. This is intended to 
increase the usage of glucagon during the treatment visit. 
• 
The patients will continue to wear their own infusion pump infusing at the temporary 
2-fold basal rate throughout the visit until the start of the structured exercise period, in 
addition to the BP. 
• 
The staff will start the BP as close as possible to a minute divisible by 5 minutes 
(i.e., on a 5-minute mark). The starting time will be considered Hour 0.  
• 
Additional calibrations will be performed at any of the BG checks throughout the day if 
the CGM value does not meet the ISO standard (<15 mg/dL difference for BG values 
<75 mg/dL; <20% absolute difference for BG values >75 mg/dL) at the time of the BG 
measurement AND it is a good time to calibrate (the CGM trend arrow is flat and there 
has been no carbohydrate intake in the last 30 minutes or glucagon boluses in the last 
15 minutes). 
• 
Blood samples will be taken from the IV at least hourly and processed for plasma 
ZP4207/glucagon. If BG is <150 mg/dL, more frequent samples for plasma 
ZP4207/glucagon may be drawn at the discretion of the Investigator. The actual time 
of sampling will be recorded in the eCRF. 
• 
Plasma glucose samples will be taken from the IV at least hourly in parallel with 
ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT Plus. 
If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for 
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes. 
If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then 
sampling will be every 10 minutes. The actual time of sampling will be recorded in the 
eCRF. 
• 
Patients will be asked to rate any nausea and/or infusion site pain on 10 cm visual 
analog scales (VAS) at the beginning of the visit once the infusion sites have been 
placed but no drug has yet been administered, then approximately at the top of every 
hour during the visit, and at the end of the visit. Trial staff will also evaluate their infusion 
sites to document any erythema or edema at the same times. If moderate or severe 
pain is reported or swelling or redness occurs at the infusion site, the infusion site will 
be replaced in a different location. If moderate or severe pain, swelling, or redness 
continues at the old site for more than 30 minutes after the infusion site is removed, or 
if moderate or severe pain, swelling, or redness occurs at the new site, all infusion 
sites will be removed and the patient will be discontinued from the study. Any such 
symptoms will be followed until resolution. 
• 
From the start of closed loop control until approximately Hour 3, the patients will 
continue to fast. 
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• 
Between approximately Hour 3 and Hour 4, patients will be provided with a lunch meal 
of their choice in the Diabetes Research Center from a menu of choices from nearby 
restaurants. They will be asked to choose a meal that is a “typical meal” for them. The 
content of their meal will not be restricted in any way, with the exception that the 
number of carbohydrates should be in the “typical” range for them at lunch, and that 
they must eat the same meal at the same time during both visits. 
• 
At approximately 15 minutes before the meal, patients will administer a bolus for the 
meal with their own insulin pump based on the carbohydrate count for the meal. 
• 
After lunch is completed, the patients will not be allowed any carbohydrate intake 
(non-caloric drinks will be permitted) until the trial is completed (except as necessary 
to treat hypoglycemia), to allow the BP to control the post-prandial BG without further 
interruption.  
• 
Between approximately Hour 6 and Hour 7, the patients will start a period of structured 
exercise. 
• 
At the start of the exercise period, patients will restore their normal basal insulin profile 
so that they will not have elevated insulin levels at the end of the study period when 
they are to transition back to their usual care.  
• 
Patients will exercise on a stationary bike with a heart rate from 120-140 beats per 
minute for a total of 4,000 heart beats (approximately 30 minutes). Patients will rate 
their exercise intensity using the Borg scale every 5 minutes, with the target intensity 
level between 12 and 14. Heart rate will be measured every 5 minutes. 
• 
BG measurements will be obtained off of the IV line every 10 minutes. If BG is 
<80 mg/dL, BG measurements will be obtained off of the IV line every 5 minutes.  
o 
Carbohydrates will be given for any BG <50 mg/dL according to the following 
protocol: Dextrose (g) = BSA (m2)/[1.7 m2 (women) or 1.9 m2 (men)] *15 g. 
o 
Repeat treatments will be given at 15-minute intervals as long as BG remains 
<50 mg/dL.  
• 
If there is an interruption in the Dexcom CGM output, trial staff will assist the patient in 
recovering CGM data streaming. If this requires replacement of the CGM sensor, BGs 
will be checked every 10 minutes (every 5 minutes if BG is <80 mg/dL) using blood 
from the IV until the CGM is able to be calibrated again. These BGs will be entered 
into the BP, which will treat them as CGM values and dose insulin and/or glucagon 
appropriately. 
• 
If there is a complete failure of the BP operation, patients will take over their own BG 
control using their personal insulin pump until the BP can be brought back online. If BP 
control cannot be promptly resumed (e.g., within 30 minutes), the patient may be asked 
to repeat that trial day once. 
• 
Patients may choose to withdraw from the trial at any time. If they withdraw from the 
trial, they should alert a provider immediately. 
• 
Just prior to the end of the study visit, vital signs including body temperature and blood 
pressure will be obtained and a 12-lead ECG will be performed.   
• 
After approximately Hour 8, but not earlier than at least 60 minutes after end of 
exercise, the BP will be stopped and the patient will continue with their personal insulin 
pump. 
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• 
If the patient experiences seizure or unconsciousness, persistent nausea or vomiting, 
diabetic ketoacidosis, persistent hyperglycemia with ketonemia, hemodynamic 
changes such as hypotension, or other medically significant findings, a longer 
observation period at the trial site may be necessary until the patient is considered 
stable for discharge. If the Investigator or trial staff determines that the patient requires 
further observation or treatment, the patient may be transferred to the emergency room 
for additional monitoring and/or medical care. At discharge, patients will be provided 
with any necessary instructions concerning personal insulin pump usage, food intake, 
and driving arrangements.    
• 
The maximum amount of blood loss per study visit will be approximately 230 mL. The 
total blood loss for the entire study will be up to 460 mL. 
• 
Patients will answer questionnaires (see Appendix C). 
• 
Chemistry and hematology samples will be collected at visit end (see Appendix B). 
• 
The BP and glucose meters will be collected and downloaded. 
• 
A trial MD will review the last several hours of insulin and glucagon dosing and assist 
the patient in resuming their usual diabetes care. A longer observation period at the 
trial site may be necessary. Patients will be instructed to call trial staff with any 
questions, issues, or concerns.  
7.4.2 
Data Collected During the Treatment Visits 
• 
CGM glucose every 5 minutes from the Dexcom G4 Platinum CGM  
• 
All BG measurements taken  
• 
Insulin total dose by the BP and the patient’s own insulin pump 
• 
Glucagon total dose  
• 
Timing and content of the meal eaten and carbohydrate amount 
• 
Timing of meal announcement and size of meal announced  
• 
Timing and glucose values at calibrations  
• 
Timing and amount of carbohydrates taken for hypoglycemia 
• 
Data from a questionnaire about attitudes and expectations regarding the BP before 
and after each treatment arm (see Appendix C) 
• 
Time patients were not under BP control for any reason 
• 
List of technical faults associated with the BP including cause and resolution 
• 
ZP4207/glucagon sampling will be collected at least hourly. If BG is <150 mg/dL, more 
frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the 
Investigator.  
• 
Plasma glucose sampling will be collected at least hourly in parallel with 
ZP4207/glucagon exposure sampling. If BG is <150 mg/dL, then sampling will be every 
30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is 
<80 mg/dL, then sampling will be every 10 minutes. 
• 
Nausea and infusion site pain on a VAS at visit start (after insertion and before any 
drug administration), hourly, and at visit end  
• 
Infusion site reaction according to the Draize scale at visit start (after insertion and 
before any drug administration), hourly, and at visit end  
• 
Patient reports of symptoms, any other complaints, and AEs 
• 
Vital signs including body temperature and blood pressure (at visit start and visit end) 
and weight 
• 
Concomitant medications 
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• 
Chemistry and hematology samples (see Appendix B) at visit start and visit end 
• 
ADA (Visit 3 only)  
• 
12-lead ECG at visit start and visit end 
• 
Urine HCG pregnancy test for women of childbearing potential 
7.4.3 
Response to Hypoglycemia  
• 
Patients are encouraged to check their BG for any symptoms of hypoglycemia.  
• 
Patients will be permitted to take 15 grams of carbohydrates for any BG value 
<60 mg/dL. Trial staff will ensure proper functioning of the BP, infusion set, and insulin 
pump, and will encourage the patient to wait for the BP to treat the low blood sugar for 
as long as they feel comfortable. 
• 
Patients will be required to take 15 grams of carbohydrates for any BG value 
<50 mg/dL. After treatment of hypoglycemia, a follow-up measurement will be taken 
15 minutes later. Repeated measurements will be taken every 15 minutes until the 
BG is >60 mg/dL. Treatment will be repeated if subsequent BG values are still 
<50 mg/dL. All carbohydrate treatments for hypoglycemia will be documented by trial 
staff (amount and time).  
• 
Trial staff will check the infusion site, BP, and insulin pump for normal operation any 
time hypoglycemia occurs. If there is any suspicion of infusion set malfunction, the site 
should be replaced. Trial staff will check the BP for any malfunction and correct any 
problems that are found. 
• 
If no correctable fault is found, but there is doubt regarding the correct function of the 
BP system, an entirely new backup BP system may be started. 
• 
If a patient experiences a seizure or unconsciousness associated with hypoglycemia, 
his or her participation in the trial will be discontinued.  
7.4.4 
Response to Hyperglycemia  
• 
Trial staff will check the infusion site, BP, and insulin pump for normal operation any 
time BG is >300 mg/dL. If there is any suspicion of infusion set malfunction, the site 
should be replaced. Trial staff will check the BP for any malfunction and correct any 
problems that are found. If the BG remains >300 mg/dL for 2 hours despite 
troubleshooting, blood ketones will be measured. If the blood ketone result is 
>1.5 mmol/L, the visit will be stopped and rescheduled. The patient will be provided 
with insulin and a syringe to give an injection based on their correction factor. 
• 
If a patient experiences diabetic ketoacidosis, his or her participation in the trial will be 
discontinued. 
• 
If no correctable fault is found, but there is doubt regarding the correct function of the 
BP system, the treatment visit may be stopped and the visit rescheduled. 
7.4.5 
Response to Nausea/Vomiting 
If significant nausea (e.g., that prevents the patient from eating normally) or any vomiting 
occurs, trial staff will notify the Investigator. Trial staff will assist the patient in troubleshooting, 
such as checking BG and the calibration of the CGM (excessive glucagon dosing may occur 
if the CGM is reading lower than the true BG). If a patient experiences persistent nausea and 
vomiting thought to be related to glucagon dosing, his or her participation in the trial will be 
discontinued. 
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7.4.6 
Response to Other Medical Needs  
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911.  
7.4.7 
Monitoring of Bionic Pancreas Performance 
Bionic pancreas inventors and developers 
, 
, and/or an 
engineer trained by them will be readily available by phone for consultation for the trial staff at 
all times during the course of the trial.  
7.4.8 
Supervision by Trial Staff  
A trial MD will be on call at all times during the course of the trial. An RN or MD will be with 
the trial patients in the Diabetes Research Center at all times. 
7.5 
Anti-drug Antibodies Assessment Visit (Visit 5) 
Patients will return for an ADA Assessment Visit 10 days ±3 days following the last day of 
dosing (Visit 4) for ADA sampling and a review of AEs and concomitant medications. 
7.6 
Follow-up Visit (Visit 6) 
Patients will return for a Follow-up Visit 25 days ±4 days following the last day of dosing 
(Visit 4), for chemistry, hematology, and ADA sampling, and a review of AEs and 
concomitant medications.  
8 
ENDPOINTS  
8.1 
Primary Endpoint 
The primary endpoint is the safety and tolerability of ZP4207 in the BP using either the iLet 
or the iPhone platform as assessed by: 
•
Number and type of AEs
•
Clinical laboratory measurements
•
Vital signs
•
12-lead ECG
•
Local tolerability and infusion site reactions as measured with the Draize scale
•
Immunogenicity as measured by ADA
•
Pain as measured on a 10 cm VAS
•
Nausea as measured on a 10 cm VAS
8.2 
Secondary Endpoints 
The secondary endpoints include measurements of BP function as well as glycemic and 
non-glycemic measurements. 
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8.2.1 
Bionic Pancreas Function  
This endpoint data will be generated from the BP data during each treatment visit: 
• 
Average percent insulin dose amounts calculated by the BP control algorithm that are 
successfully delivered by the pump 
• 
Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts successfully issued to the pump by the BP control 
algorithm that are successfully delivered by the pump (calculated doses are not issued 
unless the pump is accessible and its delivery channel is available) 
o Average percent insulin dose amounts successfully issued to the pump by the 
BP control algorithm that are successfully delivered by the pump 
o Average percent glucagon/ZP4207 dose amounts successfully issued to the 
pump by the BP control algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts calculated by the BP algorithm that are successfully 
issued to the pump by the BP (calculated doses are not issued unless the pump is 
accessible and its delivery channel is available) 
o Average percent insulin dose amounts calculated by the BP control algorithm 
that are successfully issued by the BP 
o Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully issued by the BP 
• 
Average percent of 5-minute steps during which the BP is functioning nominally in all 
respects based on real-time CGM data (new CGM glucose reading captured, dose 
calculated, and dose issued to pumps)  
• 
Average percent of 5-minute steps during which the BP is functioning nominally with 
or without a new CGM glucose reading captured (dose calculated and dose issued to 
pumps). If a CGM signal is not available, the dose calculated may be based on weight 
or historical basal rates. 
• 
CGM reliability index, calculated as percent of possible values actually recorded by 
CGM 
• 
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter 
download 
• 
List of technical faults associated with the BP including cause and resolution 
8.2.2 
Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit: 
• 
Fraction of time spent within each of the following glucose ranges: 
o <50 mg/dL 
o <60 mg/dL 
o <70 mg/dL 
o 70-120 mg/dL 
o 70-140 mg/dL 
o 70-180 mg/dL  
o >180 mg/dL 
o >250 mg/dL 
o >300 mg/dL 
• 
Number of severe hypoglycemic events (patients unable to self-treat, requiring the 
assistance of another person) 
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• 
Number of episodes of symptomatic hypoglycemia 
• 
Number of carbohydrate interventions for hypoglycemia 
• 
Total grams of carbohydrates taken for hypoglycemia 
• 
Mean CGM glucose 
8.2.3 
Non-glycemic  
• 
Glucagon/ZP4207 total delivery per kg of body mass 
• 
Insulin total delivery per kg of body mass 
• 
Number of unscheduled infusion set replacements 
• 
Number of unscheduled CGM sensor changes 
9 
LABORATORY ASSESSMENTS 
Descriptions of sample handling and sample processing, storage, and shipment at the site will 
be included in the laboratory manual. 
 
The responsible laboratories are listed in the address list. 
 
9.1 
Safety Laboratory Assessments 
Chemistry and hematology samples will be collected at specified time points. See Appendix A 
for the schedule of procedures and Appendix B for a list of clinical laboratory analytes. 
 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) 
At Visit 3 and Visit 4, plasma glucose samples will be taken from the IV at least hourly in 
parallel with ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT 
Plus. If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for 
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is 
<100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will 
be every 10 minutes. The actual time of sampling will be recorded in the eCRF. 
 
9.3 
Exposure Assessments (ZP4207 and Glucagon) 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the 
discretion of the Investigator. The actual time of sampling will be recorded in the eCRF. 
 
Bioanalytical Reports will be prepared. 
 
9.4 
Anti-drug Antibodies Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken at Visit 3, the ADA Assessment Visit (Visit 5), and the Follow-up Visit 
(Visit 6). Any patient that tests positive for ADA will be monitored until the ADA levels return 
to baseline. 
 
Bioanalytical Reports will be prepared. 
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10 
SAFETY REPORTING 
10.1 
Adverse Events  
An AE is any untoward medical occurrence in a trial patient administered an IMP and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be 
any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not considered related to 
the IMP. Patients should be instructed to report any AE they experience to the Investigator. 
Note: This includes events from the first trial-related activity from Visit 3.  
 
AEs for ZP4207 include: 
• 
A clinically significant worsening of a concomitant illness 
• 
A clinical laboratory abnormality which is clinically significant, i.e., any abnormality that 
suggests a disease and/or organ toxicity and is of a severity that requires active 
management. Active management includes active treatment or further investigations, 
for example, change of medicine dose or more frequent follow-up due to the 
abnormality. 
• 
Hypoglycemic episodes  
• 
Injection site reactions 
 
The following should not be recorded as AEs, if recorded prior to randomization (on the 
Screening Form or the eCRF): 
• 
Pre-planned procedure, unless the condition for which the procedure was planned has 
worsened from the first trial-related activity from Visit 3. 
• 
Pre-existing conditions found as a result of screening procedures (pre-existing 
conditions should be reported as medical history or concomitant illness). 
 
For known (listed) AEs for Glucagon and Humalog, please refer to SPC for Glucagon and 
Humalog. 
10.1.1 
Follow-up of Adverse Events 
All AEs that are ongoing at the end of the patient’s participation in the trial will be followed-up 
until the event is resolved or reaches a satisfactory outcome as deemed by the Investigator. 
Follow-up actions for all serious adverse events (SAEs) will be performed according to 
appropriate clinical care practices and may depend on the nature of the event. These will be 
determined after internal review and/or Sponsor review. The follow-up information should only 
include new (updated and/or additional) information that reflects the situation at the time of the 
Investigator’s signature. 
 
Follow-up information on (S)AEs will be updated using the (S)AE Form. If a non-serious event 
becomes serious during the follow-up, the AE Form and SAE Form must be used and reporting 
timelines follow those of an SAE. 
 
The Investigator must forward follow-up information on SAEs, and if previously non-serious 
AEs become SAEs, to the Sponsor. 
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10.1.2 
Precautions 
Normal precautions taken for a human trial will be taken during this trial. Qualified and 
well-trained physicians and medical staff will instruct the patients. During a patient’s 
participation in the trial, the Investigator should ensure that adequate medical care is provided 
to the patient for any AEs, including clinically significant laboratory values related to the trial. 
The Investigator should inform the patient when medical care is needed for intercurrent 
illnesses of which the Investigator becomes aware.  
For further information on safety precautions for ZP4207, Lilly glucagon, and Lilly Humalog, 
please refer to the current version of the Investigator’s Brochure (IB) for ZP4207 (Zealand 
Pharma A/S, 2015, or any updates hereof), and the SPC for Glucagon (Eli Lilly, 2012) and 
Humalog (Eli Lilly, 2015), respectively. 
10.1.3 
Assessment of Adverse Events by the Investigator 
Intensity of an Adverse Event 
The maximum intensity (severity) of all AEs must be assessed by the Investigator and 
documented. Severity should be graded when the AE outcome is known: 
•
Mild: A type of AE that is usually transient and may require only minimal treatment or
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
•
Moderate: A type of AE that is usually alleviated with additional specific therapeutic
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the patient. 
•
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects
clinical status, or may require intensive therapeutic intervention. 
A “severe” reaction does not necessarily deem the AE as “serious,” and an SAE may not be 
“severe” in nature. 
Causality Relationship to IMP 
Insulin (insulin lispro, Lilly Humalog), glucagon (glucagon for injection, Eli Lilly), and ZP4207 
are all regarded as IMP. 
The causality of each AE should be assessed by the Investigator according to the following 
classification: 
•
Related: Good reason and sufficient documentation to assume a causal relationship.
•
Not related: No relationship to trial product can be established.
Outcome of an Adverse Event 
The outcome of all AEs must be assessed by the Investigator and documented by his/her 
staff. The following definitions should be used: 
•
Recovered/resolved: The patient has fully recovered, or by medical or surgical
treatment the condition has returned to the level observed at the first trial-related 
activity from Visit 3. 
•
Recovering/resolving: The condition is improving and the patient is expected to recover
from the event. This term is only applicable if the patient has completed the trial.
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• 
Recovered/resolved with sequelae: The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment, or procedure. If a sequela meets 
an SAE criterion, the AE must be reported as an SAE. 
• 
Not recovered/not resolved: The condition of the patient has not improved and the 
symptoms are unchanged, or the outcome is not known. 
• 
Fatal: This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he/she died should 
be assessed as “recovered/resolved,” “recovering/resolving,” “recovered/resolved with 
sequelae,” or “not recovered/not resolved.” An AE with a fatal outcome must be 
reported as an SAE. 
• 
Unknown: This term is only applicable if the patient is lost to follow-up. 
 
10.2 
Serious Adverse Events   
An SAE is any untoward medical occurrence that at any dose:  
• 
Results in death  
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Medically important 
 
Medical judgement must be exercised in deciding whether an AE is believed to be “medically 
important.” Medically important events may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require intervention to prevent 
1 of the other outcomes listed in the definition above. 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is an AE fulfilling 1 of the criteria of seriousness and being assessed as related to 
an IMP, the nature or severity of which is not consistent with the applicable reference 
document (e.g., ZP4207 IB or package leaflet/SPC for an approved product). 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety, any life-threatening problem or 
death caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the application; or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. 
 
10.3 
Adverse Event Reporting – Procedures for Investigators  
The Principal Investigator and co-investigators will review any AEs and report any SAEs to 
the Sponsor as soon as possible and within 24 hours of obtaining knowledge of the event. The 
Principal Investigator and co-investigators will promptly report AEs to the Partner’s Institutional 
Review Board (IRB) and to the BU IRB (unless oversight is ceded by the BU IRB to the 
Partners IRB), in accordance with local requirements.  
 
Ed Damiano is the Sponsor of the Investigational Device Exception for the BP and Zealand 
Pharma A/S is the Sponsor of the IND for ZP4207.  
 
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 The following must be collected:  
• 
Initial information of the pregnancy  
• 
Information on the outcome of the pregnancy, including the health status of the 
newborn infant(s) at the age of 1 month 
• 
All AEs in connection with the pregnancy and pregnancy outcome must be reported 
on the pregnancy forms. It must be clear in the description if the event occurs in the 
patient/patient’s partner, the fetus, or the newborn infant. 
• 
All SAEs in connection with the pregnancy and pregnancy outcome must be reported 
on the pregnancy forms following the same timelines as required for other SAEs. It 
must be clear in the description if the event occurs in the patient/patient’s partner, the 
fetus, or the newborn infant.  
 
The SAEs that must be reported include abnormal outcome – such as congenital anomalies, 
fetal death, and termination of pregnancy (spontaneous or elective abortion), including any 
anomalies of the fetus observed at gross examination or during autopsy – as well as other 
pregnancy complications (ectopic pregnancy) fulfilling the criteria of an SAE. 
 
10.5 
Hypoglycemia 
Hypoglycemia will be regarded as an AE and will be recorded and documented on an AE 
Form. For the purposes of AE reporting, the following definitions of hypoglycemia will be used: 
• 
Symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia 
are accompanied by a BG concentration ≤70 mg/dL 
• 
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of 
hypoglycemia but with a BG concentration ≤50 mg/dL 
• 
Severe hypoglycemia: an event requiring assistance of another person to actively 
administer carbohydrates, glucagon, or take other corrective actions 
 
10.6 
Safety Monitoring 
10.6.1 
Data and Safety Monitoring Board 
An external DSMB will oversee the conduct of the trial, as set forth in the DSMB Charter. 
Additionally, the DSMB will be informed in the event of any serious and unexpected AEs. The 
DSMB will be informed if there are any changes to the trial protocol that could significantly 
impact the safety or scientific validity of the trial. A final DSMB meeting will convene after the 
completion of the trial. 
 
The participation of individual patients will be discontinued if they experience: 
• 
Seizure or unconsciousness associated with hypoglycemia and associated with 
participation in the trial  
• 
Persistent nausea and vomiting thought to be related to glucagon dosing associated 
with participation in the trial 
• 
Hospitalization associated with participation in the trial 
• 
Pregnancy 
• 
Diabetic ketoacidosis 
 
If more than 1 patient must be withdrawn from the trial for these reasons, the trial will stop and 
a vote of the DSMB will be required to restart it. All AEs that are serious and unexpected but 
related will be reported to the DSMB within 5 working days. 
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Note that patients may discontinue participation at any time. Patients may be removed from 
the trial for other reasons, for instance, failure to comply with trial procedures or intercurrent 
illness that is unrelated to the BP but that precludes safe participation. Discontinuation of 
participation for these reasons will not contribute to a decision to discontinue the trial.  
10.6.2 
Zealand Pharma Safety Committee 
The internal Zealand Pharma Safety Committee is constituted to perform ongoing safety 
surveillance of clinical trials within ZP4207, including this trial. 
 
If safety signals are observed either based on reported SAEs, periodic review of laboratory 
parameters, planned review of all AEs reported between the safety committee meetings, or 
on notification of significant findings, the Safety Committee will take appropriate measures to 
safeguard the patients. 
11 
STATISTICS 
For all analysis, the 2 treatment arms from Part 1 (iPhone-based BP) will be compared, and 
the 2 treatment arms from Part 2 (iLet) will be compared. The analysis of Part 1 will be 
completely separate from the analysis of Part 2. 
 
11.1 
Analysis Populations  
The following analysis sets are defined in accordance with the ICH-E9 guidance: 
 
The Full Analysis Set is based on the intention-to-treat principle and includes all randomized 
patients. In exceptional cases, patients from the Full Analysis Set may be excluded (will be 
decided in the database review [DBR] meeting). In such cases, the exclusion will be justified 
and documented. Patients will contribute to the evaluation “as randomized.” 
 
The Per-Protocol Set includes all patients of the Full Analysis Set who completed the trial 
without any major protocol violations. Patients in the Per-Protocol Set will contribute to the 
evaluation “as treated.” This analysis will only be used if it is different than the Full Analysis 
Set. 
 
The Safety Analysis Set includes all patients receiving at least 1 dose of the IMP. Patients in 
the Safety Analysis Set will contribute to the evaluation “as treated.”  
 
Analyses of efficacy endpoints will be based on the Full Analysis Set (and the Per-Protocol 
Set if necessary). This decision will be made in the DBR meeting. The analysis of the safety 
endpoints will be based on the Safety Analysis Set.  
 
Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. At this time, it will be 
determined if patients and/or data should be excluded from the analysis. Furthermore, outliers 
will be identified by data review according to ICH-E9. 
 
Obviously erroneous data points may be excluded from the analyses or re-analyzed 
(e.g., serum concentrations). The decision to re-analyze or exclude data points from the 
statistical analysis is the joint responsibility of the Sponsor, the Principal Investigator, and the 
Trial Statistician. 
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The patients or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to database release. The documentation 
will be stored together with the remaining trial documentation. The patients and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report. 
 
11.2 
Statistical Methods  
Medpace will be responsible for the statistical analysis. The statistical planning and conduct 
of analyses of the data from this trial will follow the principles defined in relevant ICH guidelines 
and Medpace’s biostatistical standard operating procedures (SOPs). A general description of 
the statistical methods to be used is given in this section, specific details will be provided in 
the Statistical Analysis Plan (SAP), which will be prepared before database lock. All statistical 
analyses will be performed using SAS® (SAS Institute Inc., Cary, North Carolina, USA), 
version 9.3 or later.  
11.2.1 
Analysis of Safety 
The following variables will be evaluated according to treatment for safety purposes: 
 
Adverse Events 
All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). Individual AEs will be presented in a listing including relationship to trial 
product/device, severity, and treatment period at onset. If more than 20 treatment-emergent 
AEs (AEs with onset after [first] dosing at Visit 3 until the Follow-up Visit 6) are registered, a 
summary table including number of AEs, number of patients with at least 1 AE, and percentage 
of exposed patients with at least 1 AE will be made by system organ class and treatment 
period at onset. 
  
Local Tolerability 
Local tolerability at the injection site will be summarized using descriptive statistics as 
appropriate. 
 
Laboratory Safety Assessments 
Laboratory assessments will be summarized. A listing of abnormal values will be provided.  
 
Physical Examination 
A frequency table will show the number and percentage of physical examination results.  
 
Vital Signs 
Vital signs will be summarized using descriptive statistics. 
 
12-lead ECG 
The Investigator’s evaluations of 12-lead ECGs will be summarized and abnormal individual 
evaluations will be listed together with the Investigator’s comments. Changes in 12-lead ECG 
between measurements will be recorded as AEs if the Investigator judges them to be clinically 
significant.  
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11.2.2 
Analysis of Efficacy 
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
 
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis, any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. Further details will be included in the 
SAP. 
 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow.  
11.2.3 
Interim Analysis 
An interim database lock may occur upon completion of Part 1 of the trial to analyze the 
iPhone-based BP data. 
11.2.4 
Sample Size Determination 
No formal sample size calculations were made. It is expected that between 20 and 24 patients 
will be randomized in the trial. The sample size is based on a clinical rather than statistical 
rationale. The sample size is considered adequate to address the primary trial objective of 
exploring the safety of ZP4207 when used in the BP and with reference to Lilly glucagon used 
in the BP. 
12 
DATA MANAGEMENT AND RECORD KEEPING 
Data Management is the responsibility of Medpace. The complete Data Management process 
will be described in detail and agreed on in the Data Management Plan for this trial. 
 
12.1 
Data Handling 
Case Report Forms 
Electronic Case Report Forms will be used in this trial. The Data Management Department of 
Medpace will provide the eCRFs. All further information regarding the eCRFs and the data 
flow will be described and agreed on in the Data Management Plan. 
 
Device-Related Data 
During the trial, CGM data, calibration data, insulin dosing data, and glucagon dosing data will 
be automatically stored in the BP device (from which it will be downloaded at intervals), 
combined in a single database that will be compared against the primary data files for integrity, 
and ultimately transferred to Medpace.  
 
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12.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
12.3 
Data Entry 
Data must be recorded using the electronic data capture (EDC) system as the trial is in 
progress. The patient questionnaires will be transcribed into the EDC system by site 
personnel. All site personnel must log into the system using their secure user name and 
password in order to enter, review, or correct trial data. These procedures must comply with 
Title 21 of the Code of Federal Regulations (21 CFR Part 11) and other appropriate 
international regulations. All passwords will be strictly confidential. 
12.4 
Medical Information Coding 
Adverse events and medical history will be coded using the latest version of MedDRA. Prior 
and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. 
12.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, 
will be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
12.6 
Record Keeping 
Medpace will be responsible for hosting the TMF. Records of patients, source documents, 
monitoring visit logs, eCRFs, inventory of trial product, regulatory documents, and other 
Sponsor correspondence pertaining to the trial must be kept in the appropriate trial files at the 
site. Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
evaluation and reconstruction of the clinical trial. Source data are contained in source 
documents (original records or certified copies). These records will be retained in a secure file 
for the period as set forth in the Clinical Trial Agreement. Prior to transfer or destruction of 
these records, the Sponsor must be notified in writing and be given the opportunity to further 
store such records. 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
13.1 
Ethical Conduct of the Trial 
The trial will be conducted according to Medpace, MGH, and/or the Sponsor’s written 
instructions (SOPs, working instructions, or process descriptions). Content and definitions of 
the written instructions are based on the Declaration of Helsinki and the ICH GCP.  
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13.2 
Institutional Review Board  
Written favorable opinion must be obtained from the responsible IRB prior to commencement 
of the trial. Clinical trial submission and reporting requirements before, during, and after 
completion of the trial will be performed in accordance with national law and local regulations.  
 
All amendments that affect patient safety or the trial integrity (substantial amendments) must 
not be implemented before favorable opinion has been obtained, unless necessary to 
eliminate hazards to the patients. Non-substantial amendments do not require favorable 
opinion by the IRB, but the respective IRB will be notified according to local requirements.  
 
The Sponsor and Investigator must approve any amendment in writing before its 
implementation. 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
IRB. The records should be filed in the Sponsor’s Trial Master File (TMF). 
 
13.3 
Informed Consent  
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirement(s) and adhere to the ICH GCP guideline and the 
requirements in the Declaration of Helsinki. 
 
Prior to any trial-related activity, the Investigator must give the patient oral and written 
information in a form that the patient can read and understand about all aspects of the trial 
that are relevant to the patient’s decision to participate. The patient will be given ample time 
to decide whether or not to participate in the trial. 
 
The patient must be informed that his/her personal trial-related data will be used in accordance 
with the local data protection law. The level of disclosure must also be explained to the patient. 
 
The patient must be informed that his/her medical records may be examined by authorized 
monitors or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
 
A voluntary, personally signed and dated ICF must be obtained from the patient prior to any 
trial-related activity. The ICF must also be signed and dated by the physician or designee who 
conducted the informed consent procedure. A signed copy of the ICF and any additional 
patient information must be given to each patient.  
 
The responsibility for taking informed consent must remain with that of a research physician 
or designee. If information becomes available that may be relevant to the patient’s willingness 
to continue participating in the trial, the Investigator must inform the patient in a timely manner, 
and a revised written informed consent must be obtained. 
 
Should a protocol amendment become necessary, the ICF may need to be revised to reflect 
the changes to the protocol. It is the responsibility of the Sponsor to ensure that an amended 
consent form is reviewed and has received favorable opinion from IRB, and the Investigator 
must ensure that the amended consent form is signed by all patients subsequently entered 
into the trial and those currently in the trial, if affected by the amendment. 
 
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13.4 
Trial Monitoring Requirements 
The monitoring procedures for this trial are described in detail in the Monitoring Manual. The 
objectives of the monitoring procedures are to ensure that (i) the safety and rights of the trial 
patients are respected, (ii) that accurate, valid, and complete data are collected, and (iii) that 
the trial is conducted in accordance with the trial protocol, the principles of GCP, and local 
legislation, including drug accountability. 
The monitor must be given direct access to the investigational site files and source documents 
(original documents, data, and records). Direct access includes permission to examine, 
analyze, verify, and reproduce any record(s) and report(s) that are important to evaluation of 
the clinical trial. 
Key tasks of the monitor include verifying the presence of informed consent, the adherence to 
the inclusion/exclusion criteria, the documentation of SAEs, and the recording of all safety and 
efficacy variables. The monitor will also confirm the completeness of patient records, the 
adherence to the protocol, ICH GCP, and the progress in patient enrollment and perform drug 
accountability.  
Because no information that could reveal the identity of patients may ever be removed from 
the trial site, the monitor will visit the site at regular intervals to perform these monitoring tasks. 
Other contact between the Investigator and monitors will be maintained as required through 
telephone calls and e-mail. The Investigator and/or key members of staff involved in the trial 
must be available to assist the monitors during all visits.  
Site Initiation Visit 
During the Site Initiation Visit (SIV) the CRO, Sponsor, and/or monitors will go through 
information on the IMP, the protocol, the eCRFs, and other key aspects of the trial with the 
Investigator and the key members of staff involved in the trial. The topics of the SIV are 
documented in a SIV report made available to the Investigator. Documentation on the SIV 
(e.g., power point presentation) should be filed by both Investigator and Sponsor. 
13.5 
Disclosure of Data 
Data generated by this trial must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal 
physician or other appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the trial is confidential and disclosure to third 
parties other than those noted above is prohibited. 
13.6 
Retention of Records  
Massachusetts General Hospital will maintain the patient’s medical file according to local 
regulations. MGH will archive the documentation pertaining to the trial in an archive after 
completion or discontinuation of the trial if not otherwise notified. MGH should not destroy any 
documents without prior permission from the Sponsor. 
The documentation includes all the raw data generated during the clinical trial, the 
investigational site files, and a copy of the clinical trial report. The documents will be retained 
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for a period of at least 15 years at archives by MGH, or its sub-contractor. After this period, 
the Sponsor will be contacted and their advice sought on the return or further retention of the 
trial records. 
 
The Sponsor will maintain the documentation pertaining to the trial in accordance with national 
regulations. 
 
13.7 
Publication Policy  
The Principal Investigator of the trial will review and sign the clinical trial report. A summary of 
the final clinical trial report will be submitted to the IRB and Competent Authority. 
  
According to the Declaration of Helsinki Investigators and Sponsors “have ethical obligations 
with regard to the publication and dissemination of the results of research.” The trial design 
and results may be published as 1 or more original research manuscripts/abstracts and 
presented at a scientific meeting. The Investigator and Sponsor reserve the right to review any 
proposed presentation of the results of this trial before they are submitted for publication. 
Authorship on any publication(s) resulting from this clinical trial will be assigned according to 
the recommendations of the International Committee of Medicinal Journal Editors. 
 
Participating patients will not be identified by name in any published reports about the clinical 
trial. 
 
The Sponsor is responsible for trial registration at ClinicalTrials.gov (www.clinicaltrials.gov) 
according to the requirements from the FDA. 
  
13.8 
Legal Aspects  
An implicit or explicit approval must be obtained from the Competent Authority prior to 
commencement of the trial. Clinical trial submission and reporting requirements before, during, 
and after completion of the trial will be performed in accordance with national law and local 
regulations. 
 
An implicit or explicit approval will also be mandatory before implementation of substantial 
changes. Non-substantial amendments do not require approval from the Competent Authority 
but will be notified according to local requirements. 
 
The Sponsor and Investigator must approve the amendment in writing before its 
implementation. 
 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
Competent Authority. The records should be filed in the Sponsor’s TMF. 
  
Audits and Inspections  
In the event of an audit, representatives of the Sponsor or designee, or national and 
international regulatory authorities may request access to all trial records for inspection and 
copying. Such access must be stated in the ICF signed by the patient. 
 
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13.9 
Sponsor Discontinuation Criteria  
The Sponsor, Investigator, or a pertinent regulatory authority may decide to stop the trial or 
part of the trial at any time but agreement on procedures to be followed must be obtained. 
Conditions that may warrant termination of the clinical trial include, but are not limited to: 
•
Safety or administrative reasons
•
The discovery of an unexpected, relevant, or unacceptable risk to the patients enrolled
in the clinical trial
•
A decision of the Sponsor to suspend or discontinue investigation of the IMP
If the trial is prematurely terminated or suspended, the Investigator should promptly inform the 
patients and assure appropriate therapy and follow-up. Furthermore, the Sponsor should 
promptly inform the IRB and provide a detailed written explanation. The pertinent regulatory 
authorities should be informed according to national regulations. 
If after the termination of the trial the risk/benefit analysis has changed, the new evaluation 
should be provided to the IRB in case it will have an impact on the planned follow-up of the 
patients who have participated in the trial. Necessary actions needed to protect the patients 
should be described. 
13.10 
Patient Compensation 
Financial compensation will be provided to all patients who complete the Screening Visit. 
Patients will be paid $25 for completing the Screening Visit whether or not they are eligible to 
participate in the trial. Patients will be compensated $25 for completing the Training Visit. 
Patients will be compensated $100 for completing each of the 2 treatment visits, $25 for 
completing the ADA Assessment Visit, and $25 for completing the Follow-up Visit. Thus, the 
total compensation for a patient who completes the trial would be $300. Patients who are 
unable to complete the trial or choose to stop participation will receive prorated compensation 
for each visit. In addition to the monetary compensation, the cost of the patients’ lunch meals 
during their participation in the trial, as well as the patients’ parking at each visit, will be covered 
by trial funds.  
14 
TRIAL ADMINISTRATIVE INFORMATION 
14.1 
Protocol Amendments  
Any amendments to the trial protocol will be communicated to the Investigators by Medpace 
or the Sponsor. All protocol amendments will undergo the same review and approval process 
as the original protocol. A protocol amendment may be implemented after it has been 
approved by the IRB, unless immediate implementation of the change is necessary for patient 
safety. In this case, the situation must be documented and reported to the IRB within 5 working 
days. 
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APPENDIX A: SCHEDULE OF PROCEDURES – PARTS 1 AND 2 
Trial Visit 
Visit 1 [1]
Screening 
Visit 2
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5]
(2nd Treatment 
Visit) 
Visit 5
ADA 
Assessment 
Visit [6] 
Visit 6
Follow-Up [7] 
Informed consent 
X 
Assess/confirm elig bility 
X 
X 
Demographics 
X
Medical, surgical, and social history; 
allergies  
X 
Concomitant illness 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Height, weight, physical examination, and 
vital signs including body temperature 
and blood pressure [8] 
X 
X [9] 
X [9] 
12-lead ECG 
X 
X [10] 
X [10] 
Urine HCG pregnancy test and menstrual 
history [11]   
X 
X 
X 
FSH [12] 
X 
Screening labs – HbA1c, optional 
fractionated metanephrines [13] 
X 
Safety lab sampling including chemistry 
and hematology 
X 
X [10] 
X [10] 
X 
Training on devices [14] 
X 
Monitored BP use 
X 
X 
Plasma glucose sampling [15] 
X 
X 
ZP4207/glucagon exposure sampling [16] 
X 
X 
Nausea and infusion site pain VAS and 
infusion site reaction Draize scale (visit 
start [17], hourly, & visit end) 
X 
X 
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Trial Visit 
Visit 1 [1]
Screening 
Visit 2
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5]
(2nd Treatment 
Visit) 
Visit 5
ADA 
Assessment 
Visit [6] 
Visit 6
Follow-Up [7] 
Standardized lunch [18] 
 
 
X 
X 
 
 
In-clinic exercise [19] 
 
 
X 
X 
 
 
Questionnaires (pre & post BP) 
 
 
X 
X 
 
 
ADA 
 
 
X [20] 
 
X 
X 
Adverse event review 
 
 
X 
X 
X 
X 
1. 
Once the patient has been enrolled and eligibility has been established, the order of the treatment visits will be randomized in blocks of 2 patients. 
2. 
In Part 1, each patient will participate in 2 treatment visits: 1 with the iPhone-based BP using ZP4207 and 1 with the iPhone-based BP using Lilly glucagon in a randomized order. In 
Part 2, each patient will participate in 2 treatment visits: 1 with the iLet using ZP4207 and 1 with the iLet using Lilly glucagon in a randomized order. Up to 2 patients may participate in the 
trial per day. 
3. 
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal skin and calibrate the sensor when prompted using the provided Nova StatStrip Xpress meter. 
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the BP having fasted since 12 00 AM the night before (treatment with simple carbohydrate of up to 30 g 
for a low is allowed). If the patient is not fasted, the visit will be rescheduled within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the visit window. If BG is 
<50 mg/dL, treatment with simple carbohydrate is allowed. If the patient experiences persistent hypoglycemia, the visit will be rescheduled within the visit window. 
4. 
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 30 days after screening (Visit 1). 
5. 
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum of 3 weeks between Visit 3 and Visit 4. 
6. 
Visit 5 will take place 10 days ±3 days from Visit 4.  
7. 
Visit 6 will take place 25 days ±4 days from Visit 4. 
8. 
Height and physical examination will be measured at Visit 1 only. 
9. 
Vital signs including body temperature and blood pressure will be obtained at visit start and visit end. 
10. At visit start and visit end. 
11. Urine HCG pregnancy test only for women of childbearing potential. The date of the last menstrual period in female patients will be obtained at Visit 1 only. 
12. Test for FSH level only for postmenopausal women amenorrheic for less than 1 year. 
13. If indicated by history. 
14. Patients will be trained in the insertion and calibration of the Dexcom G4 sensor, diabetes management (e.g., basal insulin rate adjustment by insulin pump) during fasting prior to and 
between the treatment visits, and trial policies and procedures. 
15. Collected at least hourly. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will 
be every 10 minutes. 
16. Collected at least hourly. If BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the Investigator. 
17. Once the infusion sites have been placed but no drug has yet been administered. 
18. Between approximately Hour 3 and Hour 4. 
19. Between approximately Hour 6 and Hour 7. 
20. Before the start of dosing. 
ADA = anti-drug antibodies; BG = blood glucose; BP = bionic pancreas; CGM = continuous glucose monitor; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
HbA1c = hemoglobin A1c; HCG = human chorionic gonadotropin; VAS = visual analog scale.
 
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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Chemistry 
Alanine aminotransferase 
Aspartate aminotransferase 
Alkaline phosphatase 
Total protein 
Albumin 
Total and direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Creatinine 
Estimated glomerular filtration rate 
Blood urea nitrogen 
Uric acid
Bicarbonate 
Sodium 
Potassium 
Calcium 
Chloride 
Phosphorus 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell count 
White blood cell count and differential 
Platelets 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Pregnancy Test 
A urine HCG pregnancy test will be performed at screening, Visit 3, and Visit 4 only for 
women of childbearing potential. 
Anti-drug Antibodies Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken prior to first dosing (Visit 3), at the ADA Assessment Visit (Visit 5), 
and at the Follow-up Visit (Visit 6). 
ZP4207/Glucagon Exposure Sampling 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at 
the discretion of the Investigator. 
Screening Visit Only 
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year 
Optional fractionated plasma metanephrines (if indicated by history) 
Hemoglobin A1c 
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APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES 
Diabetes Treatment Satisfaction Questionnaire – Status (DTSQs) 
The DTSQs measures patient satisfaction with diabetes treatment. It consists of a 6 item scale 
for assessing treatment satisfaction and two additional items assessing perceived frequency 
of hyperglycemia and hypoglycemia. The DTSQs is meant for adults and older children. 
Dr. Clare Bradley has produced a version that is appropriate for bionic pancreas studies for 
this use, along with a version for younger children. It is administered before the intervention. 
The DTSQs is valid and reliable. Administration time is less than 5 minutes. 
Diabetes Treatment Satisfaction Questionnaire – Change (DTSQc) 
Although the DTSQ is responsive to treatment changes, ceiling effects are often seen with this 
instrument, where maximum or close-to-maximum scores at baseline provide little opportunity 
for registering improvement. The DTSQc contains the same items as the DTSQs version but 
asks patients to consider their satisfaction with their current treatment compared with their 
previous treatment. The DTSQc is meant for adults and older children. Dr. Clare Bradley has 
produced a version that is appropriate for bionic pancreas studies for our use, along with a 
version for younger children. It is administered during and at the end of the intervention. The 
DTSQc is valid and reliable. Administration time is less than 5 minutes. 
T1-Diabetes Distress Scale (T1-DDS) 
The T1-DDS is a 28-item survey that assesses seven sources of diabetes distress for type 1 
adults. It captures feelings of powerlessness; management distress; hypoglycemia distress; 
negative social perceptions by others; eating distress; physician (health care) distress; and 
friend/family distress. Items are scored on a 6-point scale from not a problem to a very serious 
problem. It is administered before, during, and at the end of the intervention. The scale is valid 
and reliable, and has been shown to be sensitive to change over time. Administration time is 
5 minutes. 
Problem Areas in Diabetes Survey (PAID) 
There are three versions of the PAID: Teen (PAID-T), Parent (PAID-P), and Child (PAID-C) 
versions. This measure of diabetes-specific emotional distress in youth with diabetes and their 
parents is 26 items. A total score is generated. It is administered before, during, and at the 
end of the intervention. The PAID-T and PAID-P are valid and reliable. Psychometric analysis 
of the PAID-C is in progress. Administration time is 5 minutes. 
Hypoglycemia Fear Survey (HFS) 
There are three versions of the HFS, Adult (HFS), Youth (HFS-Y) and Parent (HFS-P). The 
HFS measures several dimensions of fear of hypoglycemia among adults with type 1 diabetes. 
It consists of 23 items and produces two sub-scale scores; a Behavior sub-scale that 
measures behaviors involved in avoidance and/or over-treatment of hypoglycemia and a 
Worry sub-scale that measures anxiety and fear surrounding hypoglycemia. The HFS-Y 
consists of 25 items and the HFS-P consists of 26 items; both produce sub-scale scores 
similar to the Adult HFS. It is administered before, during, and at the end of the intervention. 
All versions of the HFS are valid and reliable. Administration time is 5-10 minutes. 
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Impact of Daily Diabetes Demands (IDDD) 
There are four versions of the IDDD; Adult (IDDD-A), Youth (IDDD-Y), Parent (IDDD-P), and 
Significant Other (IDDD-SO). This instrument measures the burden related to the demands of 
the daily diabetes regimen and is 22 items. A total score is generated. It is administered before, 
during, and at the end of the intervention. Psychometric analysis of the IDDD-Y is in progress 
using the data from the second Bionic Pancreas Camp Study in pre-adolescent children, and 
of the IDDD-A is in progress using data from the Bionic Pancreas Multicenter Study in adults. 
Administration time is 5 minutes. 
 
Bionic Pancreas User Opinion Survey (BPUOS) 
There are four versions of the BPUOS; Adult (BPUOS-A), Youth (BPUOS-Y), Parent 
(BPUOS-P), and Significant Other (BPUOS-SO). This measure assessing both the benefits 
from, and difficulties with, use of the bionic pancreas, and consists of 38 items. A total score 
is generated. It is administered during and at the end of the intervention. Psychometric 
analysis of the BPUOS-Y is in progress using the data from the second Bionic Pancreas Camp 
Study in pre-adolescent children, and of the BPUOS -A is in progress using data from the 
Bionic Pancreas Multicenter Study in adults. Administration time is 10 minutes. 
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SUMMARY OF CHANGES DOCUMENT 
PROTOCOL NUMBER ZP4207-16051 
AMENDMENT NUMBER 4.0 
PROTOCOL TITLE: The Bionic Pancreas Feasibility Trial Testing the Bionic Pancreas with 
ZP4207 
AMENDMENT DATE: 02 September 2016 
SUMMARY AND JUSTIFICATION OF CHANGES: 
This amendment was developed to indicate that the bionic pancreas (BP) feasibility trial that uses 
the glucagon analog ZP4207 (Zealand Pharma A/S) will take place in 2 parts. Part 1 will compare 
the iPhone-based BP using ZP4207 to the iPhone-based BP using Lilly glucagon. Part 2 will 
compare the iLet using ZP4207 to the iLet using Lilly glucagon. Patients can only participate in 
1 part of the trial. The cross-over design with inclusion of 1 group of 10 T1DM patients into the 
2 iLet treatment arms and the inclusion of a second group of 10 T1DM patients into the 
2 iPhone-based BP treatment arms in a randomized order will allow for a direct comparison of the 
safety and efficacy of the 2 treatments, based on intra-patient variability only. 
The inclusion of Part 1 (the iPhone-based BP arms) will allow the comparison of the performance 
of ZP4207 to Lilly glucagon in the original iPhone-based BP, which has been well-characterized 
in a number of outpatient trials in children and adults over the past 3 years. By testing ZP4207 in 
the original iPhone-based BP, the glucagon used (ZP4207 vs. Lilly glucagon) will be the only new 
variable. This will allow optimal isolation and identification of differences, if any, that might exist 
between ZP4207 and Lilly glucagon in the context of automated glycemic control with the 
well-characterized and extensively tested iPhone-based BP. 
The incorporation of Part 1 and Part 2 has been made globally throughout the protocol 
amendment. It has been specified that for all analysis, the 2 treatment arms from Part 1 
(iPhone-based BP) will be compared, and the 2 treatment arms from Part 2 (iLet) will be 
compared. Additional language has been added to describe the BP infusion set, control unit, and 
pumps. The schedule of procedures was updated to reflect the changes specified in this 
document. Other minor edits were made throughout the protocol to provide greater clarity and 
consistency. 
SUMMARY OF CHANGES: 
The amended protocol sections and the details of the changes are summarized in the following 
sections. Revisions to the protocol are presented as strikethrough (ie, subject) for text that was 
removed and bold (ie, subject) for text that was added. 
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Synopsis, Objectives, Page 4; Section 2, Trial Objectives, Page 22 
Original Text: 
Primary: The primary objective is to conduct a trial testing the safety and tolerability of the 
iPhone-based bionic pancreas (BP) when used with ZP4207 in 10 adult (18 years of age) 
patients with T1DM. 
Secondary: The secondary objectives are to measure glycemic regulation, including 
hypoglycemia exposure (percent of time spent with continuous glucose monitor [CGM] glucose 
<60 mg/dL), evaluate BP device reliability, and to document the satisfaction of patients with the 
iPhone-based BP with the goal of optimizing the functionality and user interface of the 
iPhone-based BP. 
New Text: 
Primary: The primary objective is to conduct a trial testing the safety and tolerability of the BP 
using either the iLet or the iPhone based bionic pancreas (BP) platform when used with 
ZP4207 in 10 20 adult (18 years of age) patients with T1DM. 
Secondary: The secondary objectives are to measure glycemic regulation, including 
hypoglycemia exposure (percent of time spent with continuous glucose monitor [CGM] glucose 
<60 mg/dL), evaluate BP device reliability, and to document the satisfaction of patients with the 
iPhone based BP with the goal of optimizing the functionality and user interface of the 
iPhone based BP. 
Synopsis, Population, Page 4 
Original Text: 
Up to 20 adult (18 years of age) patients who already manage their T1DM using continuous 
subcutaneous (SC) insulin infusion pump therapy can be enrolled. It is expected that up to 
10 patients will complete the trial protocol. 
New Text: 
Up to 20 40 adult (18 years of age) patients who already manage their T1DM using continuous 
subcutaneous (SC) insulin infusion pump therapy can be enrolled. It is expected that up to 
10 patients will complete each part of the trial protocol. 
Synopsis, Trial Design, Page 4; Section 3.1, Summary of Trial Design, Page 22 
Original Text: 
This trial is a single-center, open-label, randomized cross-over trial. The trial will enroll adult 
patients with T1DM and will assess the safety and efficacy of the iPhone-based BP using the 
glucagon analog ZP4207 versus the iPhone-based BP using Lilly glucagon. The iPhone-based 
BP will also administer insulin (insulin lispro, Lilly Humalog) using the same BG control 
algorithm for both treatment arms. The trial will be conducted at a single center, the MGH 
Diabetes Center in Boston, MA. 
New Text: 
This trial is a single-center, open-label, 2-part, randomized cross-over trial. The trial will enroll 
adult patients with T1DM and will assess the safety and efficacy of the iPhone based BP using 
the glucagon analog ZP4207 versus the iPhone based BP using Lilly glucagon. The iPhone   
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BP using either the iLet or the iPhone platform using the glucagon analog ZP4207 versus 
Lilly glucagon. In Part 1, up to 10 patients will participate in two 1-day treatment arms in 
random order (iPhone-based BP using ZP4207 and iPhone-based BP using Lilly 
glucagon) according to a pre-generated randomization scheme. In Part 2, up to 10 new 
patients will participate in two 1-day treatment arms in random order (iLet using ZP4207 
and iLet using Lilly glucagon) according to a pre-generated randomization scheme. 
Patients can only participate in 1 part of the trial. An interim database lock may occur 
upon completion of Part 1 of the trial to analyze the iPhone-based BP data. The iLet and 
the iPhone-based BP will also administer insulin (insulin lispro, Lilly Humalog) using the same 
BG control algorithm for both all 4 treatment arms. The trial will be conducted at a single center, 
the MGH Diabetes Center in Boston, MA. 
Synopsis, Trial Treatment, Page 5; Section 6.1, Investigational Medicinal Products, 
Page 27  
Original Text: 
The trial also involves SC administration of Lilly glucagon in one iPhone-based BP arm. Lilly 
glucagon is commercially available by prescription and is indicated for patients with T1DM in 
severe hypoglycemia, but not for use in a BP.  
The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, in the other 
iPhone-based BP arm. ZP4207 will be made available by Zealand Pharma A/S, Denmark as 
liquid formulation in prefilled syringes of 0.6 mL. 
New Text: 
The trial also involves SC administration of Lilly glucagon in one 1 iLet arm and 
1 iPhone-based BP arm. Lilly glucagon is commercially available by prescription and is 
indicated for patients with T1DM in severe hypoglycemia, but not for use in a BP.  
The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, in the other 
iLet arm and the other iPhone-based BP arm. ZP4207 will be made available by Zealand 
Pharma A/S, Denmark as liquid formulation in prefilled syringes of 0.6 mL. 
Synopsis, Primary Endpoint, Page 5; Section 8.1, Primary Endpoint, Page 38 
Original Text: 
The primary endpoint is the safety and tolerability of ZP4207 and the iPhone-based BP as 
assessed by: 

Number and type of adverse events (AEs)

Clinical laboratory measurements

Vital signs

12-lead electrocardiogram (ECG)

Local tolerability and infusion site reactions as measured with the Draize scale

Immunogenicity as measured by anti-drug antibodies

Pain as measured on a 10 cm visual analog scale (VAS)

Nausea as measured on a 10 cm VAS
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New Text: 
The primary endpoint is the safety and tolerability of ZP4207 and in the BP using either the 
iLet or the iPhone based BP platform as assessed by: 
 
Number and type of adverse events (AEs) 
 
Clinical laboratory measurements 
 
Vital signs 
 
12-lead electrocardiogram (ECG) 
 
Local tolerability and infusion site reactions as measured with the Draize scale 
 
Immunogenicity as measured by anti-drug antibodies 
 
Pain as measured on a 10 cm visual analog scale (VAS) 
 
Nausea as measured on a 10 cm VAS 
Synopsis, Secondary Endpoints, Page 5; Section 8.2, Secondary Endpoints, Page 38 
Original Text: 
The secondary endpoints for the iPhone-based BP and ZP4207 include measurements of BP 
function as well as glycemic and non-glycemic measurements. 
New Text: 
The secondary endpoints for the iPhone based BP and ZP4207 include measurements of BP 
function as well as glycemic and non-glycemic measurements. 
Section 1.1, Background and Rationale, Page 14-15 
Original Text: 
In its last tested embodiment, the BP consisted of a Dexcom G4 CGM, and an iPhone that are 
hardwired together, with the iPhone running the control algorithm and communicating via 
Bluetooth with 2 Tandem t:slim pumps to dose insulin and glucagon.  
In order to provide automatic BG regulation, the iPhone-based BP has the ability to deliver both 
insulin and glucagon. However, currently available glucagon formulations have limited stability 
at room temperature, necessitating frequent changes to the glucagon infusion set. Therefore, 
the current trial is designed to test the glucagon analog ZP4207 in the iPhone-based BP, as 
this peptide analog of human glucagon is provided in a liquid formulation stable at room 
temperature. 
The current trial is a first feasibility trial designed to use the iPhone-based BP to compare 
ZP4207 with marketed glucagon (Lilly). The trial is intended to demonstrate the safety and 
tolerability of ZP4207 in the iPhone-based BP and the feasibility of achieving comparable 
autonomous glycemic control. It is not intended to comprehensively demonstrate the definitive 
efficacy of the iPhone-based BP in extended, continuous daily use, but rather to demonstrate 
its functionality and accuracy in a practical, albeit very controlled, clinical setting. The trial is 
expected to provide practical information that will benefit the design of a next-generation BP 
and help pave the way for a more comprehensive outpatient home-use Phase 2 trial and 
ultimately a pivotal trial where comprehensive safety and efficacy through continuous full daily 
use of the BP with ZP4207 will be documented. 
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The data derived from this trial will permit evaluation of the robustness of the iPhone-based BP 
as well as the safety and efficacy of ZP4207 when used in conjunction with the iPhone-based 
BP. 
New Text: 
In its last tested embodiment, the BP consisted of a Dexcom G4 CGM, and an iPhone that are 
hardwired together, with the iPhone running the control algorithm and communicating via 
Bluetooth with 2 Tandem t:slim pumps to dose insulin and glucagon. The connections are 
repeatedly lost among these 4 components throughout the day, an issue that has the 
potential to adversely impact BG control, whether due to missed CGM values or missed 
doses. In addition, the troubleshooting required to repair these recurring disconnections 
can be burdensome to the user. Integrating these components into a single device would 
establish seamless connectivity among them, which would eliminate the need for such 
troubleshooting. This would lead to smoother device operation with fewer interruptions, 
which would enhance its user friendliness, optimize its BG control potential, and further 
improve the quality of life of its users.  
The BU Investigators have recently designed, built, and tested a proprietary 
first-generation of such a fully integrated BP system, referred to as the iLet and the iLet 
infusion set. The iLet is a dual-chamber infusion system that currently incorporates the 
Dexcom G4 CGM technology, a custom user interface with touchscreen display, and all 
of the mathematical dosing algorithms that were tested in and validated using the 
iPhone-based BP in outpatient studies over the past 3 years. The iLet infusion set 
provides 2 independent subcutaneous (SC) fluid pathways from the iLet to the patient 
(1 for insulin and the other for glucagon). One tube connects to the prefilled insulin 
cartridge and the other tube connects to the fillable (single-use) glucagon cartridge. 
In order to provide automatic BG regulation, the iLet and the iPhone-based BP has have the 
ability to deliver both insulin and glucagon. However, currently available glucagon formulations 
have limited stability at room temperature, necessitating frequent changes to the glucagon 
infusion set. Therefore, the current trial is designed to test the glucagon analog ZP4207 in the 
iLet and the iPhone-based BP, as this peptide analog of human glucagon is provided in a liquid 
formulation stable at room temperature. 
The current trial is a first feasibility trial designed to use the first-generation iLet and iLet 
infusion set and the iPhone-based BP to compare ZP4207 with marketed glucagon (Lilly). 
The trial is intended to demonstrate the safety and tolerability of ZP4207 in the iLet and the 
iPhone-based BP and the feasibility of achieving comparable autonomous glycemic control. It 
is not intended to comprehensively demonstrate the definitive efficacy of the iPhone based BP 
in extended, continuous daily use, but rather to demonstrate its functionality and accuracy in a 
practical, albeit very controlled, clinical setting. The trial is expected to provide practical 
information that will benefit the design of a next-generation BP iLet and iLet infusion set and 
help pave the way for a more comprehensive outpatient home-use Phase 2 trial and ultimately 
a pivotal trial where comprehensive safety and efficacy through continuous full daily use of the 
BP iLet with ZP4207 will be documented. 
The data derived from this trial will permit evaluation of the robustness of the iPhone based BP 
iLet as well as the safety and efficacy of ZP4207 when used in conjunction with the iLet and 
the iPhone-based BP. The data obtained will be used to further improve the iLet and will 
allow BU/MGH to expand to larger outpatient trials using the iLet or the iPhone-based BP 
with ZP4207. 
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Section 1.5, Risk/Benefit, Page 19 
Original Text: 
Trial patients will be informed by the Investigator of the potential risks of ZP4207 and other 
trial-related procedures before they enter the trial.  
In this trial, patients with T1DM will be included to test the safety and efficacy of the 
iPhone-based BP using ZP4207 versus the iPhone-based BP using Lilly glucagon. The 
cross-over design with inclusion of the same T1DM patients into the 2 treatment arms in a 
randomized order will allow for a direct comparison of the safety and efficacy of the 
2 treatments, based on intra-patient variability only. 
New Text: 
Trial patients will be informed by the Investigator of the potential risks of ZP4207 and other 
trial-related procedures before they enter the trial.  
In this trial, patients with T1DM will be included to test the safety and efficacy of the 
iPhone based BP using either the iLet or the iPhone platform when used with ZP4207 
versus the iPhone based BP using Lilly glucagon. The cross-over design with inclusion of the 
same 1 group of 10 T1DM patients into the 2 iLet treatment arms and the inclusion of a 
second group of 10 T1DM patients into the 2 iPhone-based BP treatment arms in a 
randomized order will allow for a direct comparison of the safety and efficacy of the 
2 treatments, based on intra-patient variability only. 
Section 1.5, Risk/Benefit, Page 21 
Original Text: 
Based on experiences from previous trials of the BP and the design of this trial, patients enrolled 
in the trial may benefit from a reduction in risk of hypoglycemia and hyperglycemia and a better 
mean glucose compared to their usual diabetes care during their short trial participation.  
The data derived from this trial will allow evaluation of safety and tolerability of ZP4207 in the 
iPhone-based BP. 
New Text: 
Based on experiences from previous trials of the BP and the design of this trial, patients enrolled 
in the trial may benefit from a reduction in risk of hypoglycemia and hyperglycemia and a better 
mean glucose compared to their usual diabetes care during their short trial participation.  
The data derived from this trial will allow evaluation of safety and tolerability of ZP4207 in the 
iPhone based BP. iLet and the iPhone-based BP, and the robustness and effectiveness 
of the new BP control system. The data obtained will be used to further improve the iLet 
and will allow the expansion to larger outpatient trials using the iLet or the iPhone-based 
BP with ZP4207. 
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Section 3.3, Number of Patients, Page 23 
Original Text: 
Up to 20 adult patients with T1DM can be enrolled. The upper bound is based on the 
expectation that some patients will be excluded after the Screening Visit and the possibility that 
some patients may have to be discontinued before completion (due to, for instance, 
inter-current illness or patient withdrawal). It is expected that up to 10 patients will complete the 
trial protocol. 
New Text: 
Up to 20 40 adult patients with T1DM can be enrolled. The upper bound is based on the 
expectation that some patients will be excluded after the Screening Visit and the possibility that 
some patients may have to be discontinued before completion (due to, for instance, 
inter-current illness or patient withdrawal). It is expected that up to 10 patients will complete 
each part of the trial protocol. 
Section 5, Assignment to Treatment Groups, Page 26 
Original Text: 
This trial is an open-label, randomized cross-over trial. Patients who have completed the 
Screening Visit and meet all of the inclusion and none of exclusion criteria will be enrolled into 
the trial. All patients will participate in two 1-day treatment arms in random order (iPhone-based 
BP using ZP4207 and iPhone-based BP using Lilly glucagon) according to a pre-generated 
randomization scheme. Up to 2 patients may participate in the trial per day. The order of the 
iPhone-based BP visits will be randomized in blocks of 2 patients. 
New Text: 
This trial is an open-label, 2-part, randomized cross-over trial. Patients who have completed 
the Screening Visit and meet all of the inclusion and none of exclusion criteria will be enrolled 
into the trial. All In Part 1, up to 10 patients will participate in two 1-day treatment arms in 
random order (iPhone-based BP using ZP4207 and iPhone-based BP using Lilly glucagon) 
according to a pre-generated randomization scheme. In Part 2, up to 10 new patients will 
participate in two 1-day treatment arms in random order (iLet using ZP4207 and iLet 
using Lilly glucagon) according to a pre-generated randomization scheme. Up to 
2 patients may participate in the trial per day. The order of the iPhone based BP treatment 
visits will be randomized in blocks of 2 patients. 
Section 6.4, Doses, Page 28 
Original Text: 
The iPhone-based BP can administer isolated insulin-glucagon doses once every 5 minutes. A 
single automated bolus of insulin will not exceed 3 units per 5-minute dose (30  µl of U-100 
insulin) in both systems, and a single meal-priming dose, in response to a meal announcement 
made by the user, will not exceed 12 units (120 µl of U-100 insulin). A single bolus of glucagon 
will not exceed 80 µg (80 µl of 1 mg/mL Lilly glucagon or 1 mg/mL ZP4207). In prior studies, 
typical doses of glucagon were in the range of 0.005-0.04 mg per dose. The iPhone-based BP 
is capable of administering as little as ~0.1 µl (0.011 units of U-100 insulin or 0.1 µg of 1 mg/mL 
ZP4207). 
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New Text: 
The iLet and the iPhone-based BP can administer isolated insulin-glucagon doses once every 
5 minutes. A single automated bolus of insulin will not exceed 3 units per 5-minute dose (30  µl 
of U-100 insulin) in both systems, and a single meal-priming dose, in response to a meal 
announcement made by the user, will not exceed 12 units (120 µl of U-100 insulin). A single 
bolus of glucagon will not exceed 80 µg (80 µl of 1 mg/mL Lilly glucagon or 1 mg/mL ZP4207). 
In prior studies, typical doses of glucagon were in the range of 0.005 0.04 mg 2.5-40 µg per 
dose. The iLet and the iPhone-based BP is are capable of administering as little as ~0.51 µl 
(0.01105 units of U-100 insulin or 0.51 µg of 1 mg/mL ZP4207). 
Section 6.6, iLet Bionic Pancreas, Page 29-30 
Original Text: 
Not applicable. 
New Text: 
6.6 
iLet Bionic Pancreas  
Infusion Set: A novel, dual cannula infusion set has been designed specifically for use 
with the iLet. Patients will wear dual channel tubing that will be attached to 2 infusion 
sets with 1 steel cannula each, 1 for insulin infusion and the other for glucagon infusion. 
The tubing and infusion sets will have undergone sterilization prior to being delivered in 
a sealed pouch. The steel cannulae will be inserted in the abdominal SC tissue. 
Continuous Glucose Monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input 
to the controller. The sensor is powered by the battery within the transmitter that clips 
to the sensor and the whole assembly is held to the skin with an adhesive patch and 
communicates wirelessly with the BP. If the G4 sensor fails for any reason during the 
trial (loss of CGM signal), it will be replaced promptly.  
Bionic Pancreas Control Unit: The iLet is being built according to Class III medical device 
standards, adheres to a comprehensive and robust quality system, and is fully compliant 
with International Organization for Standardization (ISO) 13485 standards and document 
control practices. The iLet is a fully-integrated dual hormone BP system that integrates 
the CGM technology (currently the Dexcom G4 Share system) as well as 2 independent 
motor-drivetrain pumping assemblies, which independently actuate the delivery of 
insulin and glucagon from pre-filled cartridges that are separately loaded into the iLet 
housing. Each drivetrain assembly utilizes a lead screw, which is driven by a precision 
micromotor, a gear case assembly, and a motor controller unit, in a manner similar to 
what is commonly found in most insulin infusion pumps on the market today. The iLet 
has dosing accuracy that is comparable to FDA-approved insulin pumps currently on 
the market. The iLet has a built-in BTLE radio that also allows automatic communication 
with the paired CGM, as well as the Nova StatStrip® Xpress BG meter (Nova Biomedical). 
The iLet does not contain a cellular nor a WiFi radio, and does not accept input data from 
another mobile device (e.g., smartphone), other than the paired CGM and BG meter(s). 
The mathematical control algorithms (which are the same as those used in the 
iPhone-based BP), the CGM glucose engine (Dexcom), and the native user interface 
software, are all interconnected through controller framework software and reside as 
embedded systems on printed circuit boards contained within the device housing. The 
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touchscreen-enabled, menu-driven user interface and onboard processor provide a 
comprehensive and standalone platform, which allows the iLet to operate independently 
of smartphones or other devices and without the need for internet support during routine 
operation. The graphical user interface of the iLet has the same user options and 
capabilities of the iPhone BP, including having its home screen password protected and 
its settings options only accessible to trial staff via a separate password. 
Section 7.4, Treatment Visits (Visit 3 and Visit 4), Page 32-33 
Original Text: 

Up to 2 patients may participate per day.

Each patient will participate in 2 treatment visits: one with the iPhone-based BP using
ZP4207 and one with the iPhone-based BP using Lilly glucagon in a randomized order.

The night before the treatment visit, patients will place a Dexcom G4 CGM sensor in
the abdominal skin and calibrate the sensor when prompted using the provided Nova
StatStrip Xpress meter. Patients will be instructed to call if they encounter any difficulty
with their CGM.
New Text: 

Up to 2 patients may participate per day.

Each In Part 1, each patient will participate in 2 treatment visits: one 1 with the
iPhone-based BP using ZP4207 and one 1 with the iPhone-based BP using Lilly
glucagon in a randomized order.

In Part 2, each patient will participate in 2 treatment visits: 1 with the iLet using
ZP4207 and 1 with the iLet using Lilly glucagon in a randomized order.

The night before the treatment visit, patients will place a Dexcom G4 CGM sensor in
the abdominal skin and calibrate the sensor when prompted using the provided Nova
StatStrip Xpress meter. Patients will be instructed to call if they encounter any difficulty
with their CGM.
Section 11, Statistics, Page 47 
Original Text: 
Not applicable. 
New Text: 
For all analysis, the 2 treatment arms from Part 1 (iPhone-based BP) will be compared, 
and the 2 treatment arms from Part 2 (iLet) will be compared. The analysis of Part 1 will 
be completely separate from the analysis of Part 2. 
Section 11.2.3, Interim Analysis, Page 49 
Original Text: 
No interim analysis is planned. 
New Text: 
No interim analysis is planned. An interim database lock may occur upon completion of 
Part 1 of the trial to analyze the iPhone-based BP data. 
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Section 11.2.4, Sample Size Determination, Page 49 
Original Text: 
No formal sample size calculations were made. It is expected that between 10 and 12 patients 
will be randomized in the trial. The sample size is based on a clinical rather than statistical 
rationale. The sample size is considered adequate to address the primary trial objective of 
exploring the safety of ZP4207 when used in the iPhone-based BP and with reference to Lilly 
glucagon used in the iPhone-based BP. 
New Text: 
No formal sample size calculations were made. It is expected that between 10 20 and 12 24 
patients will be randomized in the trial. The sample size is based on a clinical rather than 
statistical rationale. The sample size is considered adequate to address the primary trial 
objective of exploring the safety of ZP4207 when used in the iPhone based BP and with 
reference to Lilly glucagon used in the iPhone based BP. 
Appendix A, Schedule of Procedures, Footnotes 1 and 2, Page 59 
Original Text: 
1.
Once the patient has been enrolled and eligibility has been established, the order of the
iPhone-based BP visits will be randomized in blocks of 2 patients.
2.
Each patient will participate in 2 treatment visits: one with the iPhone-based BP using
ZP4207 and one with the iPhone-based BP using Lilly glucagon in a randomized order.
Up to 2 patients may participate in the trial per day.
New Text: 
1.
Once the patient has been enrolled and eligibility has been established, the order of the
iPhone based BP treatment visits will be randomized in blocks of 2 patients.
2.
Each In Part 1, each patient will participate in 2 treatment visits: one 1 with the
iPhone-based BP using ZP4207 and one 1 with the iPhone-based BP using Lilly
glucagon in a randomized order. In Part 2, each patient will participate in 2 treatment
visits: 1 with the iLet using ZP4207 and 1 with the iLet using Lilly glucagon in a
randomized order. Up to 2 patients may participate in the trial per day.
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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary 
details for carrying out the trial as described. I will conduct this trial in accordance with the 
design and specific provision of this protocol and will make a reasonable effort to complete 
the trial within the time designated. I will provide copies of this protocol and access to all 
information furnished by Zealand Pharma A/S to trial personnel under my supervision. I will 
discuss this material with them to ensure they are fully informed about the trial product and 
trial procedures. I will let them know that this information is confidential and proprietary to 
Zealand Pharma A/S and that it may not be further disclosed to third parties. I understand that 
the trial may be terminated or enrollment suspended at any time by Zealand Pharma A/S, with 
or without cause, or by me if it becomes necessary to protect the best interests of the trial 
patients. 
I agree to conduct this trial in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations and ICH Guidelines for Good Clinical 
Practices. 
______________________________________________ 
____________________ 
Investigator’s Signature 
Date
______________________________________________ 
Investigator’s Printed Name 
9/7/2016
Steven J. Russell, MD, PhD
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SYNOPSIS 
TITLE: The Bionic Pancreas Feasibility Trial Testing the Bionic Pancreas with ZP4207 
PROTOCOL NUMBER: ZP4207-16051 
INVESTIGATIONAL PRODUCT: ZP4207 
PHASE: 2 
INDICATION: ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid 
formulation which is being studied to improve glycemic control in adults (and children) with 
type 1 diabetes mellitus (T1DM) as part of a bihormonal bionic pancreas (BP). 
OBJECTIVES: 
Primary: The primary objective is to conduct a trial testing the safety and tolerability of the BP 
using either the iLet or the iPhone platform when used with ZP4207 in 20 adult (≥18 years of 
age) patients with T1DM. 
Secondary: The secondary objectives are to measure glycemic regulation, including 
hypoglycemia exposure (percent of time spent with continuous glucose monitor [CGM] 
glucose <60 mg/dL), evaluate BP device reliability, and to document the satisfaction of 
patients with the BP with the goal of optimizing the functionality and user interface of the BP. 
POPULATION: Up to 40 adult (≥18 years of age) patients who already manage their T1DM 
using continuous subcutaneous (SC) insulin infusion pump therapy can be enrolled. It is 
expected that up to 10 patients will complete each part of the trial protocol. 
TRIAL DESIGN: This trial is a single-center, open-label, 2-part, randomized cross-over trial. 
The trial will enroll adult patients with T1DM and will assess the safety and efficacy of the BP 
using either the iLet or the iPhone platform using the glucagon analog ZP4207 versus Lilly 
glucagon. In Part 1, up to 10 patients will participate in two 1-day treatment arms in random 
order (iPhone-based BP using ZP4207 and iPhone-based BP using Lilly glucagon) according 
to a pre-generated randomization scheme. In Part 2, up to 10 new patients will participate in 
two 1-day treatment arms in random order (iLet using ZP4207 and iLet using Lilly glucagon) 
according to a pre-generated randomization scheme. Patients can only participate in 1 part of 
the trial. An interim database lock may occur upon completion of Part 1 of the trial to analyze 
the iPhone-based BP data. The iLet and the iPhone-based BP will also administer insulin 
(insulin lispro, Lilly Humalog) using the same blood glucose (BG) control algorithm for all 
4 treatment arms. The trial will be conducted at a single center, the Massachusetts General 
Hospital Diabetes Center in Boston, MA. 
TRIAL TREATMENT: The trial involves SC administration of insulin lispro (Humalog, Lilly), 
which is commercially available by prescription and is indicated for patients with T1DM, but 
not for use in a BP. 
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The trial also involves SC administration of Lilly glucagon in 1 iLet arm and 1 iPhone-based 
BP arm. Lilly glucagon is commercially available by prescription and is indicated for patients 
with T1DM in severe hypoglycemia, but not for use in a BP. 
  
The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, in the 
other iLet arm and the other iPhone-based BP arm. ZP4207 will be made available by Zealand 
Pharma A/S, Denmark as liquid formulation in prefilled syringes of 0.6 mL. 
 
PRIMARY ENDPOINT: 
The primary endpoint is the safety and tolerability of ZP4207 in the BP using either the iLet or 
the iPhone platform as assessed by: 
• 
Number and type of adverse events (AEs) 
• 
Clinical laboratory measurements 
• 
Vital signs 
• 
12-lead electrocardiogram (ECG) 
• 
Local tolerability and infusion site reactions as measured with the Draize scale 
• 
Immunogenicity as measured by anti-drug antibodies 
• 
Pain as measured on a 10 cm visual analog scale (VAS) 
• 
Nausea as measured on a 10 cm VAS 
 
SECONDARY ENDPOINTS: 
The secondary endpoints include measurements of BP function as well as glycemic and 
non-glycemic measurements. 
 
Bionic Pancreas Function 
This endpoint data will be generated from the BP data during each treatment visit: 
• 
Average percent insulin dose amounts calculated by the BP control algorithm that are 
successfully delivered by the pump 
• 
Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts successfully issued to the pump by the BP control 
algorithm that are successfully delivered by the pump (calculated doses are not issued 
unless the pump is accessible and its delivery channel is available) 
o Average percent insulin dose amounts successfully issued to the pump by the 
BP control algorithm that are successfully delivered by the pump 
o Average percent glucagon/ZP4207 dose amounts successfully issued to the 
pump by the BP control algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts calculated by the BP algorithm that are successfully 
issued to the pump by the BP (calculated doses are not issued unless the pump is 
accessible and its delivery channel is available) 
o Average percent insulin dose amounts calculated by the BP control algorithm 
that are successfully issued by the BP 
o Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully issued by the BP 
• 
Average percent of 5-minute steps during which the BP is functioning nominally in all 
respects based on real-time CGM data (new CGM glucose reading captured, dose 
calculated, and dose issued to pumps)  
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•
Average percent of 5-minute steps during which the BP is functioning nominally with
or without a new CGM glucose reading captured (dose calculated and dose issued to
pumps). If a CGM signal is not available, the dose calculated may be based on weight
or historical basal rates.
•
CGM reliability index, calculated as percent of possible values actually recorded by
CGM
•
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter
download
•
List of technical faults associated with the BP including cause and resolution
Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit: 
•
Fraction of time spent within each of the following glucose ranges:
o
<50 mg/dL
o
<60 mg/dL
o
<70 mg/dL
o
70-120 mg/dL
o
70-140 mg/dL
o
70-180 mg/dL
o
>180 mg/dL
o
>250 mg/dL
o
>300 mg/dL
•
Number of severe hypoglycemic events (patients unable to self-treat, requiring the
assistance of another person)
•
Number of episodes of symptomatic hypoglycemia
•
Number of carbohydrate interventions for hypoglycemia
•
Total grams of carbohydrates taken for hypoglycemia
•
Mean CGM glucose
Non-glycemic 
•
Glucagon/ZP4207 total delivery per kg of body mass
•
Insulin total delivery per kg of body mass
•
Number of unscheduled infusion set replacements
•
Number of unscheduled CGM sensor changes
EVALUATION OF TRIAL DATA: The following variables will be evaluated according to 
treatment for safety purposes: AEs, local tolerability, laboratory safety assessments, physical 
examination, vital signs, and 12-lead ECGs.  
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
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A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow. 
  
SPONSOR: 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Tel: +45 88 77 36 00 
Fax: +45 88 77 38 98 
 
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TABLE OF CONTENTS 
SIGNATURE PAGE ............................................................................................................. 2 
INVESTIGATOR AGREEMENT .......................................................................................... 3 
SYNOPSIS ........................................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................... 8 
LIST OF FIGURES ............................................................................................................ 11 
LIST OF ABBREVIATIONS .............................................................................................. 12 
1 
INTRODUCTION AND BACKGROUND INFORMATION ...................................... 14 
1.1 
Background and Rationale ..................................................................................... 14 
1.2 
Bihormonal Bionic Pancreas System ..................................................................... 15 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System ........................ 16 
1.4 
ZP4207 ................................................................................................................... 18 
1.5 
Risk/Benefit ............................................................................................................ 19 
2 
TRIAL OBJECTIVES .............................................................................................. 22 
2.1 
Primary Objective ................................................................................................... 22 
2.2 
Secondary Objectives ............................................................................................. 22 
3 
TRIAL DESCRIPTION ............................................................................................ 22 
3.1 
Summary of Trial Design ........................................................................................ 22 
3.2 
Indication ................................................................................................................ 23 
3.3 
Number of Patients ................................................................................................. 23 
4 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................ 23 
4.1 
Inclusion Criteria ..................................................................................................... 24 
4.2 
Exclusion Criteria .................................................................................................... 24 
4.3 
Target Population ................................................................................................... 26 
4.4 
Withdrawal Criteria ................................................................................................. 26 
5 
ASSIGNMENT TO TREATMENT GROUPS........................................................... 26 
6 
TRIAL TREATMENT .............................................................................................. 27 
6.1 
Investigational Medicinal Products ......................................................................... 27 
6.2 
Storage and Drug Accountability of IMPs ............................................................... 27 
6.3 
Dispensing and Return of IMPs .............................................................................. 27 
6.4 
Doses ..................................................................................................................... 28 
6.5 
iPhone-based Bionic Pancreas .............................................................................. 28 
6.6 
iLet Bionic Pancreas ............................................................................................... 29 
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6.7 
Other Trial Devices ................................................................................................. 30 
6.8 
Concomitant Medications ....................................................................................... 30 
6.8.1 
Permitted Medications and/or Procedures ...................................................... 30 
6.8.2 
Excluded Medications and/or Procedures ....................................................... 31 
7 
TRIAL PROCEDURES ........................................................................................... 31 
7.1 
Informed Consent ................................................................................................... 31 
7.2 
Screening Visit (Visit 1) .......................................................................................... 31 
7.2.1 
Data Collected at Screening ............................................................................ 32 
7.3 
Training Visit (Visit 2) .............................................................................................. 32 
7.4 
Treatment Visits (Visit 3 and Visit 4) ....................................................................... 32 
7.4.1 
Visit Procedures .............................................................................................. 33 
7.4.2 
Data Collected During the Treatment Visits .................................................... 36 
7.4.3 
Response to Hypoglycemia ............................................................................. 37 
7.4.4 
Response to Hyperglycemia ........................................................................... 37 
7.4.5 
Response to Nausea/Vomiting ........................................................................ 37 
7.4.6 
Response to Other Medical Needs ................................................................. 38 
7.4.7 
Monitoring of Bionic Pancreas Performance ................................................... 38 
7.4.8 
Supervision by Trial Staff ................................................................................ 38 
7.5 
Phone Call (Visit 5) ................................................................................................. 38 
7.6 
Follow-up Visit (Visit 6) ........................................................................................... 38 
8 
ENDPOINTS ........................................................................................................... 38 
8.1 
Primary Endpoint .................................................................................................... 38 
8.2 
Secondary Endpoints ............................................................................................. 38 
8.2.1 
Bionic Pancreas Function ................................................................................ 39 
8.2.2 
Glycemic .......................................................................................................... 39 
8.2.3 
Non-glycemic ................................................................................................... 40 
9 
LABORATORY ASSESSMENTS ........................................................................... 40 
9.1 
Safety Laboratory Assessments ............................................................................. 40 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) .............................................. 40 
9.3 
Exposure Assessments (ZP4207 and Glucagon) ................................................... 40 
9.4 
Anti-drug Antibody Assessments ............................................................................ 40 
10 
SAFETY REPORTING ............................................................................................ 41 
10.1 
Adverse Events ...................................................................................................... 41 
10.1.1 
Follow-up of Adverse Events ........................................................................... 41 
10.1.2 
Precautions ..................................................................................................... 42 
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10.1.3 
Assessment of Adverse Events by the Investigator ........................................ 42 
10.2 
Serious Adverse Events ......................................................................................... 43 
10.3 
Adverse Event Reporting – Procedures for Investigators ....................................... 43 
10.4 
Pregnancy Reporting .............................................................................................. 45 
10.5 
Hypoglycemia ......................................................................................................... 46 
10.6 
Safety Monitoring .................................................................................................... 46 
10.6.1 
Data and Safety Monitoring Board .................................................................. 46 
10.6.2 
Zealand Pharma Safety Committee ................................................................ 47 
11 
STATISTICS ........................................................................................................... 47 
11.1 
Analysis Populations .............................................................................................. 47 
11.2 
Statistical Methods ................................................................................................. 48 
11.2.1 
Analysis of Safety ............................................................................................ 48 
11.2.2 
Analysis of Efficacy ......................................................................................... 49 
11.2.3 
Interim Analysis ............................................................................................... 49 
11.2.4 
Sample Size Determination ............................................................................. 49 
12 
DATA MANAGEMENT AND RECORD KEEPING ................................................ 49 
12.1 
Data Handling ......................................................................................................... 49 
12.2 
Computer Systems ................................................................................................. 50 
12.3 
Data Entry ............................................................................................................... 50 
12.4 
Medical Information Coding .................................................................................... 50 
12.5 
Data Validation ....................................................................................................... 50 
12.6 
Record Keeping ...................................................................................................... 50 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ........................... 50 
13.1 
Ethical Conduct of the Trial .................................................................................... 50 
13.2 
Institutional Review Board ...................................................................................... 51 
13.3 
Informed Consent ................................................................................................... 51 
13.4 
Trial Monitoring Requirements ............................................................................... 52 
13.5 
Disclosure of Data .................................................................................................. 52 
13.6 
Retention of Records .............................................................................................. 52 
13.7 
Publication Policy ................................................................................................... 53 
13.8 
Legal Aspects ......................................................................................................... 53 
13.9 
Sponsor Discontinuation Criteria ............................................................................ 54 
13.10 
Patient Compensation ......................................................................................... 54 
14 
TRIAL ADMINISTRATIVE INFORMATION ............................................................ 54 
14.1 
Protocol Amendments ............................................................................................ 54 
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14.2 
Address List ............................................................................................................ 55 
14.2.1 
Sponsor ........................................................................................................... 55 
14.2.2 
Supplier of Device ........................................................................................... 55 
14.2.3 
Principal Investigator (Site) ............................................................................. 55 
14.2.4 
Contract Research Organization (Including Monitoring) ................................. 55 
14.2.5 
Medical Monitoring .......................................................................................... 55 
14.2.6 
Pharmacovigilance .......................................................................................... 56 
14.2.7 
Central Laboratory (Safety Laboratory and Plasma Glucose) ......................... 56 
14.2.8 
Special Laboratory (ZP4207 Exposure and ADA Analyses) ........................... 56 
14.2.9 
Special Laboratory (Glucagon Exposure) ....................................................... 56 
15 
REFERENCES ........................................................................................................ 57 
APPENDIX A: SCHEDULE OF PROCEDURES – PARTS 1 AND 2 ................................ 58 
APPENDIX B: CLINICAL LABORATORY ANALYTES ................................................... 60 
APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES ....................................... 61 
LIST OF FIGURES 
Figure 1. 
Outpatient Results Summarizing the Distribution of Mean CGM Glucose 
Levels and Hypoglycemia in the BP and Control Arms ............................. 17 
Figure 2. 
Trial Design Schematic ................................................................................. 23 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
BG 
Blood glucose 
BP 
Bionic pancreas 
BTLE 
Bluetooth Low Energy 
BU 
Boston University 
CFR 
Code of Federal Regulations 
CGM 
Continuous glucose monitor 
CRO 
Contract research organization 
DBR 
Database review 
DPP-4 
Dipeptidyl peptidase-4 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FHD 
First Human Dose 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GUI 
Graphical user interface 
HCG 
Human chorionic gonadotropin 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IV 
Intravenous 
MD 
Doctor of Medicine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH 
Massachusetts General Hospital 
MPC 
Model-predictive control 
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Abbreviation 
Definition 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
RN 
Registered nurse 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SGLT-2 
Sodium-glucose co-transporter-2 
SIV 
Site Initiation Visit 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 diabetes mellitus 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background and Rationale 
To date, clinical trials conducted by Boston University (BU) and Massachusetts General 
Hospital (MGH) in patients with type 1 diabetes mellitus (T1DM) have demonstrated the 
practicality of a wearable automated bionic pancreas (BP) control system for robust glucose 
regulation using a continuous glucose monitor (CGM) to provide the input to the control 
system. Despite current technical limitations in CGMs and infusion pumps, the trials by 
BU/MGH have shown that a bihormonal BP is capable of achieving safe and effective blood 
glucose (BG) control automatically, with minimal hypoglycemia during 11 continuous days in 
the face of unrestrained meals and exercise and with trivial patient input (optional 
announcement of meals).  
 
The BP provides automatic BG regulation and reduces hypoglycemic episodes. Additionally, 
the system spares the wearer the relentless tasks of carbohydrate counting, frequent BG 
monitoring, estimating the effects of specific meals and exercise activity on BG levels, and 
manual drug administration, which are inexact, demanding, aggravating, and require 
continuous diligence and vigilance. The degree of glycemic control achieved by the BP is 
predicted to dramatically reduce the deleterious and debilitating complications of T1DM. 
 
In its last tested embodiment, the BP consisted of a Dexcom G4 CGM, and an iPhone that are 
hardwired together, with the iPhone running the control algorithm and communicating via 
Bluetooth with 2 Tandem t:slim pumps to dose insulin and glucagon. The connections are 
repeatedly lost among these 4 components throughout the day, an issue that has the potential 
to adversely impact BG control, whether due to missed CGM values or missed doses. In 
addition, the troubleshooting required to repair these recurring disconnections can be 
burdensome to the user. Integrating these components into a single device would establish 
seamless connectivity among them, which would eliminate the need for such troubleshooting. 
This would lead to smoother device operation with fewer interruptions, which would enhance 
its user friendliness, optimize its BG control potential, and further improve the quality of life of 
its users.  
 
The BU Investigators have recently designed, built, and tested a proprietary first-generation 
of such a fully integrated BP system, referred to as the iLet and the iLet infusion set. The iLet 
is a dual-chamber infusion system that currently incorporates the Dexcom G4 CGM 
technology, a custom user interface with touchscreen display, and all of the mathematical 
dosing algorithms that were tested in and validated using the iPhone-based BP in outpatient 
studies over the past 3 years. The iLet infusion set provides 2 independent subcutaneous (SC) 
fluid pathways from the iLet to the patient (1 for insulin and the other for glucagon). One tube 
connects to the prefilled insulin cartridge and the other tube connects to the fillable (single-use) 
glucagon cartridge. 
 
In order to provide automatic BG regulation, the iLet and the iPhone-based BP have the ability 
to deliver both insulin and glucagon. However, currently available glucagon formulations have 
limited stability at room temperature, necessitating frequent changes to the glucagon infusion 
set. Therefore, the current trial is designed to test the glucagon analog ZP4207 in the iLet and 
the iPhone-based BP, as this peptide analog of human glucagon is provided in a liquid 
formulation stable at room temperature. 
 
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The current trial is a first feasibility trial designed to use the first-generation iLet and iLet 
infusion set and the iPhone-based BP to compare ZP4207 with marketed glucagon (Lilly). The 
trial is intended to demonstrate the safety and tolerability of ZP4207 in the iLet and the 
iPhone-based BP and the feasibility of achieving comparable autonomous glycemic control. It 
is not intended to comprehensively demonstrate the definitive efficacy of the BP in extended, 
continuous daily use, but rather to demonstrate its functionality and accuracy in a practical, 
albeit very controlled, clinical setting. The trial is expected to provide practical information that 
will benefit the design of a next-generation iLet and iLet infusion set and help pave the way for 
a more comprehensive outpatient home-use Phase 2 trial and ultimately a pivotal trial where 
comprehensive safety and efficacy through continuous full daily use of the iLet with ZP4207 
will be documented. 
The data derived from this trial will permit evaluation of the robustness of the iLet as well as 
the safety and efficacy of ZP4207 when used in conjunction with the iLet and the iPhone-based 
BP. The data obtained will be used to further improve the iLet and will allow BU/MGH to 
expand to larger outpatient trials using the iLet or the iPhone-based BP with ZP4207.  
1.2 
Bihormonal Bionic Pancreas System 
The BP is an autonomous, self-learning system that requires only the patient's weight for 
initialization, and then autonomously adapts, modestly or dramatically, as needed, to cope 
with the wide range of insulin requirements of adults, adolescents, and pre-adolescents with 
T1DM. The BP obviates the need for the patient to know, or even appreciate, their insulin 
requirements, and renders obsolete any need for patients or caregivers to know 
carbohydrate-to-insulin ratios, basal rates, or insulin correction factors. 
The core technology is a suite of control algorithms that orchestrate the automated dosing of 
insulin and glucagon to regulate BG levels. An insulin controller orchestrates all SC insulin 
dosing. At its centerpiece is a model-predictive control (MPC) algorithm, which bases insulin 
doses on the glucose data and insulin absorption kinetics, compensating for the slow 
absorption rate of SC insulin analogs (peak time in blood of 30-90 min, clearance in 4-8 hr). 
This enables the algorithm to refrain from stacking and overdosing insulin. Furthermore, the 
MPC algorithm automatically adjusts its insulin-dosing aggressiveness continuously and in 
real-time to different insulin needs between individuals and variable needs within the same 
individual. Running in parallel with the MPC algorithm is an algorithm that automatically 
modulates basal insulin delivery over multiple time scales, and another algorithm that 
automatically adapts insulin doses in response to optional meal announcements. Unlike 
current insulin pumps and the insulin-only control algorithms, the adaptive basal insulin 
algorithm obviates the need for the user to set, or even know, his or her “basal-rate profile.” 
Instead, it is capable of automatically adapting to, and compensating for, changes in an 
individual's basal insulin need, such as might occur over a period of hours, days, or weeks 
(e.g., circadian hormonal fluctuations, intercurrent illness, physical activity, or emotional state) 
or as might occur over a period of months or years due to developmental changes 
(e.g., hormonal changes that occur during puberty or menopause). The adaptive meal dose 
controller obviates the need for the user to set, or even know, his or her 
“carbohydrate-to-insulin ratios,” as it makes automatic adjustments based on dosing history 
for similar meal announcements made on previous days, and customizes the dose for each 
individual and for time of day.  
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The BP also includes a proportional-derivative algorithm governing SC micro-doses of 
glucagon to help prevent impending hypoglycemia. Glucagon dosing is based on the glucose 
level and rate of descent. It may occur preemptively even if glucose is above range, and it 
includes a feedback term to account for the pending effects of recent glucagon doses.  
Taken together, these mathematical algorithms provide a universal framework for a glycemic 
control strategy that requires no quantitative input from, or participation by, the user (besides 
entering body weight to initialize the system), but which automatically adapts insulin and 
glucagon dosing to meet the individual needs of each user. Another challenge met is enabling 
the technology to remain completely autonomous in managing insulin and glucagon delivery 
even when the CGM is offline. Specifically, when the CGM is offline, the BP invokes the 
high-resolution “basal rate profile” that it had recently learned and stored when the CGM was 
online. On the basis of what the system learned and stored about meal announcements when 
the CGM was online, it is able to respond to meal announcements in the same manner when 
the CGM is offline. Finally, it automatically responds to user-entered BG values when the CGM 
is offline by issuing a correction dose of insulin or glucagon based on what it learned about 
the user's insulin and glucagon needs when the CGM was online. Thus, the BP never relies 
on, or burdens the user with, the determination of subjective dosing decisions, which inevitably 
vary in quality and reliability among different users. The BP provides a turnkey solution for 
people with T1DM that comprehensively manages glycemia across a broad range of individual 
needs and across a large spectrum of circumstances and challenges to glycemic control. 
A significant challenge for the use of glucagon in a bihormonal BP is the lack of a commercially 
available glucagon formation that is stable and well-suited to infusion over several days in a 
pump reservoir. However, BU/MGH have proceeded with studies using a relatively unstable 
marketed formulation that must be reconstituted from a lyophilized powder on a daily basis. 
This allowed BU/MGH to proceed with studies of the bihormonal system while awaiting the 
production of stable glucagon formulations or stable glucagon analogs. 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System 
The BP hardware platform has evolved over the years from a laptop-driven system, which was 
used in all inpatient studies to the first truly mobile wearable iPhone-driven platform, which 
has been used in a number of outpatient studies. Using the iPhone-based BP system, 
>110 outpatient experiments of 5-11 days in duration in each subject have been conducted 
(>800 patient days or >2 patient years of data) across subjects ranging in age between 6 and 
76 years old and in body mass between 21 and 128 kg. The robust adaptation capabilities of 
the BP is evident in the fact that the average total daily dose of insulin among these subjects 
varied by over 13-fold (from 11 to 145 units/day). 
In November 2012, Food and Drug Administration (FDA) approval was obtained to conduct 
the first outpatient study testing the BP in adults 21 years or older with T1DM. This study, 
referred to as the Beacon Hill Study, followed a random-order cross-over design in which 
20 adults with T1DM participated in 5 days on the iPhone-based BP and 5 days of usual care 
in which they wore a CGM with blinded display and muted alarms. In the BP arm, subjects 
kept to a 3-square-mile geographic area centered around the Beacon Hill neighborhood in 
Boston. They ate as they chose at local restaurants, and exercised at will with access to 
2 gyms. Analysis was pre-specified to focus on Days 2-5, since glycemic control is more 
representative of BP performance after most of the adaptation by the BP occurs on Day 1 
(Russell, 2014). Results are summarized in Figure 1.  
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In April 2013, FDA approval was obtained to conduct the first outpatient study testing the BP 
in adolescents 12-20 years old with T1DM. This study, referred to as the 2013 Summer Camp 
Study, followed a random-order cross-over design in which 32 adolescents with T1DM 
participated in 5 days on the BP and 5 days of supervised camp care in which they wore a 
CGM with blinded display and muted alarms. Subjects were fully integrated into normal camp 
activities without restrictions on diet or exercise. The study used the same iPhone-based BP 
that was used in the Beacon Hill Study. Results are summarized in Figure 1 (Russell, 2014). 
In April 2014, FDA approval was obtained to conduct the first outpatient study testing the BP 
in pre-adolescents 6-11 years old with T1DM. This study, referred to as the 2014 Summer 
Camp Study, was similar in design to the 2013 Summer Camp Study. Results are summarized 
in Figure 1 (Russell, 2016).  
 
In April 2014, FDA approval was obtained to conduct the first multi-center study, which was 
also the first home study, to test the BP in adults 18 years or older with T1DM. This study, 
referred to as the Bionic Pancreas Multi-Center Study, followed a random-order cross-over 
design in which 39 adults participated in 11 days on the BP and 11 days of usual care. 
Participants went to work as usual, and lived and slept at home, all without clinical supervision. 
There were no restrictions placed on diet or exercise. The study included 4 medical centers 
(10 subjects per center), which included MGH, the University of Massachusetts Medical 
School, Stanford University, and the University of North Carolina at Chapel Hill. Results are 
summarized in Figure 1.  
 
All of these studies used marketed glucagon (glucagon for injection, Eli Lilly). Due to its limited 
stability, Lilly glucagon must be reconstituted immediately before use. Animal studies have 
previously shown that despite its limited chemical stability, Lilly glucagon maintains its 
biological activity for up to 7 days in solution. Using this data, an Investigational New Drug 
(IND) exemption was obtained from the FDA for its use in a pump for up to 27 hours. This 
allowed these studies to be performed by asking volunteers to reconstitute a new vial of 
glucagon and fill the glucagon pump at approximately the same time every day. However, 
marketed Lilly glucagon has no path forward for approval for chronic BP use. 
 
1.4 
ZP4207 
ZP4207 is a peptide analog of human glucagon that is being developed to treat hypoglycemia 
in patients with T1DM and type 2 diabetes mellitus. ZP4207 exhibits improved physical and 
chemical stability in aqueous media and is suitable for liquid formulation. ZP4207 is comprised 
of 29 amino acids and has 7 amino acid substitutions when compared to native glucagon.  
 
Two clinical Phase 1 trials have been conducted to establish safety and tolerability of ZP4207 
after single and multiple dosing to healthy patients and T1DM patients under insulin-induced 
hypoglycemic conditions. 
 
The First Human Dose (FHD) trial (ZP4207-14013) was finalized in April 2015. The trial was 
a randomized, double-blinded trial with the objectives to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of ZP4207 as compared to an active 
comparator. Part 1 included a single ascending dose in healthy volunteers in cohorts of 8. In 
each cohort, the patients were randomized 3:1 to ZP4207 (n=6) or Novo Nordisk GlucaGen® 
(n=2). Five cohorts with SC administration (0.01, 0.1, 0.3, 1.0, and 2.0 mg ZP4207 compared 
to 1 mg GlucaGen) and 3 cohorts with intramuscular (IM) administration (0.3, 1.0, and 2.0 mg 
ZP4207 compared to 1 mg GlucaGen) were included. Part 2 included 2 sequence groups of 
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10 hypoglycemic T1DM patients. The patients were treated with fixed single IM doses of 
0.7 mg ZP4207 and 1.0 mg GlucaGen in a sequential cross-over design in a randomized 
treatment order.  
The second clinical trial (ZP4207-15007) was a single-center, double-blind, Phase 1b trial 
investigating the safety and tolerability, PK and PD of ZP4207 following repeated 
administration in healthy volunteers compared to placebo. It was finalized in July 2015. Each 
of the 3 cohorts comprised 8 subjects, who received 5 repeated SC doses of ZP4207 or 
placebo in a 3:1 treatment allocation. The first cohort started with the lowest dose of 0.1 mg. 
Cohort 2 and 3 continued with 0.3 and 1.0 mg, respectively. 
The Phase 1 results did not give rise to specific safety concerns, beyond those related to the 
pharmacological effect of ZP4207. All adverse events (AEs) recorded in the trials were of mild 
or moderate severity. The most frequent systemic AE related to treatment with ZP4207 was 
nausea, which is a known side-effect following administration of glucagon. The most frequent 
injection site reaction was transient erythema, occurring in all ZP4207, glucagon, and placebo 
treatment groups, irrespective of dose. No anti-drug antibodies (ADA) incidences were 
observed. 
The observed PD response, in terms of increased plasma glucose, in insulin-induced 
hypoglycemic patients with T1DM following dosing with 0.7 mg ZP4207 administered IM was 
similar to that observed following IM dosing with 1.0 mg glucagon (GlucaGen, Novo Nordisk). 
An increase in plasma glucose of ≥20 mg/dL from hypoglycemic levels was achieved within 
30 minutes for all patients. 
In terms of PK, ZP4207 had a short half-life and high clearance and dose proportionality for 
both maximum plasma concentration and area under the concentration-time curve from 
time 0 to 300 minutes in the dose range 0.1 to 2.0 mg following SC administration. Following 
IM administration, dose proportionality was shown in the investigated dose range of 0.3 to 
2.0 mg. The PK properties of 0.7 mg ZP4207 IM were comparable with those of 1.0 mg 
glucagon (GlucaGen, Novo Nordisk) with IM administration. 
1.5 
Risk/Benefit 
While the potential risks are minimal, the findings of this trial may reveal information that can 
substantially improve medical care for persons with diabetes. Therefore, the overall 
risk/benefit for patients participating in this trial is assessed as acceptable. 
Potential Risks and Discomforts  
Trial patients will be informed by the Investigator of the potential risks of ZP4207 and other 
trial-related procedures before they enter the trial.  
In this trial, patients with T1DM will be included to test the safety and efficacy of the BP using 
either the iLet or the iPhone platform when used with ZP4207 versus Lilly glucagon. The 
cross-over design with inclusion of 1 group of 10 T1DM patients into the 2 iLet treatment arms 
and the inclusion of a second group of 10 T1DM patients into the 2 iPhone-based BP treatment 
arms in a randomized order will allow for a direct comparison of the safety and efficacy of the 
2 treatments, based on intra-patient variability only.  
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Patients may experience mild discomfort associated with the insertion of the infusion sets and 
sensor into the SC tissues. The risk of discomfort due to insertion of infusion sets and sensors 
is expected to be slightly greater than in their lives outside the trial because more infusion sets 
will be inserted and a CGM sensor will be inserted. Most patients will use only 1 infusion set 
and not all will use a CGM sensor in usual care.  
 
There is a potential risk of hypoglycemia, since recombinant insulin analog will be 
administered. Due to frequent monitoring of glucose and direct supervision by a registered 
nurse (RN) or Doctor of Medicine (MD) at all times, the risk of a hypoglycemic episodes leading 
to significant harm to patients is expected to be substantially lower than their risk during their 
usual therapy.  
 
There is a risk of hyperglycemia. This risk is expected to be less than the risk during the 
patients’ lives outside of the trial based on data from earlier BP trials and the design of this 
trial.  
 
Treatment with ZP4207 and marketed glucagon can result in undesired effects or complaints. 
Undesired effects and complaints such as gastrointestinal side effects including nausea, 
vomiting, and diarrhea are known side effects of glucagon administration at higher dose levels. 
The frequency of nausea associated with the administration of 1 mg of glucagon according to 
the Summary of Product Characteristics (SPC) for Glucagon is described to be between 1/10 
and 1/100. The frequency of vomiting is described to be between 1/100 and 1/1000 
(Novo Nordisk, 2015). Similar gastrointestinal side effects have also been observed to a 
limited degree in the 2 clinical trials conducted with ZP4207, again at higher dose levels. The 
individual doses of ZP4207 and Lilly glucagon delivered by the BP are expected to be 
significantly lower than doses typically associated with nausea. Episodes of low blood 
pressure have also been observed after administration of higher doses of glucagon and 
ZP4207. As with every novel drug substance, new and yet unknown side effects may also 
occur. 
 
There are limited data available to describe the immunogenic potential of glucagon products 
available on the market, but the data available indicate that marketed glucagon only has a 
small immunogenic potential. A Phase 1 trial performed with recombinant human glucagon 
and animal derived glucagon in 75 healthy patients did not show signs of ADA measured 
13 weeks after trial product administration (Eli Lilly, 2005). In the ZP4207 FHD trial, 
ZP4207-14013, no confirmed anti-ZP4207 or anti-glucagon antibodies were detected in any 
of the samples. In addition, the 5 sequential administrations of ZP4207, as applied in trial 
ZP4207-15007, were not associated with the development of antibodies against ZP4207 in 
the 18 subjects enrolled to receive ZP4207. The optimized formulation of ZP4207, as applied 
in the present trial is not expected to change the immunogenic potential of the Investigational 
Medicinal Product (IMP).  
 
In relation to diabetes therapy, development of insulin-antibodies is documented more 
substantially and route of administration has been shown to influence immunogenic potential 
of insulins. However, these antibodies against insulin generally do not have an impact on 
insulin action and are thus not clinically relevant. 
 
In terms of consequence, development of high titer antibodies against ZP4207 could, in theory 
reduce the activity of endogenous glucagon, which again, in theory could influence 
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hypoglycemic episodes. However, most patients with T1DM do not secrete glucagon normally 
in response to hypoglycemia, so they would be less likely to be negatively impacted by 
anti-glucagon antibodies. Limited suppression of glucagon would, however, not be considered 
critical, as low glucose levels can also be corrected by other means, including oral intake of 
glucose and by other endogenous hormones such as oxyntomodulin.  
 
Overall, ZP4207 is judged to be a low-risk molecule, based upon the available clinical data as 
well as the outcome of the risk-based approach to the immunogenicity assessment made. The 
present trial will include sampling for measurement of antibodies against ZP4207 prior to first 
dosing (Visit 3) and at the Follow-up Visit. In line with regulatory guidance documents, these 
samples will be appropriately analyzed and the results will be included in the overall 
assessment of the immunogenic potential of ZP4207 after completion of each trial and as the 
clinical development program advances. 
 
Administration of ZP4207 may be associated with a risk of allergic reactions similar to those 
observed for other therapeutic peptides or proteins. Patients with known or suspected allergies 
to the trial products or related products will be excluded from the trial. Mild or moderate allergic 
reactions may include symptoms of rash, fever, flu-like symptoms, nausea, headache, and 
myalgia. Acute generalized hypersensitivity reactions are usually very rare but may include 
symptoms of flushing, sweating, dizziness, change in blood pressure, and difficulties in 
breathing. The risk of acute hypersensitivity reactions is described to be less than 1/10,000 
for native glucagon. No severe acute hypersensitivity reactions have been observed in the 
2 clinical trials conducted with ZP4207.  
 
Potential Benefits 
 
Based on experiences from previous trials of the BP and the design of this trial, patients 
enrolled in the trial may benefit from a reduction in risk of hypoglycemia and hyperglycemia 
and a better mean glucose compared to their usual diabetes care during their short trial 
participation.  
 
The data derived from this trial will allow evaluation of safety and tolerability of ZP4207 in the 
iLet and the iPhone-based BP, and the robustness and effectiveness of the new BP control 
system. The data obtained will be used to further improve the iLet and will allow the expansion 
to larger outpatient trials using the iLet or the iPhone-based BP with ZP4207.  
 
This trial is a necessary step in preparing the BP with ZP4207 to become available to people 
with T1DM. Wide availability of the BP with ZP4207 could improve the medical care of adults 
and children with T1DM. 
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2 
TRIAL OBJECTIVES  
2.1 
Primary Objective  
The primary objective is to conduct a trial testing the safety and tolerability of the BP using 
either the iLet or the iPhone platform when used with ZP4207 in 20 adult (≥18 years of age) 
patients with T1DM. 
 
2.2 
Secondary Objectives  
The secondary objectives are to measure glycemic regulation, including hypoglycemia 
exposure (percent of time spent with CGM glucose <60 mg/dL), evaluate BP device reliability, 
and to document the satisfaction of patients with the BP with the goal of optimizing the 
functionality and user interface of the BP. 
3 
TRIAL DESCRIPTION  
3.1 
Summary of Trial Design  
This trial is a single-center, open-label, 2-part, randomized cross-over trial. The trial will enroll 
adult patients with T1DM and will assess the safety and efficacy of the BP using either the iLet 
or the iPhone platform using the glucagon analog ZP4207 versus Lilly glucagon. In Part 1, up 
to 10 patients will participate in two 1-day treatment arms in random order (iPhone-based BP 
using ZP4207 and iPhone-based BP using Lilly glucagon) according to a pre-generated 
randomization scheme. In Part 2, up to 10 new patients will participate in two 1-day treatment 
arms in random order (iLet using ZP4207 and iLet using Lilly glucagon) according to a 
pre-generated randomization scheme. Patients can only participate in 1 part of the trial. An 
interim database lock may occur upon completion of Part 1 of the trial to analyze the 
iPhone-based BP data. The iLet and the iPhone-based BP will also administer insulin (insulin 
lispro, Lilly Humalog) using the same BG control algorithm for all 4 treatment arms. The trial 
will be conducted at a single center, the MGH Diabetes Center in Boston, MA. 
 
The overall trial design schematic is displayed in Figure 2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 2. 
Trial Design Schematic 
Part 1: 
Part 2: 
Patients can only participate in 1 part of the trial. 
BP = bionic pancreas. 
3.2 
Indication 
ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid formulation which 
is being studied to improve glycemic control in adults (and children) with T1DM as part of a 
bihormonal BP. 
3.3 
Number of Patients 
Up to 40 adult patients with T1DM can be enrolled. The upper bound is based on the 
expectation that some patients will be excluded after the Screening Visit and the possibility 
that some patients may have to be discontinued before completion (due to, for instance, 
inter-current illness or patient withdrawal). It is expected that up to 10 patients will complete 
each part of the trial protocol. 
4 
SELECTION AND WITHDRAWAL OF PATIENTS 
The trial will enroll patients who already manage their T1DM using continuous SC insulin 
infusion pump therapy. This requirement is imposed because multiple daily injection therapy 
involves the use of medium-acting or long-acting basal insulin that would require an extended 
washout period. 
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4.1 
Inclusion Criteria 
1.
Male and female patients with T1DM for at least 1 year, as defined by the American
Diabetes Association
2.
Age ≥18 years
3.
Diabetes managed using an insulin pump for ≥6 months
4.
Prescription medication regimen stable for >1 month (except for medications that will
not affect the safety of the trial and are not expected to affect any outcome of the trial,
in the judgment of the Investigator)
5.
Informed consent obtained before any trial-related activities (trial-related activities are
any procedure that would not have been performed during normal management of the
patient)
6.
Patients in good health according to age (medical history, physical examination, vital
signs, 12-lead electrocardiograms [ECGs], laboratory assessments), as judged by the
Investigator
4.2 
Exclusion Criteria  
1.
Unable to provide informed consent (e.g., impaired cognition or judgment)
2.
Unable to safely comply with trial procedures and reporting requirements
(e.g., impairment of vision or dexterity that prevents safe operation of the BP, impaired
memory, unable to speak and read English)
3.
Participation in another clinical trial of an investigational agent or device concurrently
or within 1 month (or 5 half-lives) prior to the Screening Visit
4.
Previous exposure to ZP4207
5.
Females of childbearing potential who are pregnant (positive urine human chorionic
gonadotropin [HCG]), breast feeding, plan to become pregnant in the immediate future,
or sexually active without using highly effective contraception methods (highly effective
methods are considered those with a failure rate less than 1% undesired pregnancies
per year including surgical sterilization, hormonal intrauterine devices [coil], oral
hormonal contraceptives, sexual abstinence, or a surgically sterilized partner) or
postmenopausal 
women 
amenorrheic 
for 
less 
than 
1 year 
with 
serum
follicle-stimulating hormone (FSH) level ≤40 IU/L and not using highly effective
contraceptive methods during the trial and until 1 month after last dosing in the trial
6.
Male who is sexually active and not surgically sterilized who or whose partner(s) is not
using highly effective contraceptive methods (highly effective contraceptive measures
include surgical sterilization, hormonal intrauterine devices [coil], oral hormonal
contraceptives, each in combination with spermicide-coated condoms), or who is not
willing to refrain from sexual intercourse from the first dosing until 1 month after last
dosing in the trial
7.
Current alcohol abuse (intake averaging >3 drinks daily in last 30 days) or use within
the last 6 months of controlled substances without a prescription (other than marijuana)
8.
New onset clinically significant illness within 4 weeks prior to screening, as judged by
the Investigator
9.
Unwilling or unable to refrain on the treatment visits from:
a.
Acetaminophen in any form
b.
Use of drugs that may dull the sensorium, reduce sensitivity to symptoms of
hypoglycemia, or hinder decision making during the period of participation in
the trial (use of beta blockers will be allowed as long as the dose is stable and
the patient does not meet the criteria for hypoglycemia unawareness while
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taking that stable dose, but use of benzodiazepines or narcotics, even if by 
prescription, may be excluded according to the judgment of the Investigator) 
10. History of liver disease that is expected to interfere with the anti-hypoglycemia action 
of glucagon (e.g., liver failure or cirrhosis). Other liver disease (i.e., active hepatitis, 
steatosis, active biliary disease, any tumor of the liver, hemochromatosis, glycogen 
storage disease) may exclude the patient if it causes significant compromise to liver 
function or may do so in an unpredictable fashion. 
11. Aspartate 
aminotransferase >2 
× 
upper limit of 
normal (ULN), alanine 
aminotransferase >2 × ULN, or bilirubin >1.5 × ULN on screening laboratories 
12. Renal failure on dialysis or estimated glomerular filtration rate <30 mL/min/1.73 m2 on 
screening laboratories 
13. Hemoglobin <12 gm/dL for men and <11 gm/dL for women 
14. Personal history of cystic fibrosis, pancreatitis, pancreatic tumor, or any other 
pancreatic disease besides T1DM 
15. Any known history of coronary artery disease including, but not limited to, history of 
myocardial infarction, stress test showing ischemia, history of angina, or history of 
intervention such as coronary artery bypass grafting, percutaneous coronary 
intervention, or enzymatic lysis of a presumed coronary occlusion) 
16. Congestive heart failure with New York Heart Association Functional Classification III 
or IV  
17. History of transient ischemic attack or stroke in the last 12 months 
18. Seizure disorder, history of any non-hypoglycemic seizure within the last 2 years, or 
ongoing treatment with anticonvulsants 
19. History of hypoglycemic seizures (grand-mal) or coma in the last 12 months 
20. History of hypoglycemic unawareness in the last 12 months 
21. History of pheochromocytoma: fractionated metanephrines will be tested in patients 
with history increasing the risk for a catecholamine secreting tumor: 
a. Episodic or treatment refractory (requiring 4 or more medications to achieve 
normotension) hypertension 
b. Paroxysms of tachycardia, pallor, or headache 
c. Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or 
von Hippel-Lindau disease 
22. History of adrenal disease or tumor 
23. Hypertension with systolic blood pressure ≥160 mm Hg or diastolic blood pressure 
≥100 mm Hg despite treatment 
24. Untreated or inadequately treated mental illness (indicators would include symptoms 
such as psychosis, hallucinations, mania, and any psychiatric hospitalization in the last 
year), or treatment with anti-psychotic medications that are known to affect glucose 
regulation 
25. Electrically powered implants (e.g., cochlear implants, neurostimulators) that might be 
susceptible to radio frequency interference 
26. History of adverse reaction to glucagon (including allergy) besides nausea and 
vomiting 
27. History of severe hypersensitivity to milk proteins or lactose 
28. Established history of allergy or severe reaction to adhesive or tape that must be used 
in the trial 
29. Use of oral anti-diabetic medications (e.g., thiazolidinediones, biguanides, 
sulfonylureas, glitinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose 
co-transporter-2 [SGLT-2] inhibitors) 
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30. Inadequate venous access as determined by trial nurse or physician at time of 
screening 
31. Any factors that, in the opinion of the Investigator, would interfere with trial endpoints 
or the safe completion of the trial  
 
4.3 
Target Population  
Patients who meet all of the inclusion and none of the exclusion criteria will be considered as 
candidates for this trial. Individuals who have previously inquired about participation in 
BU/MGH trials and have asked to have their contact information kept on file will be contacted. 
In addition, advertisements for the trial may be posted at the MGH Diabetes Center and other 
places, and may be distributed in the weekly broadcast e-mail of research studies seeking 
volunteers. A letter may be sent to adult endocrinologists in the Boston metropolitan as well 
as selected nearby endocrinologists informing them of the trial and asking them to refer any 
eligible patients who might be interested. Information will be posted about the trial along with 
contact 
information 
on 
the 
BU/MGH 
website 
www.bionicpancreas.org 
and 
on 
www.clinicaltrials.gov. 
  
4.4 
Withdrawal Criteria  
The participation of individual patients will be discontinued if they experience: 
• 
Seizure or unconsciousness associated with hypoglycemia and associated with 
participation in the trial  
• 
Persistent nausea and vomiting thought to be related to glucagon dosing associated 
with participation in the trial 
• 
Hospitalization associated with participation in the trial 
• 
Pregnancy 
• 
Diabetic ketoacidosis 
 
If more than 1 patient must be withdrawn from the trial for these reasons, the trial will stop and 
a vote of the Data and Safety Monitoring Board (DSMB) will be required to restart it. All AEs 
that are serious and unexpected but related will be reported to the DSMB within 5 working 
days. 
Note that patients may discontinue participation at any time. Patients may be removed from 
the trial for other reasons, for instance, failure to comply with trial procedures or intercurrent 
illness that is unrelated to the BP but that precludes safe participation. Discontinuation of 
participation for these reasons will not contribute to a decision to discontinue the trial.  
5 
ASSIGNMENT TO TREATMENT GROUPS 
This trial is an open-label, 2-part, randomized cross-over trial. Patients who have completed 
the Screening Visit and meet all of the inclusion and none of exclusion criteria will be enrolled 
into the trial. In Part 1, up to 10 patients will participate in two 1-day treatment arms in random 
order (iPhone-based BP using ZP4207 and iPhone-based BP using Lilly glucagon) according 
to a pre-generated randomization scheme. In Part 2, up to 10 new patients will participate in 
two 1-day treatment arms in random order (iLet using ZP4207 and iLet using Lilly glucagon) 
according to a pre-generated randomization scheme. Up to 2 patients may participate in the 
trial per day. The order of the treatment visits will be randomized in blocks of 2 patients. 
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6 
TRIAL TREATMENT 
6.1 
Investigational Medicinal Products 
Insulin: The trial involves SC administration of insulin lispro (Humalog, Lilly), which is 
commercially available by prescription and is indicated for patients with T1DM, but not for use 
in a BP. 
 
Glucagon: The trial also involves SC administration of Lilly glucagon in 1 iLet arm and 
1 iPhone-based BP arm. Lilly glucagon is commercially available by prescription and is 
indicated for patients with T1DM in severe hypoglycemia, but not for use in a BP. 
  
ZP4207: The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, 
in the other iLet arm and the other iPhone-based BP arm. ZP4207 will be made available by 
Zealand Pharma A/S, Denmark as liquid formulation in prefilled syringes of 0.6 mL. 
 
6.2 
Storage and Drug Accountability of IMPs 
All IMPs will be stored and handled in accordance with the Sponsor’s instructions and/or the 
product labeling at the Investigator’s site, e.g., refrigerated (+2ºC to +8ºC) and should not be 
exposed to excessive heat, direct sunlight and never be frozen. 
 
All used, partly used, and unused vials or prefilled syringes must be kept by the Investigator 
and stored between +2ºC and +8ºC (unused) or at room temperature (partly used and used). 
Used and unused pre-filled syringes must be stored separately.  
 
The Investigator must ensure the availability of proper storage conditions and record and 
evaluate the temperature. Temperature of the refrigerator used for drug storage is monitored 
continuously, an alarm system is established. The Investigator must inform the monitor 
immediately if any IMP has been stored outside specified conditions (e.g., outside temperature 
storage). Investigational Medicinal Product that has been stored improperly must not be 
dispensed to any patient before it has been re-evaluated and approved for further use. The 
Investigator must take appropriate action to ensure correct storage. 
  
For the IMP, the Investigator must keep an accurate record of all IMPs received and the 
products used for each patient in a Drug Accountability Record. Storage locations, batch 
numbers, and expiry dates are also documented in this form. 
 
The drug accountability must be performed in a timely manner by the monitor.  
 
6.3 
Dispensing and Return of IMPs 
No IMPs may be dispensed to any person not enrolled in the trial. 
 
Upon completion of the trial, the Sponsor will be responsible for destruction or storage of IMPs 
(used, partially used, or unused). These duties can be delegated to a contract research 
organization (CRO) and must be documented in the trial files. 
 
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6.4 
Doses 
The iLet and the iPhone-based BP can administer isolated insulin-glucagon doses once every 
5 minutes. A single automated bolus of insulin will not exceed 3 units per 5-minute dose (30 µl 
of U-100 insulin) in both systems, and a single meal-priming dose, in response to a meal 
announcement made by the user, will not exceed 12 units (120 µl of U-100 insulin). A single 
bolus of glucagon will not exceed 80 µg (80 µl of 1 mg/mL Lilly glucagon or 1 mg/mL ZP4207). 
In prior studies, typical doses of glucagon were in the range of 2.5-40 µg per dose. The iLet 
and the iPhone-based BP are capable of administering as little as ~0.5 µl (0.05 units of U-100 
insulin or 0.5 µg of 1 mg/mL ZP4207). 
 
It is expected that the mean total daily doses of glucagon/ZP4207 will be <1.0 mg daily as in 
previous studies. The mean daily glucagon dose in a previous 11-day outpatient trial was 
0.5 mg/day (range 0.2-0.9 mg/day). Currently, single doses of up to 2 mg ZP4207 have been 
administered in clinical trials. The recommended dose of marketed glucagon for adult patients 
suffering from severe hypoglycemia is 1 mg as a single injection. Mean glucagon levels in 
previous inpatient studies have been above the normal fasting range for glucagon only 1% of 
the time. Therefore, the glucagon exposure of patients is expected to be modest. 
 
6.5 
iPhone-based Bionic Pancreas 
Infusion Set: Patients will wear 2 FDA-approved commercially available infusion sets, 1 for 
insulin infusion and 1 for glucagon infusion. Infusion sets that are compatible with the Tandem 
t:slim infusion pump (luer lock connection) will be provided. 
 
Continuous Glucose Monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to 
the controller. The sensor is powered by the battery within the transmitter that clips to the 
sensor and the whole assembly is held to the skin with an adhesive patch and communicates 
wirelessly with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM 
signal), it will be replaced promptly.  
 
Bionic Pancreas Control Unit: The control unit consists of a stock iPhone 4S and a Dexcom 
G4 Platinum receiver connected with a custom hardware interface and placed back-to-back 
in a custom enclosure. The G4 receiver converts the raw wireless signal from the transmitter 
into an estimated BG signal that is sent via a hardwired connection to the iPhone.  
 
 
The iPhone runs iOS 6 in “Guided Access” mode, where the only app accessible to the patient 
is the Beta Bionics app, which runs the control algorithm. The home screen, where typical user 
options reside, is password protected. Access to other functions on the iPhone (primarily the 
Settings options) is separately password protected and only accessible to the study staff. This 
prevents accidental activation of other apps that could interfere with the function of the BP. 
The control algorithm app has a graphical user interface (GUI) that displays the current CGM 
glucose, a graphical history of the CGM glucose, and doses of insulin and glucagon delivered 
by the control algorithm. The GUI can also be used to input meal announcements, designating 
the size of the meal as larger than typical, typical in size, smaller than typical, or just a bite, 
and the type of meal as breakfast, lunch, or dinner. This will trigger a partial meal-priming 
bolus the size of which will adapt during the course of the trial to meet a target of 75% of the 
insulin needs for that size and type of meal.  
 
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The target glucose level will be programmed to 100 mg/dL by the study engineers prior to the 
start of each experiment. This will be locked for each arm of the study; the patient will be 
unable to accidentally change or tamper with this setting.  
 
The GUI can be used to manage meal boluses and correction boluses during periods when 
the CGM is offline, such as the period after a sensor is replaced and before the new sensor 
has been calibrated. During these times the control algorithm will determine and direct the 
administration of insulin basal rates based on the patient's weight. The controller will also 
administer insulin and/or glucagon as appropriate in response to any entered BG values, just 
as if they were CGM values. 
 
The GUI also displays visual alarms associated with an audio signal if communication is 
dropped between the CGM transmitter and the BP control unit or between the control unit and 
the 2 insulin pumps. 
 
 
The iPhone communicates wirelessly via the Bluetooth Low Energy (BTLE) protocol with 
2 Tandem t:slim insulin pumps to deliver insulin and glucagon. 
 
Tandem t:slim Pumps: These pumps are FDA-approved insulin pumps with reservoirs 
capable of holding 300 units (3 mL) of insulin or 3 mL of glucagon or ZP4207 solution. The 
pumps have a mechanical dosing resolution of 1/120 (0.00833) unit and can deliver liquids at 
a maximal rate of ~33 µl per minute (2 mL per hour). They are slave to the BP control unit and 
are controlled wirelessly via the BTLE protocol by the iPhone 4S. 
 
6.6 
iLet Bionic Pancreas  
Infusion Set: A novel, dual cannula infusion set has been designed specifically for use with 
the iLet. Patients will wear dual channel tubing that will be attached to 2 infusion sets with 
1 steel cannula each, 1 for insulin infusion and the other for glucagon infusion. The tubing and 
infusion sets will have undergone sterilization prior to being delivered in a sealed pouch. The 
steel cannulae will be inserted in the abdominal SC tissue. 
 
Continuous Glucose Monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to 
the controller. The sensor is powered by the battery within the transmitter that clips to the 
sensor and the whole assembly is held to the skin with an adhesive patch and communicates 
wirelessly with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM 
signal), it will be replaced promptly.  
 
Bionic Pancreas Control Unit: The iLet is being built according to Class III medical device 
standards, adheres to a comprehensive and robust quality system, and is fully compliant with 
International Organization for Standardization (ISO) 13485 standards and document control 
practices. The iLet is a fully-integrated dual-hormone BP system that integrates the CGM 
technology (currently the Dexcom G4 Share system) as well as 2 independent motor-drivetrain 
pumping assemblies, which independently actuate the delivery of insulin and glucagon from 
pre-filled cartridges that are separately loaded into the iLet housing. Each drivetrain assembly 
utilizes a lead screw, which is driven by a precision micromotor, a gear case assembly, and a 
motor controller unit, in a manner similar to what is commonly found in most insulin infusion 
pumps on the market today. The iLet has dosing accuracy that is comparable to 
FDA-approved insulin pumps currently on the market. The iLet has a built-in BTLE radio that 
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also allows automatic communication with the paired CGM, as well as the Nova StatStrip® 
Xpress BG meter (Nova Biomedical). The iLet does not contain a cellular nor a WiFi radio, 
and does not accept input data from another mobile device (e.g., smartphone), other than the 
paired CGM and BG meter(s). 
 
The mathematical control algorithms (which are the same as those used in the iPhone-based 
BP), the CGM glucose engine (Dexcom), and the native user interface software, are all 
interconnected through controller framework software and reside as embedded systems on 
printed circuit boards contained within the device housing. The touchscreen-enabled, 
menu-driven user interface and onboard processor provide a comprehensive and standalone 
platform, which allows the iLet to operate independently of smartphones or other devices and 
without the need for internet support during routine operation. The graphical user interface of 
the iLet has the same user options and capabilities of the iPhone BP, including having its 
home screen password protected and its settings options only accessible to trial staff via a 
separate password. 
 
6.7 
Other Trial Devices  
YSI 2300 STAT Plus™ (Yellow Springs Instruments): The YSI 2300 STAT Plus is an 
FDA-approved glucose analyzer. Blood glucose measurements using the YSI 2300 STAT 
Plus will be obtained off of the intravenous (IV) line during both treatment visits.   
 
Nova Biomedical StatStrip Xpress Glucose Meter: The Nova StatStrip Xpress glucose 
meter is an FDA-approved glucose meter that is commercially available. Blood glucose 
measurements for CGM calibration will be obtained with the Nova StatStrip Xpress during both 
treatment visits if the YSI 2300 STAT Plus fails and via fingerstick with the Nova StatStrip 
Xpress during any periods when IV blood samples are not available for any reason or the IV 
fails. 
 
Exercise Bike: The trial will utilize a stationary exercise bike (ergometer) for the in-clinic 
exercise at the treatment visits. This bike will be stored at the Diabetes Research Center when 
not in use. 
 
6.8 
Concomitant Medications 
6.8.1 
Permitted Medications and/or Procedures  
Patients may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference with 
CGM sensing. All concomitant medications, including over-the-counter medications, should 
be recorded. 
 
Use of beta blockers will be allowed as long as the dose is stable and the patient does not 
meet the criteria for hypoglycemia unawareness while taking that stable dose. 
 
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911. 
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6.8.2 
Excluded Medications and/or Procedures 
During the trial, patients will not use any recreational drugs or drugs of abuse. The need to 
take prescription drugs that dull the sensorium, reduce sensitivity to symptoms of 
hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion from the 
trial or discontinuation of participation, a decision that will be made by the Investigator. 
Use of benzodiazepines or narcotics, even if by prescription, may be excluded according to 
the judgment of the Investigator. Use of oral anti-diabetic medications (e.g., thiazolidinediones, 
biguanides, sulfonylureas, glitinides, DPP-4 inhibitors, SGLT-2 inhibitors) will also be 
excluded. 
7 
TRIAL PROCEDURES  
7.1 
Informed Consent 
After potential patients have had time to review the consent document, and prior to any 
trial-related activities, they will meet with a trial MD or designee who will explain the trial, 
answer any questions, and administer informed consent. In the event that a volunteer is a 
patient of 1 of the trial MDs, another staff MD or designee will answer questions and administer 
consent. The patients will be fully informed of their responsibilities and their rights while 
participating in the trial as well as of the possible risks and potential benefits of participation in 
the trial. They will have the opportunity to discuss all questions and ample time to consider 
participation. 
Trial-related activities are any procedures that would not have been performed during normal 
management of the patient. Patients who wish to participate in the trial will be asked to 
personally date and sign an informed consent form (ICF). Likewise, the Investigator must also 
personally date and sign the ICF. All patients will be provided with a copy of their own signed 
and dated ICF. 
Trial staff will answer any questions that the patients may have during their participation. They 
will share any new information in a timely manner that may be relevant to the patient's 
willingness to continue participating in the trial. The patients may choose to discontinue their 
participation at any time.  
7.2 
Screening Visit (Visit 1) 
All patients will have a Screening Visit to confirm eligibility. The patient will be interviewed and 
the electronic Case Report Form (eCRF) will be completed by trial staff to establish whether 
the patient is eligible. 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits per the 
medical judgment of the Investigator. 
Once all of the results have been returned, a trial MD will review the eCRF to determine patient 
eligibility. If a patient is not eligible to continue in the trial, the results of abnormal tests will be 
reported to the patient and to a health care provider of their choosing. 
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7.2.1 
Data Collected at Screening 
• 
Age, sex, race, and ethnicity 
• 
Date of last menstrual period in female patients  
• 
Medical, surgical, and social history, allergies, and review of systems relevant to 
inclusion and exclusion criteria, including: 
o Date of diabetes diagnosis 
o Duration of insulin pump use and type of insulin used in pump 
o Type/model of insulin pump 
o Insulin regimen (basal rate, sensitivity factor, and carbohydrate ratio) 
o Average total daily dose of insulin in the last 30 days as available (from pump 
history) 
o Usage of CGM, if any (type of CGM, days per month worn, usage of data, 
whether insulin is dosed based on CGM alone, alarm settings) 
• 
Concomitant illness (any illness present at screening) 
• 
Concomitant medications (prescription and non-prescription) and date of last change 
in medication regimen  
• 
Height, weight, physical examination, and vital signs including body temperature and 
blood pressure 
• 
12-lead ECG 
• 
Hemoglobin A1c 
• 
Chemistry and hematology samples (see Appendix B) 
• 
Urine HCG pregnancy test for women of childbearing potential 
• 
FSH level for postmenopausal women amenorrheic for less than 1 year 
• 
Fractionated plasma metanephrines (if indicated by history) 
 
7.3 
Training Visit (Visit 2) 
A Training Visit will take place before the first treatment visit. Patients will be trained in the 
insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. Trial staff 
will verify that the patients have understood the material and are competent to participate 
safely in the trial. Patients will be instructed concerning diabetes management (e.g., basal 
insulin rate adjustment by insulin pump) during fasting prior to and between the treatment 
visits per the medical judgment of the Investigator. Concomitant medications will also be 
reviewed. 
 
7.4 
Treatment Visits (Visit 3 and Visit 4) 
• 
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 
30 days after screening (Visit 1). 
• 
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum 
of 3 weeks between Visit 3 and Visit 4. 
• 
Up to 2 patients may participate per day.  
• 
In Part 1, each patient will participate in 2 treatment visits: 1 with the iPhone-based BP 
using ZP4207 and 1 with the iPhone-based BP using Lilly glucagon in a randomized 
order. 
• 
In Part 2, each patient will participate in 2 treatment visits: 1 with the iLet using ZP4207 
and 1 with the iLet using Lilly glucagon in a randomized order. 
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• 
The night before the treatment visit, patients will place a Dexcom G4 CGM sensor in 
the abdominal skin and calibrate the sensor when prompted using the provided Nova 
StatStrip Xpress meter. Patients will be instructed to call if they encounter any difficulty 
with their CGM.  
• 
Patients will be responsible for their own medications other than insulin during the trial. 
Any medical advice needed by the patients during their participation that is not directly 
related to BG control should be obtained from them in their usual manner. Patients 
may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference 
with CGM sensing. If patients experience urgent or emergent medical concerns 
outside the scope of diabetes care and their primary care physicians, they will be taken 
to the MGH walk-in clinic or emergency room, or if necessary call 911. 
• 
During the trial, patients will not use any recreational drugs or drugs of abuse. The 
need to take prescription drugs that dull the sensorium, reduce sensitivity to symptoms 
of hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion 
from the trial or discontinuation of participation, a decision that will be made by the 
Investigator.  
• 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits 
per the medical judgment of the Investigator. 
• 
Patients will not tamper with the BP, including changing any settings. 
• 
Patients may not remove the BP during the trial unless the BP failed or they are 
withdrawing from the trial. 
• 
The exact time of each procedure and assessment will be documented. 
7.4.1 
Visit Procedures  
• 
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the 
BP having fasted since 12:00 AM the night before (treatment with simple carbohydrate 
of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled 
within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the 
visit window. If BG is <50 mg/dL, treatment with simple carbohydrate is allowed. If the 
patient experiences persistent hypoglycemia, the visit will be rescheduled within the 
visit window. If the visit needs to be rescheduled due to hypoglycemia or 
hyperglycemia, trial staff will assist the patient with insulin or medication adjustments 
to address glycemic control. The patient will be instructed to contact trial staff later in 
the day if his or her BG remains uncontrolled. 
• 
Upon arrival to the visit, the patient’s weight and vital signs including body temperature 
and blood pressure will be documented. 
• 
Patient reports of symptoms, any other complaints, and AEs will be reviewed. 
• 
Concomitant medications will be recorded. 
• 
Chemistry and hematology samples will be collected at visit start (see Appendix B). 
• 
ADA samples will be collected before the start of dosing (Visit 3 only).  
• 
A 12-lead ECG will be performed. 
• 
A urine HCG pregnancy test will be performed in female patients of childbearing 
potential. If the test is positive, the patient will be informed of the result and the visit 
will be ended. 
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Patients will complete a baseline survey about their attitudes and experience with their
usual diabetes care.
•
An IV catheter will be placed for blood sampling.
•
Trial staff will assist the patient to calibrate their CGM, review the trial procedures again
and assist with the setup of the BP system, including inserting and priming infusion
sets.
•
The control algorithm will be initialized only with the patient’s weight. Diagnostics will
be performed to ensure that the CGM device is appropriately calibrated and that all of
the components of the BP systems are in working order.
•
The basal rate of the patient’s own insulin infusion pump will be changed to be 2-fold
higher than weighted mean of the basal rate during the trial period. This is intended to
increase the usage of glucagon during the treatment visit.
•
The patients will continue to wear their own infusion pump infusing at the temporary
2-fold basal rate throughout the visit until the start of the structured exercise period, in
addition to the BP.
•
The staff will start the BP as close as possible to a minute divisible by 5 minutes
(i.e., on a 5-minute mark). The starting time will be considered Hour 0.
•
Additional calibrations will be performed at any of the BG checks throughout the day if
the CGM value does not meet the ISO standard (<15 mg/dL difference for BG values
<75 mg/dL; <20% absolute difference for BG values >75 mg/dL) at the time of the BG
measurement AND it is a good time to calibrate (the CGM trend arrow is flat and there
has been no carbohydrate intake in the last 30 minutes or glucagon boluses in the last
15 minutes).
•
Blood samples will be taken from the IV at least hourly and processed for plasma
ZP4207/glucagon. If BG is <150 mg/dL, more frequent samples for plasma
ZP4207/glucagon may be drawn at the discretion of the Investigator. The actual time
of sampling will be recorded in the eCRF.
•
Plasma glucose samples will be taken from the IV at least hourly in parallel with
ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT Plus.
If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes.
If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then
sampling will be every 10 minutes. The actual time of sampling will be recorded in the
eCRF.
•
Patients will be asked to rate any nausea and/or infusion site pain on 10 cm visual
analog scales (VAS) at the beginning of the visit once the infusion sites have been
placed but no drug has yet been administered, then approximately at the top of every
hour during the visit, and at the end of the visit. Trial staff will also evaluate their infusion
sites to document any erythema or edema at the same times. If moderate or severe
pain is reported or swelling or redness occurs at the infusion site, the infusion site will
be replaced in a different location. If moderate or severe pain, swelling, or redness
continues at the old site for more than 30 minutes after the infusion site is removed, or
if moderate or severe pain, swelling, or redness occurs at the new site, all infusion
sites will be removed and the patient will be discontinued from the study. Any such
symptoms will be followed until resolution.
•
From the start of closed loop control until approximately Hour 3, the patients will
continue to fast.
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• 
Between approximately Hour 3 and Hour 4, patients will be provided with a lunch meal 
of their choice in the Diabetes Research Center from a menu of choices from nearby 
restaurants. They will be asked to choose a meal that is a “typical meal” for them. The 
content of their meal will not be restricted in any way, with the exception that the 
number of carbohydrates should be in the “typical” range for them at lunch, and that 
they must eat the same meal at the same time during both visits. 
• 
At approximately 15 minutes before the meal, patients will administer a bolus for the 
meal with their own insulin pump based on the carbohydrate count for the meal. 
• 
After lunch is completed, the patients will not be allowed any carbohydrate intake 
(non-caloric drinks will be permitted) until the trial is completed (except as necessary 
to treat hypoglycemia), to allow the BP to control the post-prandial BG without further 
interruption.  
• 
Between approximately Hour 6 and Hour 7, the patients will start a period of structured 
exercise. 
• 
At the start of the exercise period, patients will restore their normal basal insulin profile 
so that they will not have elevated insulin levels at the end of the study period when 
they are to transition back to their usual care.  
• 
Patients will exercise on a stationary bike with a heart rate from 120-140 beats per 
minute for a total of 4,000 heart beats (approximately 30 minutes). Patients will rate 
their exercise intensity using the Borg scale every 5 minutes, with the target intensity 
level between 12 and 14. Heart rate will be measured every 5 minutes. 
• 
BG measurements will be obtained off of the IV line every 10 minutes. If BG is 
<80 mg/dL, BG measurements will be obtained off of the IV line every 5 minutes.  
o 
Carbohydrates will be given for any BG <50 mg/dL according to the following 
protocol: Dextrose (g) = BSA (m2)/[1.7 m2 (women) or 1.9 m2 (men)] *15 g. 
o 
Repeat treatments will be given at 15-minute intervals as long as BG remains 
<50 mg/dL.  
• 
If there is an interruption in the Dexcom CGM output, trial staff will assist the patient in 
recovering CGM data streaming. If this requires replacement of the CGM sensor, BGs 
will be checked every 10 minutes (every 5 minutes if BG is <80 mg/dL) using blood 
from the IV until the CGM is able to be calibrated again. These BGs will be entered 
into the BP, which will treat them as CGM values and dose insulin and/or glucagon 
appropriately. 
• 
If there is a complete failure of the BP operation, patients will take over their own BG 
control using their personal insulin pump until the BP can be brought back online. If BP 
control cannot be promptly resumed (e.g., within 30 minutes), the patient may be asked 
to repeat that trial day once. 
• 
Patients may choose to withdraw from the trial at any time. If they withdraw from the 
trial, they should alert a provider immediately. 
• 
Just prior to the end of the study visit, vital signs including body temperature and blood 
pressure will be obtained and a 12-lead ECG will be performed.   
• 
After approximately Hour 8, but not earlier than at least 60 minutes after end of 
exercise, the BP will be stopped and the patient will continue with their personal insulin 
pump. 
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•
If the patient experiences seizure or unconsciousness, persistent nausea or vomiting,
diabetic ketoacidosis, persistent hyperglycemia with ketonemia, hemodynamic
changes such as hypotension, or other medically significant findings, a longer
observation period at the trial site may be necessary until the patient is considered
stable for discharge. If the Investigator or trial staff determines that the patient requires
further observation or treatment, the patient may be transferred to the emergency room
for additional monitoring and/or medical care. At discharge, patients will be provided
with any necessary instructions concerning personal insulin pump usage, food intake,
and driving arrangements.
•
The maximum amount of blood loss per study visit will be approximately 230 mL. The
total blood loss for the entire study will be up to 460 mL.
•
Patients will answer questionnaires (see Appendix C).
•
Chemistry and hematology samples will be collected at visit end (see Appendix B).
•
The BP and glucose meters will be collected and downloaded.
•
A trial MD will review the last several hours of insulin and glucagon dosing and assist
the patient in resuming their usual diabetes care. A longer observation period at the
trial site may be necessary. Patients will be instructed to call trial staff with any
questions, issues, or concerns.
7.4.2 
Data Collected During the Treatment Visits 
•
CGM glucose every 5 minutes from the Dexcom G4 Platinum CGM
•
All BG measurements taken
•
Insulin total dose by the BP and the patient’s own insulin pump
•
Glucagon total dose
•
Timing and content of the meal eaten and carbohydrate amount
•
Timing of meal announcement and size of meal announced
•
Timing and glucose values at calibrations
•
Timing and amount of carbohydrates taken for hypoglycemia
•
Data from a questionnaire about attitudes and expectations regarding the BP before
and after each treatment arm (see Appendix C)
•
Time patients were not under BP control for any reason
•
List of technical faults associated with the BP including cause and resolution
•
ZP4207/glucagon sampling will be collected at least hourly. If BG is <150 mg/dL, more
frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the
Investigator.
•
Plasma glucose sampling will be collected at least hourly in parallel with
ZP4207/glucagon exposure sampling. If BG is <150 mg/dL, then sampling will be every
30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is
<80 mg/dL, then sampling will be every 10 minutes.
•
Nausea and infusion site pain on a VAS at visit start (after insertion and before any
drug administration), hourly, and at visit end
•
Infusion site reaction according to the Draize scale at visit start (after insertion and
before any drug administration), hourly, and at visit end
•
Patient reports of symptoms, any other complaints, and AEs
•
Vital signs including body temperature and blood pressure (at visit start and visit end)
and weight
•
Concomitant medications
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• 
Chemistry and hematology samples (see Appendix B) at visit start and visit end 
• 
ADA (Visit 3 only)  
• 
12-lead ECG at visit start and visit end 
• 
Urine HCG pregnancy test for women of childbearing potential 
7.4.3 
Response to Hypoglycemia  
• 
Patients are encouraged to check their BG for any symptoms of hypoglycemia.  
• 
Patients will be permitted to take 15 grams of carbohydrates for any BG value 
<60 mg/dL. Trial staff will ensure proper functioning of the BP, infusion set, and insulin 
pump, and will encourage the patient to wait for the BP to treat the low blood sugar for 
as long as they feel comfortable. 
• 
Patients will be required to take 15 grams of carbohydrates for any BG value 
<50 mg/dL. After treatment of hypoglycemia, a follow-up measurement will be taken 
15 minutes later. Repeated measurements will be taken every 15 minutes until the 
BG is >60 mg/dL. Treatment will be repeated if subsequent BG values are still 
<50 mg/dL. All carbohydrate treatments for hypoglycemia will be documented by trial 
staff (amount and time).  
• 
Trial staff will check the infusion site, BP, and insulin pump for normal operation any 
time hypoglycemia occurs. If there is any suspicion of infusion set malfunction, the site 
should be replaced. Trial staff will check the BP for any malfunction and correct any 
problems that are found. 
• 
If no correctable fault is found, but there is doubt regarding the correct function of the 
BP system, an entirely new backup BP system may be started. 
• 
If a patient experiences a seizure or unconsciousness associated with hypoglycemia, 
his or her participation in the trial will be discontinued.  
7.4.4 
Response to Hyperglycemia  
• 
Trial staff will check the infusion site, BP, and insulin pump for normal operation any 
time BG is >300 mg/dL. If there is any suspicion of infusion set malfunction, the site 
should be replaced. Trial staff will check the BP for any malfunction and correct any 
problems that are found. If the BG remains >300 mg/dL for 2 hours despite 
troubleshooting, blood ketones will be measured. If the blood ketone result is 
>1.5 mmol/L, the visit will be stopped and rescheduled. The patient will be provided 
with insulin and a syringe to give an injection based on their correction factor. 
• 
If a patient experiences diabetic ketoacidosis, his or her participation in the trial will be 
discontinued. 
• 
If no correctable fault is found, but there is doubt regarding the correct function of the 
BP system, the treatment visit may be stopped and the visit rescheduled. 
7.4.5 
Response to Nausea/Vomiting 
If significant nausea (e.g., that prevents the patient from eating normally) or any vomiting 
occurs, trial staff will notify the Investigator. Trial staff will assist the patient in troubleshooting, 
such as checking BG and the calibration of the CGM (excessive glucagon dosing may occur 
if the CGM is reading lower than the true BG). If a patient experiences persistent nausea and 
vomiting thought to be related to glucagon dosing, his or her participation in the trial will be 
discontinued. 
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7.4.6 
Response to Other Medical Needs  
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911.  
7.4.7 
Monitoring of Bionic Pancreas Performance 
Bionic pancreas inventors and developers 
, 
, and/or an 
engineer trained by them will be readily available by phone for consultation for the trial staff at 
all times during the course of the trial.  
7.4.8 
Supervision by Trial Staff  
A trial MD will be on call at all times during the course of the trial. An RN or MD will be with 
the trial patients in the Diabetes Research Center at all times. 
7.5 
Phone Call (Visit 5) 
A phone call will be conducted 7 days ±3 days following the last day of dosing (Visit 4) to 
review AEs and concomitant medications. 
7.6 
Follow-up Visit (Visit 6) 
Patients will return for a Follow-up Visit 25 days ±4 days following the last day of dosing 
(Visit 4), for chemistry, hematology, and ADA sampling, and a review of AEs and 
concomitant medications.  
8 
ENDPOINTS  
8.1 
Primary Endpoint 
The primary endpoint is the safety and tolerability of ZP4207 in the BP using either the iLet 
or the iPhone platform as assessed by: 
•
Number and type of AEs
•
Clinical laboratory measurements
•
Vital signs
•
12-lead ECG
•
Local tolerability and infusion site reactions as measured with the Draize scale
•
Immunogenicity as measured by ADA
•
Pain as measured on a 10 cm VAS
•
Nausea as measured on a 10 cm VAS
8.2 
Secondary Endpoints 
The secondary endpoints include measurements of BP function as well as glycemic and 
non-glycemic measurements. 
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8.2.1 
Bionic Pancreas Function  
This endpoint data will be generated from the BP data during each treatment visit: 
• 
Average percent insulin dose amounts calculated by the BP control algorithm that are 
successfully delivered by the pump 
• 
Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts successfully issued to the pump by the BP control 
algorithm that are successfully delivered by the pump (calculated doses are not issued 
unless the pump is accessible and its delivery channel is available) 
o Average percent insulin dose amounts successfully issued to the pump by the 
BP control algorithm that are successfully delivered by the pump 
o Average percent glucagon/ZP4207 dose amounts successfully issued to the 
pump by the BP control algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts calculated by the BP algorithm that are successfully 
issued to the pump by the BP (calculated doses are not issued unless the pump is 
accessible and its delivery channel is available) 
o Average percent insulin dose amounts calculated by the BP control algorithm 
that are successfully issued by the BP 
o Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully issued by the BP 
• 
Average percent of 5-minute steps during which the BP is functioning nominally in all 
respects based on real-time CGM data (new CGM glucose reading captured, dose 
calculated, and dose issued to pumps)  
• 
Average percent of 5-minute steps during which the BP is functioning nominally with 
or without a new CGM glucose reading captured (dose calculated and dose issued to 
pumps). If a CGM signal is not available, the dose calculated may be based on weight 
or historical basal rates. 
• 
CGM reliability index, calculated as percent of possible values actually recorded by 
CGM 
• 
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter 
download 
• 
List of technical faults associated with the BP including cause and resolution 
8.2.2 
Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit: 
• 
Fraction of time spent within each of the following glucose ranges: 
o <50 mg/dL 
o <60 mg/dL 
o <70 mg/dL 
o 70-120 mg/dL 
o 70-140 mg/dL 
o 70-180 mg/dL  
o >180 mg/dL 
o >250 mg/dL 
o >300 mg/dL 
• 
Number of severe hypoglycemic events (patients unable to self-treat, requiring the 
assistance of another person) 
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•
Number of episodes of symptomatic hypoglycemia
•
Number of carbohydrate interventions for hypoglycemia
•
Total grams of carbohydrates taken for hypoglycemia
•
Mean CGM glucose
8.2.3 
Non-glycemic 
•
Glucagon/ZP4207 total delivery per kg of body mass
•
Insulin total delivery per kg of body mass
•
Number of unscheduled infusion set replacements
•
Number of unscheduled CGM sensor changes
9 
LABORATORY ASSESSMENTS 
Descriptions of sample handling and sample processing, storage, and shipment at the site will 
be included in the laboratory manual. 
The responsible laboratories are listed in the address list. 
9.1 
Safety Laboratory Assessments 
Chemistry and hematology samples will be collected at specified time points. See Appendix A 
for the schedule of procedures and Appendix B for a list of clinical laboratory analytes. 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) 
At Visit 3 and Visit 4, plasma glucose samples will be taken from the IV at least hourly in 
parallel with ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT 
Plus. If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for 
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is 
<100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will 
be every 10 minutes. The actual time of sampling will be recorded in the eCRF. 
9.3 
Exposure Assessments (ZP4207 and Glucagon) 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the 
discretion of the Investigator. The actual time of sampling will be recorded in the eCRF. 
Bioanalytical Reports will be prepared. 
9.4 
Anti-drug Antibody Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken at Visit 3 and the Follow-up Visit 6. 
Bioanalytical Reports will be prepared. 
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10 
SAFETY REPORTING 
10.1 
Adverse Events 
An AE is any untoward medical occurrence in a trial patient administered an IMP and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be 
any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not considered related to 
the IMP. Patients should be instructed to report any AE they experience to the Investigator. 
Note: This includes events from the first trial-related activity from Visit 3.  
AEs for ZP4207 include: 
•
A clinically significant worsening of a concomitant illness
•
A clinical laboratory abnormality which is clinically significant, i.e., any abnormality that
suggests a disease and/or organ toxicity and is of a severity that requires active
management. Active management includes active treatment or further investigations,
for example, change of medicine dose or more frequent follow-up due to the
abnormality.
•
Hypoglycemic episodes  
•
Injection site reactions
The following should not be recorded as AEs, if recorded prior to randomization (on the 
Screening Form or the eCRF): 
•
Pre-planned procedure, unless the condition for which the procedure was planned has
worsened from the first trial-related activity from Visit 3. 
•
Pre-existing conditions found as a result of screening procedures (pre-existing
conditions should be reported as medical history or concomitant illness). 
For known (listed) AEs for Glucagon and Humalog, please refer to SPC for Glucagon and 
Humalog. 
10.1.1 
Follow-up of Adverse Events 
All AEs that are ongoing at the end of the patient’s participation in the trial will be followed-up 
until the event is resolved or reaches a satisfactory outcome as deemed by the Investigator. 
Follow-up actions for all serious adverse events (SAEs) will be performed according to 
appropriate clinical care practices and may depend on the nature of the event. These will be 
determined after internal review and/or Sponsor review. The follow-up information should only 
include new (updated and/or additional) information that reflects the situation at the time of the 
Investigator’s signature. 
Follow-up information on (S)AEs will be updated using the (S)AE Form. If a non-serious event 
becomes serious during the follow-up, the AE Form and SAE Form must be used and reporting 
timelines follow those of an SAE. 
The Investigator must forward follow-up information on SAEs, and if previously non-serious 
AEs become SAEs, to the Sponsor. 
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10.1.2 
Precautions 
Normal precautions taken for a human trial will be taken during this trial. Qualified and 
well-trained physicians and medical staff will instruct the patients. During a patient’s 
participation in the trial, the Investigator should ensure that adequate medical care is provided 
to the patient for any AEs, including clinically significant laboratory values related to the trial. 
The Investigator should inform the patient when medical care is needed for intercurrent 
illnesses of which the Investigator becomes aware.  
For further information on safety precautions for ZP4207, Lilly glucagon, and Lilly Humalog, 
please refer to the current version of the Investigator’s Brochure (IB) for ZP4207 (Zealand 
Pharma A/S, 2015, or any updates hereof), and the SPC for Glucagon (Eli Lilly, 2012) and 
Humalog (Eli Lilly, 2015), respectively. 
10.1.3 
Assessment of Adverse Events by the Investigator 
Intensity of an Adverse Event 
The maximum intensity (severity) of all AEs must be assessed by the Investigator and 
documented. Severity should be graded when the AE outcome is known: 
•
Mild: A type of AE that is usually transient and may require only minimal treatment or
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
•
Moderate: A type of AE that is usually alleviated with additional specific therapeutic
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the patient. 
•
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects
clinical status, or may require intensive therapeutic intervention. 
A “severe” reaction does not necessarily deem the AE as “serious,” and an SAE may not be 
“severe” in nature. 
Causality Relationship to IMP 
Insulin (insulin lispro, Lilly Humalog), glucagon (glucagon for injection, Eli Lilly), and ZP4207 
are all regarded as IMP. 
The causality of each AE should be assessed by the Investigator according to the following 
classification: 
•
Related: Good reason and sufficient documentation to assume a causal relationship.
•
Not related: No relationship to trial product can be established.
Outcome of an Adverse Event 
The outcome of all AEs must be assessed by the Investigator and documented by his/her 
staff. The following definitions should be used: 
•
Recovered/resolved: The patient has fully recovered, or by medical or surgical
treatment the condition has returned to the level observed at the first trial-related 
activity from Visit 3. 
•
Recovering/resolving: The condition is improving and the patient is expected to recover
from the event. This term is only applicable if the patient has completed the trial.
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• 
Recovered/resolved with sequelae: The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment, or procedure. If a sequela meets 
an SAE criterion, the AE must be reported as an SAE. 
• 
Not recovered/not resolved: The condition of the patient has not improved and the 
symptoms are unchanged, or the outcome is not known. 
• 
Fatal: This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he/she died should 
be assessed as “recovered/resolved,” “recovering/resolving,” “recovered/resolved with 
sequelae,” or “not recovered/not resolved.” An AE with a fatal outcome must be 
reported as an SAE. 
• 
Unknown: This term is only applicable if the patient is lost to follow-up. 
 
10.2 
Serious Adverse Events   
An SAE is any untoward medical occurrence that at any dose:  
• 
Results in death  
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Medically important 
 
Medical judgement must be exercised in deciding whether an AE is believed to be “medically 
important.” Medically important events may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require intervention to prevent 
1 of the other outcomes listed in the definition above. 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is an AE fulfilling 1 of the criteria of seriousness and being assessed as related to 
an IMP, the nature or severity of which is not consistent with the applicable reference 
document (e.g., ZP4207 IB or package leaflet/SPC for an approved product). 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety, any life-threatening problem or 
death caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the application; or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. 
 
10.3 
Adverse Event Reporting – Procedures for Investigators  
The Principal Investigator and co-investigators will review any AEs and report any SAEs to 
the Sponsor as soon as possible and within 24 hours of obtaining knowledge of the event. The 
Principal Investigator and co-investigators will promptly report AEs to the Partner’s Institutional 
Review Board (IRB) and to the BU IRB (unless oversight is ceded by the BU IRB to the 
Partners IRB), in accordance with local requirements.  
 
Ed Damiano is the Sponsor of the Investigational Device Exception for the BP and Zealand 
Pharma A/S is the Sponsor of the IND for ZP4207.  
 
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 The following must be collected:  
•
Initial information of the pregnancy
•
Information on the outcome of the pregnancy, including the health status of the
newborn infant(s) at the age of 1 month
•
All AEs in connection with the pregnancy and pregnancy outcome must be reported
on the pregnancy forms. It must be clear in the description if the event occurs in the
patient/patient’s partner, the fetus, or the newborn infant.
•
All SAEs in connection with the pregnancy and pregnancy outcome must be reported
on the pregnancy forms following the same timelines as required for other SAEs. It
must be clear in the description if the event occurs in the patient/patient’s partner, the
fetus, or the newborn infant.
The SAEs that must be reported include abnormal outcome – such as congenital anomalies, 
fetal death, and termination of pregnancy (spontaneous or elective abortion), including any 
anomalies of the fetus observed at gross examination or during autopsy – as well as other 
pregnancy complications (ectopic pregnancy) fulfilling the criteria of an SAE. 
10.5 
Hypoglycemia 
Hypoglycemia will be regarded as an AE and will be recorded and documented on an AE 
Form. For the purposes of AE reporting, the following definitions of hypoglycemia will be used: 
•
Symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia
are accompanied by a BG concentration ≤70 mg/dL 
•
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of
hypoglycemia but with a BG concentration ≤50 mg/dL 
•
Severe hypoglycemia: an event requiring assistance of another person to actively
administer carbohydrates, glucagon, or take other corrective actions 
10.6 
Safety Monitoring 
10.6.1 
Data and Safety Monitoring Board 
An external DSMB will oversee the conduct of the trial, as set forth in the DSMB Charter. 
Additionally, the DSMB will be informed in the event of any serious and unexpected AEs. The 
DSMB will be informed if there are any changes to the trial protocol that could significantly 
impact the safety or scientific validity of the trial. A final DSMB meeting will convene after the 
completion of the trial. 
The participation of individual patients will be discontinued if they experience: 
•
Seizure or unconsciousness associated with hypoglycemia and associated with
participation in the trial 
•
Persistent nausea and vomiting thought to be related to glucagon dosing associated
with participation in the trial 
•
Hospitalization associated with participation in the trial
•
Pregnancy
•
Diabetic ketoacidosis
If more than 1 patient must be withdrawn from the trial for these reasons, the trial will stop and 
a vote of the DSMB will be required to restart it. All AEs that are serious and unexpected but 
related will be reported to the DSMB within 5 working days. 
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Note that patients may discontinue participation at any time. Patients may be removed from 
the trial for other reasons, for instance, failure to comply with trial procedures or intercurrent 
illness that is unrelated to the BP but that precludes safe participation. Discontinuation of 
participation for these reasons will not contribute to a decision to discontinue the trial.  
10.6.2 
Zealand Pharma Safety Committee 
The internal Zealand Pharma Safety Committee is constituted to perform ongoing safety 
surveillance of clinical trials within ZP4207, including this trial. 
If safety signals are observed either based on reported SAEs, periodic review of laboratory 
parameters, planned review of all AEs reported between the safety committee meetings, or 
on notification of significant findings, the Safety Committee will take appropriate measures to 
safeguard the patients. 
11 
STATISTICS 
For all analysis, the 2 treatment arms from Part 1 (iPhone-based BP) will be compared, and 
the 2 treatment arms from Part 2 (iLet) will be compared. The analysis of Part 1 will be 
completely separate from the analysis of Part 2. 
11.1 
Analysis Populations 
The following analysis sets are defined in accordance with the ICH-E9 guidance: 
The Full Analysis Set is based on the intention-to-treat principle and includes all randomized 
patients. In exceptional cases, patients from the Full Analysis Set may be excluded (will be 
decided in the database review [DBR] meeting). In such cases, the exclusion will be justified 
and documented. Patients will contribute to the evaluation “as randomized.” 
The Per-Protocol Set includes all patients of the Full Analysis Set who completed the trial 
without any major protocol violations. Patients in the Per-Protocol Set will contribute to the 
evaluation “as treated.” This analysis will only be used if it is different than the Full Analysis 
Set. 
The Safety Analysis Set includes all patients receiving at least 1 dose of the IMP. Patients in 
the Safety Analysis Set will contribute to the evaluation “as treated.”  
Analyses of efficacy endpoints will be based on the Full Analysis Set (and the Per-Protocol 
Set if necessary). This decision will be made in the DBR meeting. The analysis of the safety 
endpoints will be based on the Safety Analysis Set.  
Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. At this time, it will be 
determined if patients and/or data should be excluded from the analysis. Furthermore, outliers 
will be identified by data review according to ICH-E9. 
Obviously erroneous data points may be excluded from the analyses or re-analyzed 
(e.g., serum concentrations). The decision to re-analyze or exclude data points from the 
statistical analysis is the joint responsibility of the Sponsor, the Principal Investigator, and the 
Trial Statistician. 
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 The patients or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to database release. The documentation 
will be stored together with the remaining trial documentation. The patients and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report. 
 
11.2 
Statistical Methods  
Medpace will be responsible for the statistical analysis. The statistical planning and conduct 
of analyses of the data from this trial will follow the principles defined in relevant ICH guidelines 
and Medpace’s biostatistical standard operating procedures (SOPs). A general description of 
the statistical methods to be used is given in this section, specific details will be provided in 
the Statistical Analysis Plan (SAP), which will be prepared before database lock. All statistical 
analyses will be performed using SAS® (SAS Institute Inc., Cary, North Carolina, USA), 
version 9.3 or later.  
11.2.1 
Analysis of Safety 
The following variables will be evaluated according to treatment for safety purposes: 
 
Adverse Events 
All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). Individual AEs will be presented in a listing including relationship to trial 
product/device, severity, and treatment period at onset. If more than 20 treatment-emergent 
AEs (AEs with onset after [first] dosing at Visit 3 until the Follow-up Visit 6) are registered, a 
summary table including number of AEs, number of patients with at least 1 AE, and percentage 
of exposed patients with at least 1 AE will be made by system organ class and treatment 
period at onset. 
  
Local Tolerability 
Local tolerability at the injection site will be summarized using descriptive statistics as 
appropriate. 
 
Laboratory Safety Assessments 
Laboratory assessments will be summarized. A listing of abnormal values will be provided.  
 
Physical Examination 
A frequency table will show the number and percentage of physical examination results.  
 
Vital Signs 
Vital signs will be summarized using descriptive statistics. 
 
12-lead ECG 
The Investigator’s evaluations of 12-lead ECGs will be summarized and abnormal individual 
evaluations will be listed together with the Investigator’s comments. Changes in 12-lead ECG 
between measurements will be recorded as AEs if the Investigator judges them to be clinically 
significant.  
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11.2.2 
Analysis of Efficacy 
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis, any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. Further details will be included in the 
SAP. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow.  
11.2.3 
Interim Analysis 
An interim database lock may occur upon completion of Part 1 of the trial to analyze the 
iPhone-based BP data. 
11.2.4 
Sample Size Determination 
No formal sample size calculations were made. It is expected that between 20 and 24 patients 
will be randomized in the trial. The sample size is based on a clinical rather than statistical 
rationale. The sample size is considered adequate to address the primary trial objective of 
exploring the safety of ZP4207 when used in the BP and with reference to Lilly glucagon used 
in the BP. 
12 
DATA MANAGEMENT AND RECORD KEEPING 
Data Management is the responsibility of Medpace. The complete Data Management process 
will be described in detail and agreed on in the Data Management Plan for this trial. 
12.1 
Data Handling 
Case Report Forms 
Electronic Case Report Forms will be used in this trial. The Data Management Department of 
Medpace will provide the eCRFs. All further information regarding the eCRFs and the data 
flow will be described and agreed on in the Data Management Plan. 
Device-Related Data 
During the trial, CGM data, calibration data, insulin dosing data, and glucagon dosing data will 
be automatically stored in the BP device (from which it will be downloaded at intervals), 
combined in a single database that will be compared against the primary data files for integrity, 
and ultimately transferred to Medpace.  
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12.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
 
12.3 
Data Entry 
Data must be recorded using the electronic data capture (EDC) system as the trial is in 
progress. The patient questionnaires will be transcribed into the EDC system by site 
personnel. All site personnel must log into the system using their secure user name and 
password in order to enter, review, or correct trial data. These procedures must comply with 
Title 21 of the Code of Federal Regulations (21 CFR Part 11) and other appropriate 
international regulations. All passwords will be strictly confidential. 
 
12.4 
Medical Information Coding  
Adverse events and medical history will be coded using the latest version of MedDRA. Prior 
and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. 
 
12.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, 
will be referred to the investigative site for resolution through data queries. 
 
The eCRFs must be reviewed and electronically signed by the Investigator. 
 
12.6 
Record Keeping 
Medpace will be responsible for hosting the TMF. Records of patients, source documents, 
monitoring visit logs, eCRFs, inventory of trial product, regulatory documents, and other 
Sponsor correspondence pertaining to the trial must be kept in the appropriate trial files at the 
site. Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
evaluation and reconstruction of the clinical trial. Source data are contained in source 
documents (original records or certified copies). These records will be retained in a secure file 
for the period as set forth in the Clinical Trial Agreement. Prior to transfer or destruction of 
these records, the Sponsor must be notified in writing and be given the opportunity to further 
store such records. 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
13.1 
Ethical Conduct of the Trial 
The trial will be conducted according to Medpace, MGH, and/or the Sponsor’s written 
instructions (SOPs, working instructions, or process descriptions). Content and definitions of 
the written instructions are based on the Declaration of Helsinki and the ICH GCP.  
 
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13.2 
Institutional Review Board  
Written favorable opinion must be obtained from the responsible IRB prior to commencement 
of the trial. Clinical trial submission and reporting requirements before, during, and after 
completion of the trial will be performed in accordance with national law and local regulations. 
All amendments that affect patient safety or the trial integrity (substantial amendments) must 
not be implemented before favorable opinion has been obtained, unless necessary to 
eliminate hazards to the patients. Non-substantial amendments do not require favorable 
opinion by the IRB, but the respective IRB will be notified according to local requirements.  
The Sponsor and Investigator must approve any amendment in writing before its 
implementation. 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
IRB. The records should be filed in the Sponsor’s Trial Master File (TMF). 
13.3 
Informed Consent 
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirement(s) and adhere to the ICH GCP guideline and the 
requirements in the Declaration of Helsinki. 
Prior to any trial-related activity, the Investigator must give the patient oral and written 
information in a form that the patient can read and understand about all aspects of the trial 
that are relevant to the patient’s decision to participate. The patient will be given ample time 
to decide whether or not to participate in the trial. 
The patient must be informed that his/her personal trial-related data will be used in accordance 
with the local data protection law. The level of disclosure must also be explained to the patient. 
The patient must be informed that his/her medical records may be examined by authorized 
monitors or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
A voluntary, personally signed and dated ICF must be obtained from the patient prior to any 
trial-related activity. The ICF must also be signed and dated by the physician or designee who 
conducted the informed consent procedure. A signed copy of the ICF and any additional 
patient information must be given to each patient.  
The responsibility for taking informed consent must remain with that of a research physician 
or designee. If information becomes available that may be relevant to the patient’s willingness 
to continue participating in the trial, the Investigator must inform the patient in a timely manner, 
and a revised written informed consent must be obtained. 
Should a protocol amendment become necessary, the ICF may need to be revised to reflect 
the changes to the protocol. It is the responsibility of the Sponsor to ensure that an amended 
consent form is reviewed and has received favorable opinion from IRB, and the Investigator 
must ensure that the amended consent form is signed by all patients subsequently entered 
into the trial and those currently in the trial, if affected by the amendment. 
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13.4 
Trial Monitoring Requirements  
The monitoring procedures for this trial are described in detail in the Monitoring Manual. The 
objectives of the monitoring procedures are to ensure that (i) the safety and rights of the trial 
patients are respected, (ii) that accurate, valid, and complete data are collected, and (iii) that 
the trial is conducted in accordance with the trial protocol, the principles of GCP, and local 
legislation, including drug accountability. 
 
The monitor must be given direct access to the investigational site files and source documents 
(original documents, data, and records). Direct access includes permission to examine, 
analyze, verify, and reproduce any record(s) and report(s) that are important to evaluation of 
the clinical trial. 
 
Key tasks of the monitor include verifying the presence of informed consent, the adherence to 
the inclusion/exclusion criteria, the documentation of SAEs, and the recording of all safety and 
efficacy variables. The monitor will also confirm the completeness of patient records, the 
adherence to the protocol, ICH GCP, and the progress in patient enrollment and perform drug 
accountability.  
 
Because no information that could reveal the identity of patients may ever be removed from 
the trial site, the monitor will visit the site at regular intervals to perform these monitoring tasks. 
Other contact between the Investigator and monitors will be maintained as required through 
telephone calls and e-mail. The Investigator and/or key members of staff involved in the trial 
must be available to assist the monitors during all visits.  
 
Site Initiation Visit 
During the Site Initiation Visit (SIV) the CRO, Sponsor, and/or monitors will go through 
information on the IMP, the protocol, the eCRFs, and other key aspects of the trial with the 
Investigator and the key members of staff involved in the trial. The topics of the SIV are 
documented in a SIV report made available to the Investigator. Documentation on the SIV 
(e.g., power point presentation) should be filed by both Investigator and Sponsor. 
 
13.5 
Disclosure of Data 
Data generated by this trial must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal 
physician or other appropriate medical personnel responsible for their welfare. 
 
Patient medical information obtained during the trial is confidential and disclosure to third 
parties other than those noted above is prohibited. 
 
13.6 
Retention of Records  
Massachusetts General Hospital will maintain the patient’s medical file according to local 
regulations. MGH will archive the documentation pertaining to the trial in an archive after 
completion or discontinuation of the trial if not otherwise notified. MGH should not destroy any 
documents without prior permission from the Sponsor. 
 
The documentation includes all the raw data generated during the clinical trial, the 
investigational site files, and a copy of the clinical trial report. The documents will be retained 
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for a period of at least 15 years at archives by MGH, or its sub-contractor. After this period, 
the Sponsor will be contacted and their advice sought on the return or further retention of the 
trial records. 
The Sponsor will maintain the documentation pertaining to the trial in accordance with national 
regulations. 
13.7 
Publication Policy  
The Principal Investigator of the trial will review and sign the clinical trial report. A summary of 
the final clinical trial report will be submitted to the IRB and Competent Authority. 
According to the Declaration of Helsinki Investigators and Sponsors “have ethical obligations 
with regard to the publication and dissemination of the results of research.” The trial design 
and results may be published as 1 or more original research manuscripts/abstracts and 
presented at a scientific meeting. The Investigator and Sponsor reserve the right to review any 
proposed presentation of the results of this trial before they are submitted for publication. 
Authorship on any publication(s) resulting from this clinical trial will be assigned according to 
the recommendations of the International Committee of Medicinal Journal Editors. 
Participating patients will not be identified by name in any published reports about the clinical 
trial. 
The Sponsor is responsible for trial registration at ClinicalTrials.gov (www.clinicaltrials.gov) 
according to the requirements from the FDA. 
13.8 
Legal Aspects 
An implicit or explicit approval must be obtained from the Competent Authority prior to 
commencement of the trial. Clinical trial submission and reporting requirements before, during, 
and after completion of the trial will be performed in accordance with national law and local 
regulations. 
An implicit or explicit approval will also be mandatory before implementation of substantial 
changes. Non-substantial amendments do not require approval from the Competent Authority 
but will be notified according to local requirements. 
The Sponsor and Investigator must approve the amendment in writing before its 
implementation. 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
Competent Authority. The records should be filed in the Sponsor’s TMF. 
Audits and Inspections  
In the event of an audit, representatives of the Sponsor or designee, or national and 
international regulatory authorities may request access to all trial records for inspection and 
copying. Such access must be stated in the ICF signed by the patient. 
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13.9 
Sponsor Discontinuation Criteria  
The Sponsor, Investigator, or a pertinent regulatory authority may decide to stop the trial or 
part of the trial at any time but agreement on procedures to be followed must be obtained. 
Conditions that may warrant termination of the clinical trial include, but are not limited to: 
•
Safety or administrative reasons
•
The discovery of an unexpected, relevant, or unacceptable risk to the patients enrolled
in the clinical trial
•
A decision of the Sponsor to suspend or discontinue investigation of the IMP
If the trial is prematurely terminated or suspended, the Investigator should promptly inform the 
patients and assure appropriate therapy and follow-up. Furthermore, the Sponsor should 
promptly inform the IRB and provide a detailed written explanation. The pertinent regulatory 
authorities should be informed according to national regulations. 
If after the termination of the trial the risk/benefit analysis has changed, the new evaluation 
should be provided to the IRB in case it will have an impact on the planned follow-up of the 
patients who have participated in the trial. Necessary actions needed to protect the patients 
should be described. 
13.10 
Patient Compensation 
Financial compensation will be provided to all patients who complete the Screening Visit. 
Patients will be paid $25 for completing the Screening Visit whether or not they are eligible to 
participate in the trial. Patients will be compensated $25 for completing the Training Visit. 
Patients will be compensated $100 for completing each of the 2 treatment visits, $25 for 
completing the phone call, and $25 for completing the Follow-up Visit. Thus, the total 
compensation for a patient who completes the trial would be $300. Patients who are unable 
to complete the trial or choose to stop participation will receive prorated compensation for 
each visit. In addition to the monetary compensation, the cost of the patients’ lunch meals 
during their participation in the trial, as well as the patients’ parking at each visit, will be covered 
by trial funds.  
14 
TRIAL ADMINISTRATIVE INFORMATION 
14.1 
Protocol Amendments  
Any amendments to the trial protocol will be communicated to the Investigators by Medpace 
or the Sponsor. All protocol amendments will undergo the same review and approval process 
as the original protocol. A protocol amendment may be implemented after it has been 
approved by the IRB, unless immediate implementation of the change is necessary for patient 
safety. In this case, the situation must be documented and reported to the IRB within 5 working 
days. 
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APPENDIX A: SCHEDULE OF PROCEDURES – PARTS 1 AND 2 
Trial Visit 
Visit 1 [1]
Screening 
Visit 2
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5]
(2nd Treatment 
Visit) 
Visit 5
Phone Call [6] 
Visit 6
Follow-Up [7] 
Informed consent 
X 
 
 
 
 
 
Assess/confirm elig bility 
X 
X 
 
 
 
 
Demographics 
X
Medical, surgical, and social history; 
allergies  
X 
 
 
 
 
 
Concomitant illness 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Height, weight, physical examination, and 
vital signs including body temperature 
and blood pressure [8] 
X 
 
X [9] 
X [9] 
 
 
12-lead ECG 
X 
 
X [10] 
X [10] 
 
 
Urine HCG pregnancy test and menstrual 
history [11]   
X 
 
X 
X 
 
 
FSH [12] 
X 
 
 
 
 
 
Screening labs – HbA1c, optional 
fractionated metanephrines [13] 
X 
 
 
 
 
 
Safety lab sampling including chemistry 
and hematology 
X 
 
X [10] 
X [10] 
 
X 
Training on devices [14] 
 
X 
 
 
 
 
Monitored BP use 
 
 
X 
X 
 
 
Plasma glucose sampling [15] 
 
 
X 
X 
 
 
ZP4207/glucagon exposure sampling [16] 
 
 
X 
X 
 
 
Nausea and infusion site pain VAS and 
infusion site reaction Draize scale (visit 
start [17], hourly, & visit end) 
 
 
X 
X 
 
 
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Trial Visit 
Visit 1 [1]
Screening 
Visit 2
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5]
(2nd Treatment 
Visit) 
Visit 5
Phone Call [6] 
Visit 6
Follow-Up [7] 
Standardized lunch [18] 
X 
X 
In-clinic exercise [19] 
X 
X 
Questionnaires (pre & post BP) 
X 
X 
ADA 
X [20] 
X 
Adverse event review 
X 
X 
X 
X 
1.
Once the patient has been enrolled and eligibility has been established, the order of the treatment visits will be randomized in blocks of 2 patients.
2.
In Part 1, each patient will participate in 2 treatment visits: 1 with the iPhone-based BP using ZP4207 and 1 with the iPhone-based BP using Lilly glucagon in a randomized order. In
Part 2, each patient will participate in 2 treatment visits: 1 with the iLet using ZP4207 and 1 with the iLet using Lilly glucagon in a randomized order. Up to 2 patients may participate in the
trial per day.
3.
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal skin and calibrate the sensor when prompted using the provided Nova StatStrip Xpress meter.
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the BP having fasted since 12 00 AM the night before (treatment with simple carbohydrate of up to 30 g
for a low is allowed). If the patient is not fasted, the visit will be rescheduled within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the visit window. If BG is
<50 mg/dL, treatment with simple carbohydrate is allowed. If the patient experiences persistent hypoglycemia, the visit will be rescheduled within the visit window.
4.
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 30 days after screening (Visit 1).
5.
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum of 3 weeks between Visit 3 and Visit 4.
6.
Visit 5 will take place 7 days ±3 days from Visit 4.
7.
Visit 6 will take place 25 days ±4 days from Visit 4.
8.
Height and physical examination will be measured at Visit 1 only.
9.
Vital signs including body temperature and blood pressure will be obtained at visit start and visit end.
10.
At visit start and visit end.
11.
Urine HCG pregnancy test only for women of childbearing potential. The date of the last menstrual period in female patients will be obtained at Visit 1 only.
12.
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year.
13.
If indicated by history.
14.
Patients will be trained in the insertion and calibration of the Dexcom G4 sensor, diabetes management (e.g., basal insulin rate adjustment by insulin pump) during fasting prior to and
between the treatment visits, and trial policies and procedures.
15.
Collected at least hourly. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will
be every 10 minutes.
16.
Collected at least hourly. If BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the Investigator.
17.
Once the infusion sites have been placed but no drug has yet been administered.
18.
Between approximately Hour 3 and Hour 4.
19.
Between approximately Hour 6 and Hour 7.
20.
Before the start of dosing.
ADA = anti-drug antibodies; BG = blood glucose; BP = bionic pancreas; CGM = continuous glucose monitor; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
HbA1c = hemoglobin A1c; HCG = human chorionic gonadotropin; VAS = visual analog scale.
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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Chemistry 
Alanine aminotransferase 
Aspartate aminotransferase 
Alkaline phosphatase 
Total protein 
Albumin 
Total and direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Creatinine 
Estimated glomerular filtration rate 
Blood urea nitrogen 
Uric acid
Bicarbonate 
Sodium 
Potassium 
Calcium 
Chloride 
Phosphorus 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell count 
White blood cell count and differential 
Platelets 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Pregnancy Test 
A urine HCG pregnancy test will be performed at screening, Visit 3, and Visit 4 only for 
women of childbearing potential. 
Anti-drug Antibody Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken prior to first dosing (Visit 3) and at the Follow-up Visit (Visit 6). 
ZP4207/Glucagon Exposure Sampling 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at 
the discretion of the Investigator. 
Screening Visit Only 
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year 
Optional fractionated plasma metanephrines (if indicated by history) 
Hemoglobin A1c 
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APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES  
Diabetes Treatment Satisfaction Questionnaire – Status (DTSQs)  
The DTSQs measures patient satisfaction with diabetes treatment. It consists of a 6 item scale 
for assessing treatment satisfaction and two additional items assessing perceived frequency 
of hyperglycemia and hypoglycemia. The DTSQs is meant for adults and older children. 
Dr. Clare Bradley has produced a version that is appropriate for bionic pancreas studies for 
this use, along with a version for younger children. It is administered before the intervention. 
The DTSQs is valid and reliable. Administration time is less than 5 minutes. 
 
Diabetes Treatment Satisfaction Questionnaire – Change (DTSQc) 
Although the DTSQ is responsive to treatment changes, ceiling effects are often seen with this 
instrument, where maximum or close-to-maximum scores at baseline provide little opportunity 
for registering improvement. The DTSQc contains the same items as the DTSQs version but 
asks patients to consider their satisfaction with their current treatment compared with their 
previous treatment. The DTSQc is meant for adults and older children. Dr. Clare Bradley has 
produced a version that is appropriate for bionic pancreas studies for our use, along with a 
version for younger children. It is administered during and at the end of the intervention. The 
DTSQc is valid and reliable. Administration time is less than 5 minutes. 
 
T1-Diabetes Distress Scale (T1-DDS) 
The T1-DDS is a 28-item survey that assesses seven sources of diabetes distress for type 1 
adults. It captures feelings of powerlessness; management distress; hypoglycemia distress; 
negative social perceptions by others; eating distress; physician (health care) distress; and 
friend/family distress. Items are scored on a 6-point scale from not a problem to a very serious 
problem. It is administered before, during, and at the end of the intervention. The scale is valid 
and reliable, and has been shown to be sensitive to change over time. Administration time is 
5 minutes. 
 
Problem Areas in Diabetes Survey (PAID) 
There are three versions of the PAID: Teen (PAID-T), Parent (PAID-P), and Child (PAID-C) 
versions. This measure of diabetes-specific emotional distress in youth with diabetes and their 
parents is 26 items. A total score is generated. It is administered before, during, and at the 
end of the intervention. The PAID-T and PAID-P are valid and reliable. Psychometric analysis 
of the PAID-C is in progress. Administration time is 5 minutes. 
 
Hypoglycemia Fear Survey (HFS) 
There are three versions of the HFS, Adult (HFS), Youth (HFS-Y) and Parent (HFS-P). The 
HFS measures several dimensions of fear of hypoglycemia among adults with type 1 diabetes. 
It consists of 23 items and produces two sub-scale scores; a Behavior sub-scale that 
measures behaviors involved in avoidance and/or over-treatment of hypoglycemia and a 
Worry sub-scale that measures anxiety and fear surrounding hypoglycemia. The HFS-Y 
consists of 25 items and the HFS-P consists of 26 items; both produce sub-scale scores 
similar to the Adult HFS. It is administered before, during, and at the end of the intervention. 
All versions of the HFS are valid and reliable. Administration time is 5-10 minutes. 
 
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Impact of Daily Diabetes Demands (IDDD) 
There are four versions of the IDDD; Adult (IDDD-A), Youth (IDDD-Y), Parent (IDDD-P), and 
Significant Other (IDDD-SO). This instrument measures the burden related to the demands of 
the daily diabetes regimen and is 22 items. A total score is generated. It is administered before, 
during, and at the end of the intervention. Psychometric analysis of the IDDD-Y is in progress 
using the data from the second Bionic Pancreas Camp Study in pre-adolescent children, and 
of the IDDD-A is in progress using data from the Bionic Pancreas Multicenter Study in adults. 
Administration time is 5 minutes. 
Bionic Pancreas User Opinion Survey (BPUOS) 
There are four versions of the BPUOS; Adult (BPUOS-A), Youth (BPUOS-Y), Parent 
(BPUOS-P), and Significant Other (BPUOS-SO). This measure assessing both the benefits 
from, and difficulties with, use of the bionic pancreas, and consists of 38 items. A total score 
is generated. It is administered during and at the end of the intervention. Psychometric 
analysis of the BPUOS-Y is in progress using the data from the second Bionic Pancreas Camp 
Study in pre-adolescent children, and of the BPUOS -A is in progress using data from the 
Bionic Pancreas Multicenter Study in adults. Administration time is 10 minutes. 
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SUMMARY OF CHANGES DOCUMENT 
PROTOCOL NUMBER ZP4207-16051 
AMENDMENT NUMBER 3.0 
 
PROTOCOL TITLE: The Bionic Pancreas Feasibility Trial Testing the Bionic Pancreas with 
ZP4207 
AMENDMENT DATE: 17 August 2016 
SUMMARY AND JUSTIFICATION OF CHANGES: 
This amendment was developed to indicate that the device used in this trial to administer insulin, 
Lilly glucagon, and the glucagon analog ZP4207, has been changed from the iLet to the 
iPhone-based bionic pancreas (BP). This change has been made globally throughout the protocol 
amendment. Additional language has been added to describe the iPhone-based BP infusion set, 
control unit, and pumps. Other minor edits were made throughout the protocol to provide greater 
clarity and consistency. 
SUMMARY OF CHANGES: 
The amended protocol sections and the details of the changes are summarized in the following 
sections. Revisions to the protocol are presented as strikethrough (ie, subject) for text that was 
removed and bold (ie, subject) for text that was added. 
 
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Global 
Original Text: 
iLet 
New Text: 
iLet iPhone-based bionic pancreas 
Protocol Title, Page 1 
Original Text: 
The iLet Feasibility Trial Testing the iLet, a Fully Integrated Bihormonal Bionic Pancreas with 
ZP4207 
New Text: 
The iLet Bionic Pancreas Feasibility Trial Testing the iLet, a Fully Integrated Bihormonal Bionic 
Pancreas with ZP4207 
Section 1.1, Background and Rationale, Page 14 
Original Text: 
In its last tested embodiment, the BP consisted of a Dexcom G4 CGM, and an iPhone that are 
hardwired together, with the iPhone running the control algorithm and communicating via 
Bluetooth with 2 Tandem t:slim pumps to dose insulin and glucagon. The connections are 
repeatedly lost among these 4 components throughout the day, an issue that has the potential 
to adversely impact BG control, whether due to missed CGM values or missed doses. In 
addition, the troubleshooting required to repair these recurring disconnections can be 
burdensome to the user. Integrating these components into a single device would establish 
seamless connectivity among them, which would eliminate the need for such troubleshooting. 
This would lead to a smoother device operation with fewer interruptions, which would enhance 
its user friendliness, optimize its BG control potential, and further improve the quality of life of 
its users.  
The BU Investigators have recently designed, built, and tested a proprietary first-generation of 
such a fully integrated BP system, referred to as the iLet and the iLet infusion set. The iLet is a 
dual chamber infusion system that currently incorporates the Dexcom G4 CGM technology, a 
custom user interface with touchscreen display, and all of the mathematical dosing algorithms 
that were tested in and validated using the iPhone-based BP in outpatient studies over the past 
3 years. The iLet infusion set provides 2 independent subcutaneous (SC) fluid pathways from 
the iLet to the patient (1 for insulin and the other for glucagon). One tube connects to the 
prefilled insulin cartridge and the other tube connects to the fillable (single use) glucagon 
cartridge. 
New Text: 
In its last tested embodiment, the BP consisted of a Dexcom G4 CGM, and an iPhone that are 
hardwired together, with the iPhone running the control algorithm and communicating via 
Bluetooth with 2 Tandem t:slim pumps to dose insulin and glucagon. The connections are 
repeatedly lost among these 4 components throughout the day, an issue that has the potential 
to adversely impact BG control, whether due to missed CGM values or missed doses. In 
addition, the troubleshooting required to repair these recurring disconnections can be 
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burdensome to the user. Integrating these components into a single device would establish 
seamless connectivity among them, which would eliminate the need for such troubleshooting. 
This would lead to a smoother device operation with fewer interruptions, which would enhance 
its user friendliness, optimize its BG control potential, and further improve the quality of life of 
its users.  
The BU Investigators have recently designed, built, and tested a proprietary first generation of 
such a fully integrated BP system, referred to as the iLet and the iLet infusion set. The iLet is a 
dual chamber infusion system that currently incorporates the Dexcom G4 CGM technology, a 
custom user interface with touchscreen display, and all of the mathematical dosing algorithms 
that were tested in and validated using the iPhone based BP in outpatient studies over the past 
3 years. The iLet infusion set provides 2 independent subcutaneous (SC) fluid pathways from 
the iLet to the patient (1 for insulin and the other for glucagon). One tube connects to the 
prefilled insulin cartridge and the other tube connects to the fillable (single use) glucagon 
cartridge. 
Section 1.1, Background and Rationale, Page 14 
Original Text: 
The current trial is a first feasibility trial designed to use the first-generation iLet and iLet infusion 
set to compare ZP4207 with marketed glucagon (Lilly). The trial is intended to demonstrate the 
safety and tolerability of ZP4207 in the iLet and the feasibility of achieving comparable 
autonomous glycemic control. It is not intended to comprehensively demonstrate the definitive 
efficacy of the iLet in extended, continuous daily use, but rather to demonstrate its functionality 
and accuracy in a practical, albeit very controlled, clinical setting. The trial is expected to provide 
practical information that will benefit the design of a next-generation iLet and iLet infusion set 
and help pave the way for a more comprehensive outpatient home-use Phase 2 trial and 
ultimately a pivotal trial where comprehensive safety and efficacy through continuous full daily 
use of the iLet with ZP4207 will be documented. 
The data derived from this trial will permit evaluation of the robustness of the iLet as well as the 
safety and efficacy of ZP4207 when used in conjunction with the iLet. The data obtained will be 
used to further improve the iLet and will allow BU/MGH to expand to larger outpatient trials 
using the iLet with ZP4207. 
New Text: 
The current trial is a first feasibility trial designed to use the first generation iLet iPhone-based 
BP and iLet infusion set to compare ZP4207 with marketed glucagon (Lilly). The trial is intended 
to demonstrate the safety and tolerability of ZP4207 in the iLet iPhone-based BP and the 
feasibility of achieving comparable autonomous glycemic control. It is not intended to 
comprehensively demonstrate the definitive efficacy of the iLet iPhone-based BP in extended, 
continuous daily use, but rather to demonstrate its functionality and accuracy in a practical, 
albeit very controlled, clinical setting. The trial is expected to provide practical information that 
will benefit the design of a next-generation iLet BP and iLet infusion set and help pave the way 
for a more comprehensive outpatient home-use Phase 2 trial and ultimately a pivotal trial where 
comprehensive safety and efficacy through continuous full daily use of the iLet BP with ZP4207 
will be documented. 
 
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The data derived from this trial will permit evaluation of the robustness of the iLet iPhone-based 
BP as well as the safety and efficacy of ZP4207 when used in conjunction with the iLet 
iPhone-based BP. The data obtained will be used to further improve the iLet and will allow 
BU/MGH to expand to larger outpatient trials using the iLet with ZP4207. 
Section 1.5, Risk/Benefit, Page 21 
Original Text: 
The data derived from this trial will allow evaluation of safety and tolerability of ZP4207 in the 
iLet, and the robustness and effectiveness of the new BP control system. The data obtained 
will be used to further improve the iLet and will allow the expansion to larger outpatient trials 
using the iLet with ZP4207.  
New Text: 
The data derived from this trial will allow evaluation of safety and tolerability of ZP4207 in the 
iLet iPhone-based BP, and the robustness and effectiveness of the new BP control system. 
The data obtained will be used to further improve the iLet and will allow the expansion to larger 
outpatient trials using the iLet with ZP4207. 
Section 6.5, iPhone-based Bionic Pancreas, Page 27-28 
Original Text: 
6.5 
iLet Bionic Pancreas 
Infusion set: A novel, dual cannula infusion set has been designed specifically for use with the 
iLet. Patients will wear dual channel tubing that will be attached to 2 infusion sets with 1 steel 
cannula each, one for insulin infusion and the other for glucagon infusion. The tubing and 
infusion sets will have undergone sterilization prior to being delivered in a sealed pouch. The 
steel cannulae will be inserted in the abdominal SC tissue. 
Continuous glucose monitors: The iLet is being built according to Class III medical device 
standards, adheres to a comprehensive and robust quality system, and is fully compliant with 
International Organization for Standardization (ISO) 13485 standards and document control 
practices. The iLet is a fully-integrated dual hormone BP system that integrates the CGM 
technology (currently the Dexcom G4 Share system) as well as 2 independent motor-drivetrain 
pumping assemblies, which independently actuate the delivery of insulin and glucagon from 
pre-filled cartridges that are separately loaded into the iLet housing. Each drivetrain assembly 
utilizes a lead screw, which is driven by a precision micromotor, a gear case assembly, and a 
motor controller unit, in a manner similar to what is commonly found in most insulin infusion 
pumps on the market today. The iLet has dosing accuracy that is comparable to FDA-approved 
insulin pumps currently on the market. The iLet has a built-in Bluetooth Low Energy radio that 
also allows automatic communication with the paired CGM, as well as the Nova StatStrip® 
Xpress BG meter (Nova Biomedical). The iLet does not contain a cellular nor a WiFi radio, and 
does not accept input data from another mobile device (e.g., smartphone), other than the paired 
CGM and BG meter(s). 
The mathematical control algorithms (which are the same as those used in the iPhone-based 
BP), the CGM glucose engine (Dexcom), and the native user interface software, are all 
interconnected through controller framework software and reside as embedded systems on 
printed circuit boards contained within the device housing. The touchscreen-enabled, menu 
driven user interface and onboard processor provide a comprehensive and standalone 
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platform, which allows the iLet to operate independently of smartphones or other devices and 
without the need for internet support during routine operation. The graphical user interface of 
the iLet has the same user options and capabilities of the iPhone BP, including having its home 
screen password protected and its settings options only accessible to trial staff via a separate 
password. 
New Text: 
6.5 
iLet iPhone-based Bionic Pancreas  
Infusion sSet: A novel, dual cannula infusion set has been designed specifically for use with 
the iLet. Patients will wear dual channel tubing that will be attached to 2 infusion sets with 1 
steel cannula each, one for insulin infusion and the other for glucagon infusion. The tubing and 
infusion sets will have undergone sterilization prior to being delivered in a sealed pouch. The 
steel cannulae will be inserted in the abdominal SC tissue. Patients will wear 2 FDA-approved 
commercially available infusion sets, one for insulin infusion and one for glucagon 
infusion, when applicable. Infusion sets that are compatible with the Tandem t:slim 
insulin pump (luer lock connection) will be provided. 
Continuous gGlucose mMonitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to the 
controller. The sensor is powered by the battery within the transmitter that clips to the sensor 
and the whole assembly is held to the skin with an adhesive patch and communicates wirelessly 
with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM signal), it will be 
replaced promptly.  
Bionic Pancreas Control Unit: The control unit consists of a stock iPhone 4S and a DexCom 
G4 Platinum receiver connected with a custom hardware interface and placed 
back-to-back in a custom enclosure. The G4 receiver converts the raw wireless signal 
from the transmitter into an estimated BG signal that is sent via a hardwired connection 
to the iPhone.  
The iPhone runs iOS 6 in “Guided Access” mode, where the only app accessible to the 
patient is the Beta Bionics app, which runs the control algorithm. The home screen, 
where typical user options reside, is password protected. Access to other functions on 
the iPhone (primarily the Settings options) is separately password protected and only 
accessible to the study staff. This prevents accidental activation of other apps that could 
interfere with the function of the BP. The control algorithm app has a graphical user 
interface (GUI) that displays the current CGM glucose, a graphical history of the CGM 
glucose, and doses of insulin and glucagon delivered by the control algorithm. The GUI 
can also be used to input meal announcements, designating the size of the meal as 
larger than typical, typical in size, smaller than typical, or just a bite, and the type of meal 
as breakfast, lunch, or dinner. This will trigger a partial meal-priming bolus the size of 
which will adapt during the course of the trial to meet a target of 75% of the insulin needs 
for that size and type of meal.  
The target glucose level will be programmed to 100 mg/dL by the study engineers prior 
to the start of each experiment. This will be locked for each arm of the study; the patient 
will be unable to accidentally change or tamper with this setting.  
The GUI can be used to manage meal boluses and correction boluses during periods 
when the CGM is offline, such as the period after a sensor is replaced and before the 
new sensor has been calibrated. During these times the control algorithm will determine 
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and direct the administration of insulin basal rates based on the patient's weight. The 
controller will also administer insulin and/or glucagon as appropriate in response to any 
entered BG values, just as if they were CGM values. 
The GUI also displays visual alarms associated with an audio signal if communication 
is dropped between the CGM transmitter and the BP control unit or between the control 
unit and the 2 insulin pumps. 
The iPhone communicates wirelessly via the Bluetooth Low Energy (BTLE) protocol with 
2 Tandem t:slim insulin pumps to deliver insulin and glucagon. 
The iLet is being built according to Class III medical device standards, adheres to a 
comprehensive and robust quality system, and is fully compliant with International Organization 
for Standardization (ISO) 13485 standards and document control practices. The iLet is a 
fully integrated dual hormone BP system that integrates the CGM technology (currently the 
Dexcom G4 Share system) as well as 2 independent motor drivetrain pumping assemblies, 
which independently actuate the delivery of insulin and glucagon from pre filled cartridges that 
are separately loaded into the iLet housing. Each drivetrain assembly utilizes a lead screw, 
which is driven by a precision micromotor, a gear case assembly, and a motor controller unit, 
in a manner similar to what is commonly found in most insulin infusion pumps on the market 
today. The iLet has dosing accuracy that is comparable to FDA approved insulin pumps 
currently on the market. The iLet has a built in Bluetooth Low Energy radio that also allows 
automatic communication with the paired CGM, as well as the Nova StatStrip® Xpress BG meter 
(Nova Biomedical). The iLet does not contain a cellular nor a WiFi radio, and does not accept 
input data from another mobile device (e.g., smartphone), other than the paired CGM and BG 
meter(s). 
The mathematical control algorithms (which are the same as those used in the iPhone based 
BP), the CGM glucose engine (Dexcom), and the native user interface software, are all 
interconnected through controller framework software and reside as embedded systems on 
printed circuit boards contained within the device housing. The touchscreen enabled, menu 
driven user interface and onboard processor provide a comprehensive and standalone 
platform, which allows the iLet to operate independently of smartphones or other devices and 
without the need for internet support during routine operation. The graphical user interface of 
the iLet has the same user options and capabilities of the iPhone BP, including having its home 
screen password protected and its settings options only accessible to trial staff via a separate 
password. 
Tandem t:slim Pumps: These pumps are FDA-approved insulin pumps with reservoirs 
capable of holding 300 units (3 mL) of insulin or 3 mL of glucagon or ZP4207 solution. 
The pumps have a mechanical dosing resolution of 1/120 (0.00833) unit and can deliver 
liquids at a maximal rate of ~ 33 µl per minute (2 mL per hour). They are slave to the BP 
control unit and are controlled wirelessly via the BTLE protocol by the iPhone 4S. 
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INVESTIGATOR AGREEMENT
By signing below I agree that:
I have read this protocol. I approve this document and I agree that it contains all necessary 
details for carrying out the trial as described. I will conduct this trial in accordance with the 
design and specific provision of this protocol and will make a reasonable effort to complete 
the trial within the time designated. I will provide copies of this protocol and access to all 
information furnished by Zealand Pharma A/S to trial personnel under my supervision. I will 
discuss this material with them to ensure they are fully informed about the trial product and 
trial procedures. I will let them know that this information is confidential and proprietary to 
Zealand Pharma A/S and that it may not be further disclosed to third parties. I understand 
that the trial may be terminated or enrollment suspended at any time by Zealand Pharma 
A/S, with or without cause, or by me if it becomes necessary to protect the best interests of 
the trial patients.
I agree to conduct this trial in full accordance with Food and Drug Administration 
Regulations, Institutional Review Board/Ethic Committee Regulations and ICH Guidelines for 
Good Clinical Practices.
________
____________________
Investigator’s Signature
Date
______________________________________________
Investigator’s Printed Name
Steven J. Russell, MD, PhD
8/17/2016
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SYNOPSIS 
TITLE: The Bionic Pancreas Feasibility Trial Testing the Bionic Pancreas with ZP4207 
PROTOCOL NUMBER: ZP4207-16051 
INVESTIGATIONAL PRODUCT: ZP4207 
PHASE: 2 
INDICATION: ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid 
formulation which is being studied to improve glycemic control in adults (and children) with 
type 1 diabetes mellitus (T1DM) as part of a bihormonal bionic pancreas (BP). 
OBJECTIVES: 
Primary: The primary objective is to conduct a trial testing the safety and tolerability of the 
iPhone-based bionic pancreas (BP) when used with ZP4207 in 10 adult (≥18 years of age) 
patients with T1DM. 
Secondary: The secondary objectives are to measure glycemic regulation, including 
hypoglycemia exposure (percent of time spent with continuous glucose monitor [CGM] 
glucose <60 mg/dL), evaluate BP device reliability, and to document the satisfaction of 
patients with the iPhone-based BP with the goal of optimizing the functionality and user 
interface of the iPhone-based BP. 
POPULATION: Up to 20 adult (≥18 years of age) patients who already manage their T1DM 
using continuous subcutaneous (SC) insulin infusion pump therapy can be enrolled. It is 
expected that up to 10 patients will complete the trial protocol. 
TRIAL DESIGN: This trial is a single-center, open-label, randomized cross-over trial. The trial 
will enroll adult patients with T1DM and will assess the safety and efficacy of the iPhone-based 
BP using the glucagon analog ZP4207 versus the iPhone-based BP using Lilly glucagon. The 
iPhone-based BP will also administer insulin (insulin lispro, Lilly Humalog) using the same 
blood glucose (BG) control algorithm for both treatment arms. The trial will be conducted at a 
single center, the Massachusetts General Hospital Diabetes Center in Boston, MA. 
TRIAL TREATMENT: The trial involves SC administration of insulin lispro (Humalog, Lilly), 
which is commercially available by prescription and is indicated for patients with T1DM, but 
not for use in a BP. 
The trial also involves SC administration of Lilly glucagon in one iPhone-based BP arm. Lilly 
glucagon is commercially available by prescription and is indicated for patients with T1DM in 
severe hypoglycemia, but not for use in a BP.  
The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, in the 
other iPhone-based BP arm. ZP4207 will be made available by Zealand Pharma A/S, 
Denmark as liquid formulation in prefilled syringes of 0.6 mL. 
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PRIMARY ENDPOINT: 
The primary endpoint is the safety and tolerability of ZP4207 and the iPhone-based BP as 
assessed by: 
• 
Number and type of adverse events (AEs) 
• 
Clinical laboratory measurements 
• 
Vital signs 
• 
12-lead electrocardiogram (ECG) 
• 
Local tolerability and infusion site reactions as measured with the Draize scale 
• 
Immunogenicity as measured by anti-drug antibodies 
• 
Pain as measured on a 10 cm visual analog scale (VAS) 
• 
Nausea as measured on a 10 cm VAS 
 
SECONDARY ENDPOINTS: 
The secondary endpoints for the iPhone-based BP and ZP4207 include measurements of BP 
function as well as glycemic and non-glycemic measurements. 
 
Bionic Pancreas Function 
This endpoint data will be generated from the BP data during each treatment visit: 
• 
Average percent insulin dose amounts calculated by the BP control algorithm that are 
successfully delivered by the pump 
• 
Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts successfully issued to the pump by the BP control 
algorithm that are successfully delivered by the pump (calculated doses are not issued 
unless the pump is accessible and its delivery channel is available) 
o Average percent insulin dose amounts successfully issued to the pump by the 
BP control algorithm that are successfully delivered by the pump 
o Average percent glucagon/ZP4207 dose amounts successfully issued to the 
pump by the BP control algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts calculated by the BP algorithm that are successfully 
issued to the pump by the BP (calculated doses are not issued unless the pump is 
accessible and its delivery channel is available) 
o Average percent insulin dose amounts calculated by the BP control algorithm 
that are successfully issued by the BP 
o Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully issued by the BP 
• 
Average percent of 5-minute steps during which the BP is functioning nominally in all 
respects based on real-time CGM data (new CGM glucose reading captured, dose 
calculated, and dose issued to pumps)  
• 
Average percent of 5-minute steps during which the BP is functioning nominally with 
or without a new CGM glucose reading captured (dose calculated and dose issued to 
pumps). If a CGM signal is not available, the dose calculated may be based on weight 
or historical basal rates. 
• 
CGM reliability index, calculated as percent of possible values actually recorded by 
CGM 
• 
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter 
download 
• 
List of technical faults associated with the BP including cause and resolution 
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Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit: 
•
Fraction of time spent within each of the following glucose ranges:
o
<50 mg/dL
o
<60 mg/dL
o
<70 mg/dL
o
70-120 mg/dL
o
70-140 mg/dL
o
70-180 mg/dL
o
>180 mg/dL
o
>250 mg/dL
o
>300 mg/dL
•
Number of severe hypoglycemic events (patients unable to self-treat, requiring the
assistance of another person)
•
Number of episodes of symptomatic hypoglycemia
•
Number of carbohydrate interventions for hypoglycemia
•
Total grams of carbohydrates taken for hypoglycemia
•
Mean CGM glucose
Non-glycemic 
•
Glucagon/ZP4207 total delivery per kg of body mass
•
Insulin total delivery per kg of body mass
•
Number of unscheduled infusion set replacements
•
Number of unscheduled CGM sensor changes
EVALUATION OF TRIAL DATA: The following variables will be evaluated according to 
treatment for safety purposes: AEs, local tolerability, laboratory safety assessments, physical 
examination, vital signs, and 12-lead ECGs.  
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow. 
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SPONSOR: 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Tel: +45 88 77 36 00 
Fax: +45 88 77 38 98 
 
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TABLE OF CONTENTS 
SIGNATURE PAGE ............................................................................................................. 2 
INVESTIGATOR AGREEMENT .......................................................................................... 3 
SYNOPSIS ........................................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................... 8 
LIST OF FIGURES ............................................................................................................ 11 
LIST OF ABBREVIATIONS .............................................................................................. 12 
1 
INTRODUCTION AND BACKGROUND INFORMATION ...................................... 14 
1.1 
Background and Rationale ..................................................................................... 14 
1.2 
Bihormonal Bionic Pancreas System ..................................................................... 15 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System ........................ 16 
1.4 
ZP4207 ................................................................................................................... 18 
1.5 
Risk/Benefit ............................................................................................................ 19 
2 
TRIAL OBJECTIVES .............................................................................................. 22 
2.1 
Primary Objective ................................................................................................... 22 
2.2 
Secondary Objectives ............................................................................................. 22 
3 
TRIAL DESCRIPTION ............................................................................................ 22 
3.1 
Summary of Trial Design ........................................................................................ 22 
3.2 
Indication ................................................................................................................ 22 
3.3 
Number of Patients ................................................................................................. 22 
4 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................ 23 
4.1 
Inclusion Criteria ..................................................................................................... 23 
4.2 
Exclusion Criteria .................................................................................................... 23 
4.3 
Target Population ................................................................................................... 25 
4.4 
Withdrawal Criteria ................................................................................................. 25 
5 
ASSIGNMENT TO TREATMENT GROUPS........................................................... 26 
6 
TRIAL TREATMENT .............................................................................................. 26 
6.1 
Investigational Medicinal Products ......................................................................... 26 
6.2 
Storage and Drug Accountability of IMPs ............................................................... 26 
6.3 
Dispensing and Return of IMPs .............................................................................. 27 
6.4 
Doses ..................................................................................................................... 27 
6.5 
iPhone-based Bionic Pancreas .............................................................................. 27 
6.6 
Other Trial Devices ................................................................................................. 28 
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6.7 
Concomitant Medications ....................................................................................... 29 
6.7.1 
Permitted Medications and/or Procedures ...................................................... 29 
6.7.2 
Excluded Medications and/or Procedures ....................................................... 29 
7 
TRIAL PROCEDURES ........................................................................................... 29 
7.1 
Informed Consent ................................................................................................... 29 
7.2 
Screening Visit (Visit 1) .......................................................................................... 30 
7.2.1 
Data Collected at Screening ............................................................................ 30 
7.3 
Training Visit (Visit 2) .............................................................................................. 30 
7.4 
Treatment Visits (Visit 3 and Visit 4) ....................................................................... 31 
7.4.1 
Visit Procedures .............................................................................................. 31 
7.4.2 
Data Collected During the Treatment Visits .................................................... 34 
7.4.3 
Response to Hypoglycemia ............................................................................. 35 
7.4.4 
Response to Hyperglycemia ........................................................................... 35 
7.4.5 
Response to Nausea/Vomiting ........................................................................ 36 
7.4.6 
Response to Other Medical Needs ................................................................. 36 
7.4.7 
Monitoring of Bionic Pancreas Performance ................................................... 36 
7.4.8 
Supervision by Trial Staff ................................................................................ 36 
7.5 
Phone Call (Visit 5) ................................................................................................. 36 
7.6 
Follow-up Visit (Visit 6) ........................................................................................... 36 
8 
ENDPOINTS ........................................................................................................... 36 
8.1 
Primary Endpoint .................................................................................................... 36 
8.2 
Secondary Endpoints ............................................................................................. 37 
8.2.1 
Bionic Pancreas Function ................................................................................ 37 
8.2.2 
Glycemic .......................................................................................................... 37 
8.2.3 
Non-glycemic ................................................................................................... 38 
9 
LABORATORY ASSESSMENTS ........................................................................... 38 
9.1 
Safety Laboratory Assessments ............................................................................. 38 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) .............................................. 38 
9.3 
Exposure Assessments (ZP4207 and Glucagon) ................................................... 38 
9.4 
Anti-drug Antibody Assessments ............................................................................ 38 
10 
SAFETY REPORTING ............................................................................................ 39 
10.1 
Adverse Events ...................................................................................................... 39 
10.1.1 
Follow-up of Adverse Events ........................................................................... 39 
10.1.2 
Precautions ..................................................................................................... 40 
10.1.3 
Assessment of Adverse Events by the Investigator ........................................ 40 
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10.2 
Serious Adverse Events ......................................................................................... 41 
10.3 
Adverse Event Reporting – Procedures for Investigators ....................................... 41 
10.4 
Pregnancy Reporting .............................................................................................. 43 
10.5 
Hypoglycemia ......................................................................................................... 44 
10.6 
Safety Monitoring .................................................................................................... 44 
10.6.1 
Data and Safety Monitoring Board .................................................................. 44 
10.6.2 
Zealand Pharma Safety Committee ................................................................ 45 
11 
STATISTICS ........................................................................................................... 45 
11.1 
Analysis Populations .............................................................................................. 45 
11.2 
Statistical Methods ................................................................................................. 46 
11.2.1 
Analysis of Safety ............................................................................................ 46 
11.2.2 
Analysis of Efficacy ......................................................................................... 46 
11.2.3 
Interim Analysis ............................................................................................... 47 
11.2.4 
Sample Size Determination ............................................................................. 47 
12 
DATA MANAGEMENT AND RECORD KEEPING ................................................ 47 
12.1 
Data Handling ......................................................................................................... 47 
12.2 
Computer Systems ................................................................................................. 47 
12.3 
Data Entry ............................................................................................................... 48 
12.4 
Medical Information Coding .................................................................................... 48 
12.5 
Data Validation ....................................................................................................... 48 
12.6 
Record Keeping ...................................................................................................... 48 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ........................... 48 
13.1 
Ethical Conduct of the Trial .................................................................................... 48 
13.2 
Institutional Review Board ...................................................................................... 48 
13.3 
Informed Consent ................................................................................................... 49 
13.4 
Trial Monitoring Requirements ............................................................................... 49 
13.5 
Disclosure of Data .................................................................................................. 50 
13.6 
Retention of Records .............................................................................................. 50 
13.7 
Publication Policy ................................................................................................... 51 
13.8 
Legal Aspects ......................................................................................................... 51 
13.9 
Sponsor Discontinuation Criteria ............................................................................ 51 
13.10 
Patient Compensation ......................................................................................... 52 
14 
TRIAL ADMINISTRATIVE INFORMATION ............................................................ 52 
14.1 
Protocol Amendments ............................................................................................ 52 
14.2 
Address List ............................................................................................................ 52 
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14.2.1 
Sponsor ........................................................................................................... 52 
14.2.2 
Supplier of Device ........................................................................................... 53 
14.2.3 
Principal Investigator (Site) ............................................................................. 53 
14.2.4 
Contract Research Organization (Including Monitoring) ................................. 53 
14.2.5 
Medical Monitoring .......................................................................................... 53 
14.2.6 
Pharmacovigilance .......................................................................................... 53 
14.2.7 
Central Laboratory (Safety Laboratory and Plasma Glucose) ......................... 54 
14.2.8 
Special Laboratory (ZP4207 Exposure and ADA Analyses) ........................... 54 
14.2.9 
Special Laboratory (Glucagon Exposure) ....................................................... 54 
15 
REFERENCES ........................................................................................................ 55 
APPENDIX A: SCHEDULE OF PROCEDURES ............................................................... 56 
APPENDIX B: CLINICAL LABORATORY ANALYTES ................................................... 58 
APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES ....................................... 59 
LIST OF FIGURES 
Figure 1. 
Outpatient Results Summarizing the Distribution of Mean CGM Glucose 
Levels and Hypoglycemia in the BP and Control Arms ............................. 17 
Figure 2. 
Trial Design Schematic ................................................................................. 22 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
BG 
Blood glucose 
BP 
Bionic pancreas 
BTLE 
Bluetooth Low Energy 
BU 
Boston University 
CFR 
Code of Federal Regulations 
CGM 
Continuous glucose monitor 
CRO 
Contract research organization 
DBR 
Database review 
DPP-4 
Dipeptidyl peptidase-4 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FHD 
First Human Dose 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GUI 
Graphical user interface 
HCG 
Human chorionic gonadotropin 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
MD 
Doctor of Medicine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH 
Massachusetts General Hospital 
MPC 
Model-predictive control 
PD 
Pharmacodynamic 
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Abbreviation 
Definition 
PK 
Pharmacokinetic 
RN 
Registered nurse 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SGLT-2 
Sodium-glucose co-transporter-2 
SIV 
Site Initiation Visit 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 diabetes mellitus 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
 
 
 
 
 
 
 
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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background and Rationale 
To date, clinical trials conducted by Boston University (BU) and Massachusetts General 
Hospital (MGH) in patients with type 1 diabetes mellitus (T1DM) have demonstrated the 
practicality of a wearable automated bionic pancreas (BP) control system for robust glucose 
regulation using a continuous glucose monitor (CGM) to provide the input to the control 
system. Despite current technical limitations in CGMs and infusion pumps, the trials by 
BU/MGH have shown that a bihormonal BP is capable of achieving safe and effective blood 
glucose (BG) control automatically, with minimal hypoglycemia during 11 continuous days in 
the face of unrestrained meals and exercise and with trivial patient input (optional 
announcement of meals).  
The BP provides automatic BG regulation and reduces hypoglycemic episodes. Additionally, 
the system spares the wearer the relentless tasks of carbohydrate counting, frequent BG 
monitoring, estimating the effects of specific meals and exercise activity on BG levels, and 
manual drug administration, which are inexact, demanding, aggravating, and require 
continuous diligence and vigilance. The degree of glycemic control achieved by the BP is 
predicted to dramatically reduce the deleterious and debilitating complications of T1DM. 
In its last tested embodiment, the BP consisted of a Dexcom G4 CGM, and an iPhone that are 
hardwired together, with the iPhone running the control algorithm and communicating via 
Bluetooth with 2 Tandem t:slim pumps to dose insulin and glucagon. 
In order to provide automatic BG regulation, the iPhone-based BP has the ability to deliver 
both insulin and glucagon. However, currently available glucagon formulations have limited 
stability at room temperature, necessitating frequent changes to the glucagon infusion set. 
Therefore, the current trial is designed to test the glucagon analog ZP4207 in the 
iPhone-based BP, as this peptide analog of human glucagon is provided in a liquid formulation 
stable at room temperature. 
The current trial is a first feasibility trial designed to use the iPhone-based BP to compare 
ZP4207 with marketed glucagon (Lilly). The trial is intended to demonstrate the safety and 
tolerability of ZP4207 in the iPhone-based BP and the feasibility of achieving comparable 
autonomous glycemic control. It is not intended to comprehensively demonstrate the definitive 
efficacy of the iPhone-based BP in extended, continuous daily use, but rather to demonstrate 
its functionality and accuracy in a practical, albeit very controlled, clinical setting. The trial is 
expected to provide practical information that will benefit the design of a next-generation BP 
and help pave the way for a more comprehensive outpatient home-use Phase 2 trial and 
ultimately a pivotal trial where comprehensive safety and efficacy through continuous full daily 
use of the BP with ZP4207 will be documented. 
The data derived from this trial will permit evaluation of the robustness of the iPhone-based 
BP as well as the safety and efficacy of ZP4207 when used in conjunction with the 
iPhone-based BP.  
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1.2 
Bihormonal Bionic Pancreas System 
The BP is an autonomous, self-learning system that requires only the patient's weight for 
initialization, and then autonomously adapts, modestly or dramatically, as needed, to cope 
with the wide range of insulin requirements of adults, adolescents, and pre-adolescents with 
T1DM. The BP obviates the need for the patient to know, or even appreciate, their insulin 
requirements, and renders obsolete any need for patients or caregivers to know 
carbohydrate-to-insulin ratios, basal rates, or insulin correction factors. 
The core technology is a suite of control algorithms that orchestrate the automated dosing of 
insulin and glucagon to regulate BG levels. An insulin controller orchestrates all subcutaneous 
(SC) insulin dosing. At its centerpiece is a model-predictive control (MPC) algorithm, which 
bases insulin doses on the glucose data and insulin absorption kinetics, compensating for the 
slow absorption rate of SC insulin analogs (peak time in blood of 30-90 min, clearance in 
4-8 hr). This enables the algorithm to refrain from stacking and overdosing insulin. 
Furthermore, the MPC algorithm automatically adjusts its insulin-dosing aggressiveness 
continuously and in real-time to different insulin needs between individuals and variable needs 
within the same individual. Running in parallel with the MPC algorithm is an algorithm that 
automatically modulates basal insulin delivery over multiple time scales, and another algorithm 
that automatically adapts insulin doses in response to optional meal announcements. Unlike 
current insulin pumps and the insulin-only control algorithms, the adaptive basal insulin 
algorithm obviates the need for the user to set, or even know, his or her “basal-rate profile.” 
Instead, it is capable of automatically adapting to, and compensating for, changes in an 
individual's basal insulin need, such as might occur over a period of hours, days, or weeks 
(e.g., circadian hormonal fluctuations, intercurrent illness, physical activity, or emotional state) 
or as might occur over a period of months or years due to developmental changes 
(e.g., hormonal changes that occur during puberty or menopause). The adaptive meal dose 
controller obviates the need for the user to set, or even know, his or her 
“carbohydrate-to-insulin ratios,” as it makes automatic adjustments based on dosing history 
for similar meal announcements made on previous days, and customizes the dose for each 
individual and for time of day.  
The BP also includes a proportional-derivative algorithm governing SC micro-doses of 
glucagon to help prevent impending hypoglycemia. Glucagon dosing is based on the glucose 
level and rate of descent. It may occur preemptively even if glucose is above range, and it 
includes a feedback term to account for the pending effects of recent glucagon doses.  
Taken together, these mathematical algorithms provide a universal framework for a glycemic 
control strategy that requires no quantitative input from, or participation by, the user (besides 
entering body weight to initialize the system), but which automatically adapts insulin and 
glucagon dosing to meet the individual needs of each user. Another challenge met is enabling 
the technology to remain completely autonomous in managing insulin and glucagon delivery 
even when the CGM is offline. Specifically, when the CGM is offline, the BP invokes the 
high-resolution “basal rate profile” that it had recently learned and stored when the CGM was 
online. On the basis of what the system learned and stored about meal announcements when 
the CGM was online, it is able to respond to meal announcements in the same manner when 
the CGM is offline. Finally, it automatically responds to user-entered BG values when the CGM 
is offline by issuing a correction dose of insulin or glucagon based on what it learned about 
the user's insulin and glucagon needs when the CGM was online. Thus, the BP never relies 
on, or burdens the user with, the determination of subjective dosing decisions, which inevitably 
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vary in quality and reliability among different users. The BP provides a turnkey solution for 
people with T1DM that comprehensively manages glycemia across a broad range of individual 
needs and across a large spectrum of circumstances and challenges to glycemic control. 
A significant challenge for the use of glucagon in a bihormonal BP is the lack of a commercially 
available glucagon formation that is stable and well-suited to infusion over several days in a 
pump reservoir. However, BU/MGH have proceeded with studies using a relatively unstable 
marketed formulation that must be reconstituted from a lyophilized powder on a daily basis. 
This allowed BU/MGH to proceed with studies of the bihormonal system while awaiting the 
production of stable glucagon formulations or stable glucagon analogs. 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System 
The BP hardware platform has evolved over the years from a laptop-driven system, which was 
used in all inpatient studies to the first truly mobile wearable iPhone-driven platform, which 
has been used in a number of outpatient studies. Using the iPhone-based BP system, 
>110 outpatient experiments of 5-11 days in duration in each subject have been conducted 
(>800 patient days or >2 patient years of data) across subjects ranging in age between 6 and 
76 years old and in body mass between 21 and 128 kg. The robust adaptation capabilities of 
the BP is evident in the fact that the average total daily dose of insulin among these subjects 
varied by over 13-fold (from 11 to 145 units/day). 
In November 2012, Food and Drug Administration (FDA) approval was obtained to conduct 
the first outpatient study testing the BP in adults 21 years or older with T1DM. This study, 
referred to as the Beacon Hill Study, followed a random-order cross-over design in which 
20 adults with T1DM participated in 5 days on the iPhone-based BP and 5 days of usual care 
in which they wore a CGM with blinded display and muted alarms. In the BP arm, subjects 
kept to a 3-square-mile geographic area centered around the Beacon Hill neighborhood in 
Boston. They ate as they chose at local restaurants, and exercised at will with access to 
2 gyms. Analysis was pre-specified to focus on Days 2-5, since glycemic control is more 
representative of BP performance after most of the adaptation by the BP occurs on Day 1 
(Russell, 2014). Results are summarized in Figure 1.  
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In April 2013, FDA approval was obtained to conduct the first outpatient study testing the BP 
in adolescents 12-20 years old with T1DM. This study, referred to as the 2013 Summer Camp 
Study, followed a random-order cross-over design in which 32 adolescents with T1DM 
participated in 5 days on the BP and 5 days of supervised camp care in which they wore a 
CGM with blinded display and muted alarms. Subjects were fully integrated into normal camp 
activities without restrictions on diet or exercise. The study used the same iPhone-based BP 
that was used in the Beacon Hill Study. Results are summarized in Figure 1 (Russell, 2014). 
In April 2014, FDA approval was obtained to conduct the first outpatient study testing the BP 
in pre-adolescents 6-11 years old with T1DM. This study, referred to as the 2014 Summer 
Camp Study, was similar in design to the 2013 Summer Camp Study. Results are summarized 
in Figure 1 (Russell, 2016).  
In April 2014, FDA approval was obtained to conduct the first multi-center study, which was 
also the first home study, to test the BP in adults 18 years or older with T1DM. This study, 
referred to as the Bionic Pancreas Multi-Center Study, followed a random-order cross-over 
design in which 39 adults participated in 11 days on the BP and 11 days of usual care. 
Participants went to work as usual, and lived and slept at home, all without clinical supervision. 
There were no restrictions placed on diet or exercise. The study included 4 medical centers 
(10 subjects per center), which included MGH, the University of Massachusetts Medical 
School, Stanford University, and the University of North Carolina at Chapel Hill. Results are 
summarized in Figure 1.  
All of these studies used marketed glucagon (glucagon for injection, Eli Lilly). Due to its limited 
stability, Lilly glucagon must be reconstituted immediately before use. Animal studies have 
previously shown that despite its limited chemical stability, Lilly glucagon maintains its 
biological activity for up to 7 days in solution. Using this data, an Investigational New Drug 
(IND) exemption was obtained from the FDA for its use in a pump for up to 27 hours. This 
allowed these studies to be performed by asking volunteers to reconstitute a new vial of 
glucagon and fill the glucagon pump at approximately the same time every day. However, 
marketed Lilly glucagon has no path forward for approval for chronic BP use. 
1.4 
ZP4207 
ZP4207 is a peptide analog of human glucagon that is being developed to treat hypoglycemia 
in patients with T1DM and type 2 diabetes mellitus. ZP4207 exhibits improved physical and 
chemical stability in aqueous media and is suitable for liquid formulation. ZP4207 is comprised 
of 29 amino acids and has 7 amino acid substitutions when compared to native glucagon.  
Two clinical Phase 1 trials have been conducted to establish safety and tolerability of ZP4207 
after single and multiple dosing to healthy patients and T1DM patients under insulin-induced 
hypoglycemic conditions. 
The First Human Dose (FHD) trial (ZP4207-14013) was finalized in April 2015. The trial was 
a randomized, double-blinded trial with the objectives to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of ZP4207 as compared to an active 
comparator. Part 1 included a single ascending dose in healthy volunteers in cohorts of 8. In 
each cohort, the patients were randomized 3:1 to ZP4207 (n=6) or Novo Nordisk GlucaGen® 
(n=2). Five cohorts with SC administration (0.01, 0.1, 0.3, 1.0, and 2.0 mg ZP4207 compared 
to 1 mg GlucaGen) and 3 cohorts with intramuscular (IM) administration (0.3, 1.0, and 2.0 mg 
ZP4207 compared to 1 mg GlucaGen) were included. Part 2 included 2 sequence groups of 
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10 hypoglycemic T1DM patients. The patients were treated with fixed single IM doses of 
0.7 mg ZP4207 and 1.0 mg GlucaGen in a sequential cross-over design in a randomized 
treatment order.  
The second clinical trial (ZP4207-15007) was a single-center, double-blind, Phase 1b trial 
investigating the safety and tolerability, PK and PD of ZP4207 following repeated 
administration in healthy volunteers compared to placebo. It was finalized in July 2015. Each 
of the 3 cohorts comprised 8 subjects, who received 5 repeated SC doses of ZP4207 or 
placebo in a 3:1 treatment allocation. The first cohort started with the lowest dose of 0.1 mg. 
Cohort 2 and 3 continued with 0.3 and 1.0 mg, respectively. 
The Phase 1 results did not give rise to specific safety concerns, beyond those related to the 
pharmacological effect of ZP4207. All adverse events (AEs) recorded in the trials were of mild 
or moderate severity. The most frequent systemic AE related to treatment with ZP4207 was 
nausea, which is a known side-effect following administration of glucagon. The most frequent 
injection site reaction was transient erythema, occurring in all ZP4207, glucagon, and placebo 
treatment groups, irrespective of dose. No anti-drug antibodies (ADA) incidences were 
observed. 
The observed PD response, in terms of increased plasma glucose, in insulin-induced 
hypoglycemic patients with T1DM following dosing with 0.7 mg ZP4207 administered IM was 
similar to that observed following IM dosing with 1.0 mg glucagon (GlucaGen, Novo Nordisk). 
An increase in plasma glucose of ≥20 mg/dL from hypoglycemic levels was achieved within 
30 minutes for all patients. 
In terms of PK, ZP4207 had a short half-life and high clearance and dose proportionality for 
both maximum plasma concentration and area under the concentration-time curve from 
time 0 to 300 minutes in the dose range 0.1 to 2.0 mg following SC administration. Following 
IM administration, dose proportionality was shown in the investigated dose range of 0.3 to 
2.0 mg. The PK properties of 0.7 mg ZP4207 IM were comparable with those of 1.0 mg 
glucagon (GlucaGen, Novo Nordisk) with IM administration. 
1.5 
Risk/Benefit 
While the potential risks are minimal, the findings of this trial may reveal information that can 
substantially improve medical care for persons with diabetes. Therefore, the overall 
risk/benefit for patients participating in this trial is assessed as acceptable. 
Potential Risks and Discomforts  
Trial patients will be informed by the Investigator of the potential risks of ZP4207 and other 
trial-related procedures before they enter the trial.  
In this trial, patients with T1DM will be included to test the safety and efficacy of the 
iPhone-based BP using ZP4207 versus the iPhone-based BP using Lilly glucagon. The 
cross-over design with inclusion of the same T1DM patients into the 2 treatment arms in a 
randomized order will allow for a direct comparison of the safety and efficacy of the 
2 treatments, based on intra-patient variability only.  
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Patients may experience mild discomfort associated with the insertion of the infusion sets and 
sensor into the SC tissues. The risk of discomfort due to insertion of infusion sets and sensors 
is expected to be slightly greater than in their lives outside the trial because more infusion sets 
will be inserted and a CGM sensor will be inserted. Most patients will use only one infusion 
set and not all will use a CGM sensor in usual care.  
 
There is a potential risk of hypoglycemia, since recombinant insulin analog will be 
administered. Due to frequent monitoring of glucose and direct supervision by a registered 
nurse (RN) or Doctor of Medicine (MD) at all times, the risk of a hypoglycemic episodes leading 
to significant harm to patients is expected to be substantially lower than their risk during their 
usual therapy.  
 
There is a risk of hyperglycemia. This risk is expected to be less than the risk during the 
patients’ lives outside of the trial based on data from earlier BP trials and the design of this 
trial.  
 
Treatment with ZP4207 and marketed glucagon can result in undesired effects or complaints. 
Undesired effects and complaints such as gastrointestinal side effects including nausea, 
vomiting, and diarrhea are known side effects of glucagon administration at higher dose levels. 
The frequency of nausea associated with the administration of 1 mg of glucagon according to 
the Summary of Product Characteristics (SPC) for Glucagon is described to be between 1/10 
and 1/100. The frequency of vomiting is described to be between 1/100 and 1/1000 
(Novo Nordisk, 2015). Similar gastrointestinal side effects have also been observed to a 
limited degree in the 2 clinical trials conducted with ZP4207, again at higher dose levels. The 
individual doses of ZP4207 and Lilly glucagon delivered by the BP are expected to be 
significantly lower than doses typically associated with nausea. Episodes of low blood 
pressure have also been observed after administration of higher doses of glucagon and 
ZP4207. As with every novel drug substance, new and yet unknown side effects may also 
occur. 
 
There are limited data available to describe the immunogenic potential of glucagon products 
available on the market, but the data available indicate that marketed glucagon only has a 
small immunogenic potential. A Phase 1 trial performed with recombinant human glucagon 
and animal derived glucagon in 75 healthy patients did not show signs of ADA measured 
13 weeks after trial product administration (Eli Lilly, 2005). In the ZP4207 FHD trial, 
ZP4207-14013, no confirmed anti-ZP4207 or anti-glucagon antibodies were detected in any 
of the samples. In addition, the 5 sequential administrations of ZP4207, as applied in trial 
ZP4207-15007, were not associated with the development of antibodies against ZP4207 in 
the 18 subjects enrolled to receive ZP4207. The optimized formulation of ZP4207, as applied 
in the present trial is not expected to change the immunogenic potential of the Investigational 
Medicinal Product (IMP).  
 
In relation to diabetes therapy, development of insulin-antibodies is documented more 
substantially and route of administration has been shown to influence immunogenic potential 
of insulins. However, these antibodies against insulin generally do not have an impact on 
insulin action and are thus not clinically relevant. 
 
In terms of consequence, development of high titer antibodies against ZP4207 could, in theory 
reduce the activity of endogenous glucagon, which again, in theory could influence 
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hypoglycemic episodes. However, most patients with T1DM do not secrete glucagon normally 
in response to hypoglycemia, so they would be less likely to be negatively impacted by 
anti-glucagon antibodies. Limited suppression of glucagon would, however, not be considered 
critical, as low glucose levels can also be corrected by other means, including oral intake of 
glucose and by other endogenous hormones such as oxyntomodulin.  
Overall, ZP4207 is judged to be a low-risk molecule, based upon the available clinical data as 
well as the outcome of the risk-based approach to the immunogenicity assessment made. The 
present trial will include sampling for measurement of antibodies against ZP4207 prior to first 
dosing (Visit 3) and at the Follow-up Visit. In line with regulatory guidance documents, these 
samples will be appropriately analyzed and the results will be included in the overall 
assessment of the immunogenic potential of ZP4207 after completion of each trial and as the 
clinical development program advances. 
Administration of ZP4207 may be associated with a risk of allergic reactions similar to those 
observed for other therapeutic peptides or proteins. Patients with known or suspected allergies 
to the trial products or related products will be excluded from the trial. Mild or moderate allergic 
reactions may include symptoms of rash, fever, flu-like symptoms, nausea, headache, and 
myalgia. Acute generalized hypersensitivity reactions are usually very rare but may include 
symptoms of flushing, sweating, dizziness, change in blood pressure, and difficulties in 
breathing. The risk of acute hypersensitivity reactions is described to be less than 1/10,000 
for native glucagon. No severe acute hypersensitivity reactions have been observed in the 
2 clinical trials conducted with ZP4207.  
Potential Benefits 
Based on experiences from previous trials of the BP and the design of this trial, patients 
enrolled in the trial may benefit from a reduction in risk of hypoglycemia and hyperglycemia 
and a better mean glucose compared to their usual diabetes care during their short trial 
participation.  
The data derived from this trial will allow evaluation of safety and tolerability of ZP4207 in the 
iPhone-based BP. 
This trial is a necessary step in preparing the BP with ZP4207 to become available to people 
with T1DM. Wide availability of the BP with ZP4207 could improve the medical care of adults 
and children with T1DM. 
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2 
TRIAL OBJECTIVES  
2.1 
Primary Objective 
The primary objective is to conduct a trial testing the safety and tolerability of the iPhone-based 
BP when used with ZP4207 in 10 adult (≥18 years of age) patients with T1DM. 
2.2 
Secondary Objectives 
The secondary objectives are to measure glycemic regulation, including hypoglycemia 
exposure (percent of time spent with CGM glucose <60 mg/dL), evaluate BP device reliability, 
and to document the satisfaction of patients with the iPhone-based BP with the goal of 
optimizing the functionality and user interface of the iPhone-based BP. 
3 
TRIAL DESCRIPTION 
3.1 
Summary of Trial Design 
This trial is a single-center, open-label, randomized cross-over trial. The trial will enroll adult 
patients with T1DM and will assess the safety and efficacy of the iPhone-based BP using the 
glucagon analog ZP4207 versus the iPhone-based BP using Lilly glucagon. The 
iPhone-based BP will also administer insulin (insulin lispro, Lilly Humalog) using the same BG 
control algorithm for both treatment arms. The trial will be conducted at a single center, the 
MGH Diabetes Center in Boston, MA. 
The overall trial design schematic is displayed in Figure 2. 
Figure 2. 
Trial Design Schematic 
BP= bionic pancreas. 
3.2 
Indication 
ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid formulation which 
is being studied to improve glycemic control in adults (and children) with T1DM as part of a 
bihormonal BP. 
3.3 
Number of Patients 
Up to 20 adult patients with T1DM can be enrolled. The upper bound is based on the 
expectation that some patients will be excluded after the Screening Visit and the possibility 
that some patients may have to be discontinued before completion (due to, for instance, 
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inter-current illness or patient withdrawal). It is expected that up to 10 patients will complete 
the trial protocol. 
4 
SELECTION AND WITHDRAWAL OF PATIENTS 
The trial will enroll patients who already manage their T1DM using continuous SC insulin 
infusion pump therapy. This requirement is imposed because multiple daily injection therapy 
involves the use of medium-acting or long-acting basal insulin that would require an extended 
washout period. 
4.1 
Inclusion Criteria 
1.
Male and female patients with T1DM for at least 1 year, as defined by the American
Diabetes Association
2.
Age ≥18 years
3.
Diabetes managed using an insulin pump for ≥6 months
4.
Prescription medication regimen stable for >1 month (except for medications that will
not affect the safety of the trial and are not expected to affect any outcome of the trial,
in the judgment of the Investigator)
5.
Informed consent obtained before any trial-related activities (trial-related activities are
any procedure that would not have been performed during normal management of the
patient)
6.
Patients in good health according to age (medical history, physical examination, vital
signs, 12-lead electrocardiograms [ECGs], laboratory assessments), as judged by the
Investigator
4.2 
Exclusion Criteria  
1.
Unable to provide informed consent (e.g., impaired cognition or judgment)
2.
Unable to safely comply with trial procedures and reporting requirements
(e.g., impairment of vision or dexterity that prevents safe operation of the BP, impaired
memory, unable to speak and read English)
3.
Participation in another clinical trial of an investigational agent or device concurrently
or within 1 month (or 5 half-lives) prior to the Screening Visit
4.
Previous exposure to ZP4207
5.
Females of childbearing potential who are pregnant (positive urine human chorionic
gonadotropin [HCG]), breast feeding, plan to become pregnant in the immediate future,
or sexually active without using highly effective contraception methods (highly effective
methods are considered those with a failure rate less than 1% undesired pregnancies
per year including surgical sterilization, hormonal intrauterine devices [coil], oral
hormonal contraceptives, sexual abstinence, or a surgically sterilized partner) or
postmenopausal 
women 
amenorrheic 
for 
less 
than 
1 year 
with 
serum
follicle-stimulating hormone (FSH) level ≤40 IU/L and not using highly effective
contraceptive methods during the trial and until 1 month after last dosing in the trial
6.
Male who is sexually active and not surgically sterilized who or whose partner(s) is not
using highly effective contraceptive methods (highly effective contraceptive measures
include surgical sterilization, hormonal intrauterine devices [coil], oral hormonal
contraceptives, each in combination with spermicide-coated condoms), or who is not
willing to refrain from sexual intercourse from the first dosing until 1 month after last
dosing in the trial
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7.
Current alcohol abuse (intake averaging >3 drinks daily in last 30 days) or use within
the last 6 months of controlled substances without a prescription (other than marijuana)
8.
New onset clinically significant illness within 4 weeks prior to screening, as judged by
the Investigator
9.
Unwilling or unable to refrain on the treatment visits from:
a.
Acetaminophen in any form
b.
Use of drugs that may dull the sensorium, reduce sensitivity to symptoms of
hypoglycemia, or hinder decision making during the period of participation in
the trial (use of beta blockers will be allowed as long as the dose is stable and
the patient does not meet the criteria for hypoglycemia unawareness while
taking that stable dose, but use of benzodiazepines or narcotics, even if by
prescription, may be excluded according to the judgment of the Investigator)
10. History of liver disease that is expected to interfere with the anti-hypoglycemia action
of glucagon (e.g., liver failure or cirrhosis). Other liver disease (i.e., active hepatitis,
steatosis, active biliary disease, any tumor of the liver, hemochromatosis, glycogen
storage disease) may exclude the patient if it causes significant compromise to liver
function or may do so in an unpredictable fashion.
11. Aspartate 
aminotransferase >2 
× 
upper limit of 
normal (ULN), alanine
aminotransferase >2 × ULN, or bilirubin >1.5 × ULN on screening laboratories
12. Renal failure on dialysis or estimated glomerular filtration rate <30 mL/min/1.73 m2 on
screening laboratories
13. Hemoglobin <12 gm/dL for men and <11 gm/dL for women
14. Personal history of cystic fibrosis, pancreatitis, pancreatic tumor, or any other
pancreatic disease besides T1DM
15. Any known history of coronary artery disease including, but not limited to, history of
myocardial infarction, stress test showing ischemia, history of angina, or history of
intervention such as coronary artery bypass grafting, percutaneous coronary
intervention, or enzymatic lysis of a presumed coronary occlusion)
16. Congestive heart failure with New York Heart Association Functional Classification III
or IV
17. History of transient ischemic attack or stroke in the last 12 months
18. Seizure disorder, history of any non-hypoglycemic seizure within the last 2 years, or
ongoing treatment with anticonvulsants
19. History of hypoglycemic seizures (grand-mal) or coma in the last 12 months
20. History of hypoglycemic unawareness in the last 12 months
21. History of pheochromocytoma: fractionated metanephrines will be tested in patients
with history increasing the risk for a catecholamine secreting tumor:
a.
Episodic or treatment refractory (requiring 4 or more medications to achieve
normotension) hypertension
b.
Paroxysms of tachycardia, pallor, or headache
c.
Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or
von Hippel-Lindau disease
22. History of adrenal disease or tumor
23. Hypertension with systolic blood pressure ≥160 mm Hg or diastolic blood pressure
≥100 mm Hg despite treatment
24. Untreated or inadequately treated mental illness (indicators would include symptoms
such as psychosis, hallucinations, mania, and any psychiatric hospitalization in the last
year), or treatment with anti-psychotic medications that are known to affect glucose
regulation
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5 
ASSIGNMENT TO TREATMENT GROUPS 
This trial is an open-label, randomized cross-over trial. Patients who have completed the 
Screening Visit and meet all of the inclusion and none of exclusion criteria will be enrolled into 
the trial. All patients will participate in two 1-day treatment arms in random order 
(iPhone-based BP using ZP4207 and iPhone-based BP using Lilly glucagon) according to a 
pre-generated randomization scheme. Up to 2 patients may participate in the trial per day. 
The order of the iPhone-based BP visits will be randomized in blocks of 2 patients. 
6 
TRIAL TREATMENT 
6.1 
Investigational Medicinal Products 
Insulin: The trial involves SC administration of insulin lispro (Humalog, Lilly), which is 
commercially available by prescription and is indicated for patients with T1DM, but not for use 
in a BP. 
Glucagon: The trial also involves SC administration of Lilly glucagon in one iPhone-based BP 
arm. Lilly glucagon is commercially available by prescription and is indicated for patients with 
T1DM in severe hypoglycemia, but not for use in a BP. 
ZP4207: The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, 
in the other iPhone-based BP arm. ZP4207 will be made available by Zealand Pharma A/S, 
Denmark as liquid formulation in prefilled syringes of 0.6 mL. 
6.2 
Storage and Drug Accountability of IMPs 
All IMPs will be stored and handled in accordance with the Sponsor’s instructions and/or the 
product labeling at the Investigator’s site, e.g., refrigerated (+2ºC to +8ºC) and should not be 
exposed to excessive heat, direct sunlight and never be frozen. 
All used, partly used, and unused vials or prefilled syringes must be kept by the Investigator 
and stored between +2ºC and +8ºC (unused) or at room temperature (partly used and used). 
Used and unused pre-filled syringes must be stored separately.  
The Investigator must ensure the availability of proper storage conditions and record and 
evaluate the temperature. Temperature of the refrigerator used for drug storage is monitored 
continuously, an alarm system is established. The Investigator must inform the monitor 
immediately if any IMP has been stored outside specified conditions (e.g., outside temperature 
storage). Investigational Medicinal Product that has been stored improperly must not be 
dispensed to any patient before it has been re-evaluated and approved for further use. The 
Investigator must take appropriate action to ensure correct storage. 
For the IMP, the Investigator must keep an accurate record of all IMPs received and the 
products used for each patient in a Drug Accountability Record. Storage locations, batch 
numbers, and expiry dates are also documented in this form. 
The drug accountability must be performed in a timely manner by the monitor. 
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6.3 
Dispensing and Return of IMPs 
No IMPs may be dispensed to any person not enrolled in the trial. 
Upon completion of the trial, the Sponsor will be responsible for destruction or storage of IMPs 
(used, partially used, or unused). These duties can be delegated to a contract research 
organization (CRO) and must be documented in the trial files. 
6.4 
Doses 
The iPhone-based BP can administer isolated insulin-glucagon doses once every 5 minutes. 
A single automated bolus of insulin will not exceed 3 units per 5-minute dose (30 µl of U-100 
insulin) in both systems, and a single meal-priming dose, in response to a meal announcement 
made by the user, will not exceed 12 units (120 µl of U-100 insulin). A single bolus of glucagon 
will not exceed 80 µg (80 µl of 1 mg/mL Lilly glucagon or 1 mg/mL ZP4207). In prior studies, 
typical doses of glucagon were in the range of 0.005-0.04 mg per dose. The iPhone-based BP 
is capable of administering as little as ~0.1 µl (0.011 units of U-100 insulin or 0.1 µg of 1 mg/mL 
ZP4207). 
It is expected that the mean total daily doses of glucagon/ZP4207 will be <1.0 mg daily as in 
previous studies. The mean daily glucagon dose in a previous 11-day outpatient trial was 
0.5 mg/day (range 0.2-0.9 mg/day). Currently, single doses of up to 2 mg ZP4207 have been 
administered in clinical trials. The recommended dose of marketed glucagon for adult patients 
suffering from severe hypoglycemia is 1 mg as a single injection. Mean glucagon levels in 
previous inpatient studies have been above the normal fasting range for glucagon only 1% of 
the time. Therefore, the glucagon exposure of patients is expected to be modest. 
6.5 
iPhone-based Bionic Pancreas 
Infusion Set: Patients will wear 2 FDA-approved commercially available infusion sets, one for 
insulin infusion and one for glucagon infusion, when applicable. Infusion sets that are 
compatible with the Tandem t:slim infusion pump (luer lock connection) will be provided. 
Continuous Glucose Monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to 
the controller. The sensor is powered by the battery within the transmitter that clips to the 
sensor and the whole assembly is held to the skin with an adhesive patch and communicates 
wirelessly with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM 
signal), it will be replaced promptly.  
Bionic Pancreas Control Unit: The control unit consists of a stock iPhone 4S and a DexCom 
G4 Platinum receiver connected with a custom hardware interface and placed back-to-back 
in a custom enclosure. The G4 receiver converts the raw wireless signal from the transmitter 
into an estimated BG signal that is sent via a hardwired connection to the iPhone.  
The iPhone runs iOS 6 in “Guided Access” mode, where the only app accessible to the patient 
is the Beta Bionics app, which runs the control algorithm. The home screen, where typical user 
options reside, is password protected. Access to other functions on the iPhone (primarily the 
Settings options) is separately password protected and only accessible to the study staff. This 
prevents accidental activation of other apps that could interfere with the function of the BP. 
The control algorithm app has a graphical user interface (GUI) that displays the current CGM 
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glucose, a graphical history of the CGM glucose, and doses of insulin and glucagon delivered 
by the control algorithm. The GUI can also be used to input meal announcements, designating 
the size of the meal as larger than typical, typical in size, smaller than typical, or just a bite, 
and the type of meal as breakfast, lunch, or dinner. This will trigger a partial meal-priming 
bolus the size of which will adapt during the course of the trial to meet a target of 75% of the 
insulin needs for that size and type of meal.  
 
The target glucose level will be programmed to 100 mg/dL by the study engineers prior to the 
start of each experiment. This will be locked for each arm of the study; the patient will be 
unable to accidentally change or tamper with this setting.  
 
The GUI can be used to manage meal boluses and correction boluses during periods when 
the CGM is offline, such as the period after a sensor is replaced and before the new sensor 
has been calibrated. During these times the control algorithm will determine and direct the 
administration of insulin basal rates based on the patient's weight. The controller will also 
administer insulin and/or glucagon as appropriate in response to any entered BG values, just 
as if they were CGM values. 
 
The GUI also displays visual alarms associated with an audio signal if communication is 
dropped between the CGM transmitter and the BP control unit or between the control unit and 
the 2 insulin pumps. 
 
 
The iPhone communicates wirelessly via the Bluetooth Low Energy (BTLE) protocol with 
2 Tandem t:slim insulin pumps to deliver insulin and glucagon. 
 
Tandem t:slim Pumps: These pumps are FDA-approved insulin pumps with reservoirs 
capable of holding 300 units (3 mL) of insulin or 3 mL of glucagon or ZP4207 solution. The 
pumps have a mechanical dosing resolution of 1/120 (0.00833) unit and can deliver liquids at 
a maximal rate of ~33 µl per minute (2 ml per hour). They are slave to the BP control unit and 
are controlled wirelessly via the BTLE protocol by the iPhone 4S. 
 
6.6 
Other Trial Devices  
YSI 2300 STAT Plus™ (Yellow Springs Instruments): The YSI 2300 STAT Plus is an 
FDA-approved glucose analyzer. Blood glucose measurements using the YSI 2300 STAT 
Plus will be obtained off of the IV line during both treatment visits.   
 
Nova Biomedical StatStrip® Xpress Glucose Meter: The Nova StatStrip Xpress glucose 
meter is an FDA-approved glucose meter that is commercially available. Blood glucose 
measurements for CGM calibration will be obtained with the Nova StatStrip Xpress during both 
treatment visits if the YSI 2300 STAT Plus fails and via fingerstick with the Nova StatStrip 
Xpress during any periods when IV blood samples are not available for any reason or the IV 
fails. 
 
Exercise Bike: The trial will utilize a stationary exercise bike (ergometer) for the in-clinic 
exercise at the treatment visits. This bike will be stored at the Diabetes Research Center when 
not in use. 
 
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6.7 
Concomitant Medications 
6.7.1 
Permitted Medications and/or Procedures 
Patients may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference with 
CGM sensing. All concomitant medications, including over-the-counter medications, should 
be recorded. 
Use of beta blockers will be allowed as long as the dose is stable and the patient does not 
meet the criteria for hypoglycemia unawareness while taking that stable dose. 
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911. 
6.7.2 
Excluded Medications and/or Procedures 
During the trial, patients will not use any recreational drugs or drugs of abuse. The need to 
take prescription drugs that dull the sensorium, reduce sensitivity to symptoms of 
hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion from the 
trial or discontinuation of participation, a decision that will be made by the Investigator. 
Use of benzodiazepines or narcotics, even if by prescription, may be excluded according to 
the judgment of the Investigator. Use of oral anti-diabetic medications (e.g., thiazolidinediones, 
biguanides, sulfonylureas, glitinides, DPP-4 inhibitors, SGLT-2 inhibitors) will also be 
excluded. 
7 
TRIAL PROCEDURES  
7.1 
Informed Consent 
After potential patients have had time to review the consent document, and prior to any 
trial-related activities, they will meet with a trial MD or designee who will explain the trial, 
answer any questions, and administer informed consent. In the event that a volunteer is a 
patient of one of the trial MDs, another staff MD or designee will answer questions and 
administer consent. The patients will be fully informed of their responsibilities and their rights 
while participating in the trial as well as of the possible risks and potential benefits of 
participation in the trial. They will have the opportunity to discuss all questions and ample time 
to consider participation. 
Trial-related activities are any procedures that would not have been performed during normal 
management of the patient. Patients who wish to participate in the trial will be asked to 
personally date and sign an informed consent form (ICF). Likewise, the Investigator must also 
personally date and sign the ICF. All patients will be provided with a copy of their own signed 
and dated ICF. 
Trial staff will answer any questions that the patients may have during their participation. They 
will share any new information in a timely manner that may be relevant to the patient's 
willingness to continue participating in the trial. The patients may choose to discontinue their 
participation at any time.  
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7.2 
Screening Visit (Visit 1) 
All patients will have a Screening Visit to confirm eligibility. The patient will be interviewed and 
the electronic Case Report Form (eCRF) will be completed by trial staff to establish whether 
the patient is eligible. 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits per the 
medical judgment of the Investigator. 
Once all of the results have been returned, a trial MD will review the eCRF to determine patient 
eligibility. If a patient is not eligible to continue in the trial, the results of abnormal tests will be 
reported to the patient and to a health care provider of their choosing. 
7.2.1 
Data Collected at Screening 
•
Age, sex, race, and ethnicity
•
Date of last menstrual period in female patients
•
Medical, surgical, and social history, allergies, and review of systems relevant to
inclusion and exclusion criteria, including:
o
Date of diabetes diagnosis
o
Duration of insulin pump use and type of insulin used in pump
o
Type/model of insulin pump
o
Insulin regimen (basal rate, sensitivity factor, and carbohydrate ratio)
o
Average total daily dose of insulin in the last 30 days as available (from pump
history)
o
Usage of CGM, if any (type of CGM, days per month worn, usage of data,
whether insulin is dosed based on CGM alone, alarm settings)
•
Concomitant illness (any illness present at screening)
•
Concomitant medications (prescription and non-prescription) and date of last change
in medication regimen
•
Height, weight, physical examination, and vital signs including body temperature and
blood pressure
•
12-lead ECG
•
Hemoglobin A1c
•
Chemistry and hematology samples (see Appendix B)
•
Urine HCG pregnancy test for women of childbearing potential
•
FSH level for postmenopausal women amenorrheic for less than 1 year
•
Fractionated plasma metanephrines (if indicated by history)
7.3 
Training Visit (Visit 2) 
A Training Visit will take place before the first treatment visit. Patients will be trained in the 
insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. Trial staff 
will verify that the patients have understood the material and are competent to participate 
safely in the trial. Patients will be instructed concerning diabetes management (e.g., basal 
insulin rate adjustment by insulin pump) during fasting prior to and between the treatment 
visits per the medical judgment of the Investigator. Concomitant medications will also be 
reviewed. 
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7.4 
Treatment Visits (Visit 3 and Visit 4) 
• 
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 
30 days after screening (Visit 1). 
• 
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum 
of 3 weeks between Visit 3 and Visit 4. 
• 
Up to 2 patients may participate per day.  
• 
Each patient will participate in 2 treatment visits: one with the iPhone-based BP using 
ZP4207 and one with the iPhone-based BP using Lilly glucagon in a randomized order. 
• 
The night before the treatment visit, patients will place a Dexcom G4 CGM sensor in 
the abdominal skin and calibrate the sensor when prompted using the provided Nova 
StatStrip Xpress meter. Patients will be instructed to call if they encounter any difficulty 
with their CGM.  
• 
Patients will be responsible for their own medications other than insulin during the trial. 
Any medical advice needed by the patients during their participation that is not directly 
related to BG control should be obtained from them in their usual manner. Patients 
may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference 
with CGM sensing. If patients experience urgent or emergent medical concerns 
outside the scope of diabetes care and their primary care physicians, they will be taken 
to the MGH walk-in clinic or emergency room, or if necessary call 911. 
• 
During the trial, patients will not use any recreational drugs or drugs of abuse. The 
need to take prescription drugs that dull the sensorium, reduce sensitivity to symptoms 
of hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion 
from the trial or discontinuation of participation, a decision that will be made by the 
Investigator.  
• 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits 
per the medical judgment of the Investigator. 
• 
Patients will not tamper with the BP, including changing any settings. 
• 
Patients may not remove the BP during the trial unless the BP failed or they are 
withdrawing from the trial. 
• 
The exact time of each procedure and assessment will be documented. 
7.4.1 
Visit Procedures  
• 
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the 
BP having fasted since 12:00 AM the night before (treatment with simple carbohydrate 
of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled 
within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the 
visit window. If BG is <50 mg/dL, treatment with simple carbohydrate is allowed. If the 
patient experiences persistent hypoglycemia, the visit will be rescheduled within the 
visit window. If the visit needs to be rescheduled due to hypoglycemia or 
hyperglycemia, trial staff will assist the patient with insulin or medication adjustments 
to address glycemic control. The patient will be instructed to contact trial staff later in 
the day if his or her BG remains uncontrolled. 
• 
Upon arrival to the visit, the patient’s weight and vital signs including body temperature 
and blood pressure will be documented. 
• 
Patient reports of symptoms, any other complaints, and AEs will be reviewed. 
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•
Concomitant medications will be recorded.
•
Chemistry and hematology samples will be collected at visit start (see Appendix B).
•
ADA samples will be collected before the start of dosing (Visit 3 only).
•
A 12-lead ECG will be performed.
•
A urine HCG pregnancy test will be performed in female patients of childbearing
potential. If the test is positive, the patient will be informed of the result and the visit
will be ended.
•
Patients will complete a baseline survey about their attitudes and experience with their
usual diabetes care.
•
An intravenous (IV) catheter will be placed for blood sampling.
•
Trial staff will assist the patient to calibrate their CGM, review the trial procedures again
and assist with the setup of the BP system, including inserting and priming infusion
sets.
•
The control algorithm will be initialized only with the patient’s weight. Diagnostics will
be performed to ensure that the CGM device is appropriately calibrated and that all of
the components of the BP systems are in working order.
•
The basal rate of the patient’s own insulin infusion pump will be changed to be 2-fold
higher than weighted mean of the basal rate during the trial period. This is intended to
increase the usage of glucagon during the treatment visit.
•
The patients will continue to wear their own infusion pump infusing at the temporary
2-fold basal rate throughout the visit until the start of the structured exercise period, in
addition to the BP.
•
The staff will start the BP as close as possible to a minute divisible by 5 minutes
(i.e., on a 5-minute mark). The starting time will be considered Hour 0.
•
Additional calibrations will be performed at any of the BG checks throughout the day if
the CGM value does not meet the International Organization for Standardization
standard (<15 mg/dL difference for BG values <75 mg/dL; <20% absolute difference
for BG values >75 mg/dL) at the time of the BG measurement AND it is a good time to
calibrate (the CGM trend arrow is flat and there has been no carbohydrate intake in
the last 30 minutes or glucagon boluses in the last 15 minutes).
•
Blood samples will be taken from the IV at least hourly and processed for plasma
ZP4207/glucagon. If BG is <150 mg/dL, more frequent samples for plasma
ZP4207/glucagon may be drawn at the discretion of the Investigator. The actual time
of sampling will be recorded in the eCRF.
•
Plasma glucose samples will be taken from the IV at least hourly in parallel with
ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT Plus.
If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes.
If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then
sampling will be every 10 minutes. The actual time of sampling will be recorded in the
eCRF.
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• 
Patients will be asked to rate any nausea and/or infusion site pain on 10 cm visual 
analog scales (VAS) at the beginning of the visit once the infusion sites have been 
placed but no drug has yet been administered, then approximately at the top of every 
hour during the visit, and at the end of the visit. Trial staff will also evaluate their infusion 
sites to document any erythema or edema at the same times. If moderate or severe 
pain is reported or swelling or redness occurs at the infusion site, the infusion site will 
be replaced in a different location. If moderate or severe pain, swelling, or redness 
continues at the old site for more than 30 minutes after the infusion site is removed, or 
if moderate or severe pain, swelling, or redness occurs at the new site, all infusion 
sites will be removed and the patient will be discontinued from the study. Any such 
symptoms will be followed until resolution. 
• 
From the start of closed loop control until approximately Hour 3, the patients will 
continue to fast. 
• 
Between approximately Hour 3 and Hour 4, patients will be provided with a lunch meal 
of their choice in the Diabetes Research Center from a menu of choices from nearby 
restaurants. They will be asked to choose a meal that is a “typical meal” for them. The 
content of their meal will not be restricted in any way, with the exception that the 
number of carbohydrates should be in the “typical” range for them at lunch, and that 
they must eat the same meal at the same time during both visits. 
• 
At approximately 15 minutes before the meal, patients will administer a bolus for the 
meal with their own insulin pump based on the carbohydrate count for the meal. 
• 
After lunch is completed, the patients will not be allowed any carbohydrate intake 
(non-caloric drinks will be permitted) until the trial is completed (except as necessary 
to treat hypoglycemia), to allow the BP to control the post-prandial BG without further 
interruption.  
• 
Between approximately Hour 6 and Hour 7, the patients will start a period of structured 
exercise. 
• 
At the start of the exercise period, patients will restore their normal basal insulin profile 
so that they will not have elevated insulin levels at the end of the study period when 
they are to transition back to their usual care.  
• 
Patients will exercise on a stationary bike with a heart rate from 120-140 beats per 
minute for a total of 4,000 heart beats (approximately 30 minutes). Patients will rate 
their exercise intensity using the Borg scale every 5 minutes, with the target intensity 
level between 12 and 14. Heart rate will be measured every 5 minutes. 
• 
BG measurements will be obtained off of the IV line every 10 minutes. If BG is 
<80 mg/dL, BG measurements will be obtained off of the IV line every 5 minutes.  
o 
Carbohydrates will be given for any BG <50 mg/dL according to the following 
protocol: Dextrose (g) = BSA (m2)/[1.7 m2 (women) or 1.9 m2 (men)] *15 g. 
o 
Repeat treatments will be given at 15-minute intervals as long as BG remains 
<50 mg/dL.  
• 
If there is an interruption in the Dexcom CGM output, trial staff will assist the patient in 
recovering CGM data streaming. If this requires replacement of the CGM sensor, BGs 
will be checked every 10 minutes (every 5 minutes if BG is <80 mg/dL) using blood 
from the IV until the CGM is able to be calibrated again. These BGs will be entered 
into the BP, which will treat them as CGM values and dose insulin and/or glucagon 
appropriately. 
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•
If there is a complete failure of the BP operation, patients will take over their own BG
control using their personal insulin pump until the BP can be brought back online. If BP
control cannot be promptly resumed (e.g., within 30 minutes), the patient may be asked
to repeat that trial day once.
•
Patients may choose to withdraw from the trial at any time. If they withdraw from the
trial, they should alert a provider immediately.
•
Just prior to the end of the study visit, vital signs including body temperature and blood
pressure will be obtained and a 12-lead ECG will be performed.
•
After approximately Hour 8, but not earlier than at least 60 minutes after end of
exercise, the BP will be stopped and the patient will continue with their personal insulin
pump.
•
If the patient experiences seizure or unconsciousness, persistent nausea or vomiting,
diabetic ketoacidosis, persistent hyperglycemia with ketonemia, hemodynamic
changes such as hypotension, or other medically significant findings, a longer
observation period at the trial site may be necessary until the patient is considered
stable for discharge. If the Investigator or trial staff determines that the patient requires
further observation or treatment, the patient may be transferred to the emergency room
for additional monitoring and/or medical care. At discharge, patients will be provided
with any necessary instructions concerning personal insulin pump usage, food intake,
and driving arrangements.
•
The maximum amount of blood loss per study visit will be approximately 230 mL. The
total blood loss for the entire study will be up to 460 mL.
•
Patients will answer questionnaires (see Appendix C).
•
Chemistry and hematology samples will be collected at visit end (see Appendix B).
•
The BP and glucose meters will be collected and downloaded.
•
A trial MD will review the last several hours of insulin and glucagon dosing and assist
the patient in resuming their usual diabetes care. A longer observation period at the
trial site may be necessary. Patients will be instructed to call trial staff with any
questions, issues, or concerns.
7.4.2 
Data Collected During the Treatment Visits 
•
CGM glucose every 5 minutes from the Dexcom G4 Platinum CGM
•
All BG measurements taken
•
Insulin total dose by the BP and the patient’s own insulin pump
•
Glucagon total dose
•
Timing and content of the meal eaten and carbohydrate amount
•
Timing of meal announcement and size of meal announced
•
Timing and glucose values at calibrations
•
Timing and amount of carbohydrates taken for hypoglycemia
•
Data from a questionnaire about attitudes and expectations regarding the BP before
and after each treatment arm (see Appendix C)
•
Time patients were not under BP control for any reason
•
List of technical faults associated with the BP including cause and resolution
•
ZP4207/glucagon sampling will be collected at least hourly. If BG is <150 mg/dL, more
frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the
Investigator.
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• 
Plasma glucose sampling will be collected at least hourly in parallel with 
ZP4207/glucagon exposure sampling. If BG is <150 mg/dL, then sampling will be every 
30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is 
<80 mg/dL, then sampling will be every 10 minutes. 
• 
Nausea and infusion site pain on a VAS at visit start (after insertion and before any 
drug administration), hourly, and at visit end  
• 
Infusion site reaction according to the Draize scale at visit start (after insertion and 
before any drug administration), hourly, and at visit end  
• 
Patient reports of symptoms, any other complaints, and AEs 
• 
Vital signs including body temperature and blood pressure (at visit start and visit end) 
and weight 
• 
Concomitant medications 
• 
Chemistry and hematology samples (see Appendix B) at visit start and visit end 
• 
ADA (Visit 3 only)  
• 
12-lead ECG at visit start and visit end 
• 
Urine HCG pregnancy test for women of childbearing potential 
7.4.3 
Response to Hypoglycemia  
• 
Patients are encouraged to check their BG for any symptoms of hypoglycemia.  
• 
Patients will be permitted to take 15 grams of carbohydrates for any BG value 
<60 mg/dL. Trial staff will ensure proper functioning of the BP, infusion set, and insulin 
pump, and will encourage the patient to wait for the BP to treat the low blood sugar for 
as long as they feel comfortable. 
• 
Patients will be required to take 15 grams of carbohydrates for any BG value 
<50 mg/dL. After treatment of hypoglycemia, a follow-up measurement will be taken 
15 minutes later. Repeated measurements will be taken every 15 minutes until the 
BG is >60 mg/dL. Treatment will be repeated if subsequent BG values are still 
<50 mg/dL. All carbohydrate treatments for hypoglycemia will be documented by trial 
staff (amount and time).  
• 
Trial staff will check the infusion site, BP, and insulin pump for normal operation any 
time hypoglycemia occurs. If there is any suspicion of infusion set malfunction, the site 
should be replaced. Trial staff will check the BP for any malfunction and correct any 
problems that are found. 
• 
If no correctable fault is found, but there is doubt regarding the correct function of the 
BP system, an entirely new backup BP system may be started. 
• 
If a patient experiences a seizure or unconsciousness associated with hypoglycemia, 
his or her participation in the trial will be discontinued.  
7.4.4 
Response to Hyperglycemia  
• 
Trial staff will check the infusion site, BP, and insulin pump for normal operation any 
time BG is >300 mg/dL. If there is any suspicion of infusion set malfunction, the site 
should be replaced. Trial staff will check the BP for any malfunction and correct any 
problems that are found. If the BG remains >300 mg/dL for 2 hours despite 
troubleshooting, blood ketones will be measured. If the blood ketone result is 
>1.5 mmol/L, the visit will be stopped and rescheduled. The patient will be provided 
with insulin and a syringe to give an injection based on their correction factor. 
• 
If a patient experiences diabetic ketoacidosis, his or her participation in the trial will be 
discontinued. 
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•
If no correctable fault is found, but there is doubt regarding the correct function of the
BP system, the treatment visit may be stopped and the visit rescheduled.
7.4.5 
Response to Nausea/Vomiting 
If significant nausea (e.g., that prevents the patient from eating normally) or any vomiting 
occurs, trial staff will notify the Investigator. Trial staff will assist the patient in troubleshooting, 
such as checking BG and the calibration of the CGM (excessive glucagon dosing may occur 
if the CGM is reading lower than the true BG). If a patient experiences persistent nausea and 
vomiting thought to be related to glucagon dosing, his or her participation in the trial will be 
discontinued. 
7.4.6 
Response to Other Medical Needs  
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911.  
7.4.7 
Monitoring of Bionic Pancreas Performance 
Bionic pancreas inventors and developers 
, 
, and/or an 
engineer trained by them will be readily available by phone for consultation for the trial staff at 
all times during the course of the trial.  
7.4.8 
Supervision by Trial Staff  
A trial MD will be on call at all times during the course of the trial. An RN or MD will be with 
the trial patients in the Diabetes Research Center at all times. 
7.5 
Phone Call (Visit 5) 
A phone call will be conducted 7 days ±3 days following the last day of dosing (Visit 4) to 
review AEs and concomitant medications. 
7.6 
Follow-up Visit (Visit 6) 
Patients will return for a Follow-up Visit 25 days ±4 days following the last day of dosing 
(Visit 4), for chemistry, hematology, and ADA sampling, and a review of AEs and concomitant 
medications.  
8 
ENDPOINTS  
8.1 
Primary Endpoint 
The primary endpoint is the safety and tolerability of ZP4207 and the iPhone-based BP as 
assessed by: 
•
Number and type of AEs
•
Clinical laboratory measurements
•
Vital signs
•
12-lead ECG
•
Local tolerability and infusion site reactions as measured with the Draize scale
•
Immunogenicity as measured by ADA
•
Pain as measured on a 10 cm VAS
•
Nausea as measured on a 10 cm VAS
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8.2 
Secondary Endpoints 
The secondary endpoints for the iPhone-based BP and ZP4207 include measurements of BP 
function as well as glycemic and non-glycemic measurements. 
8.2.1 
Bionic Pancreas Function  
This endpoint data will be generated from the BP data during each treatment visit: 
• 
Average percent insulin dose amounts calculated by the BP control algorithm that are 
successfully delivered by the pump 
• 
Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts successfully issued to the pump by the BP control 
algorithm that are successfully delivered by the pump (calculated doses are not issued 
unless the pump is accessible and its delivery channel is available) 
o Average percent insulin dose amounts successfully issued to the pump by the 
BP control algorithm that are successfully delivered by the pump 
o Average percent glucagon/ZP4207 dose amounts successfully issued to the 
pump by the BP control algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts calculated by the BP algorithm that are successfully 
issued to the pump by the BP (calculated doses are not issued unless the pump is 
accessible and its delivery channel is available) 
o Average percent insulin dose amounts calculated by the BP control algorithm 
that are successfully issued by the BP 
o Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully issued by the BP 
• 
Average percent of 5-minute steps during which the BP is functioning nominally in all 
respects based on real-time CGM data (new CGM glucose reading captured, dose 
calculated, and dose issued to pumps)  
• 
Average percent of 5-minute steps during which the BP is functioning nominally with 
or without a new CGM glucose reading captured (dose calculated and dose issued to 
pumps). If a CGM signal is not available, the dose calculated may be based on weight 
or historical basal rates. 
• 
CGM reliability index, calculated as percent of possible values actually recorded by 
CGM 
• 
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter 
download 
• 
List of technical faults associated with the BP including cause and resolution 
8.2.2 
Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit: 
• 
Fraction of time spent within each of the following glucose ranges: 
o <50 mg/dL 
o <60 mg/dL 
o <70 mg/dL 
o 70-120 mg/dL 
o 70-140 mg/dL 
o 70-180 mg/dL  
o >180 mg/dL 
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o >250 mg/dL 
o >300 mg/dL 
• 
Number of severe hypoglycemic events (patients unable to self-treat, requiring the 
assistance of another person) 
• 
Number of episodes of symptomatic hypoglycemia 
• 
Number of carbohydrate interventions for hypoglycemia 
• 
Total grams of carbohydrates taken for hypoglycemia 
• 
Mean CGM glucose 
8.2.3 
Non-glycemic  
• 
Glucagon/ZP4207 total delivery per kg of body mass 
• 
Insulin total delivery per kg of body mass 
• 
Number of unscheduled infusion set replacements 
• 
Number of unscheduled CGM sensor changes 
9 
LABORATORY ASSESSMENTS 
Descriptions of sample handling and sample processing, storage, and shipment at the site will 
be included in the laboratory manual. 
 
The responsible laboratories are listed in the address list. 
 
9.1 
Safety Laboratory Assessments 
Chemistry and hematology samples will be collected at specified time points. See Appendix A 
for the schedule of procedures and Appendix B for a list of clinical laboratory analytes. 
 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) 
At Visit 3 and Visit 4, plasma glucose samples will be taken from the IV at least hourly in 
parallel with ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT 
Plus. If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for 
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is 
<100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will 
be every 10 minutes. The actual time of sampling will be recorded in the eCRF. 
 
9.3 
Exposure Assessments (ZP4207 and Glucagon) 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the 
discretion of the Investigator. The actual time of sampling will be recorded in the eCRF. 
 
Bioanalytical Reports will be prepared. 
 
9.4 
Anti-drug Antibody Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken at Visit 3 and the Follow-up Visit 6. 
 
Bioanalytical Reports will be prepared. 
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10 
SAFETY REPORTING 
10.1 
Adverse Events 
An AE is any untoward medical occurrence in a trial patient administered an IMP and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be 
any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not considered related to 
the IMP. Patients should be instructed to report any AE they experience to the Investigator. 
Note: This includes events from the first trial-related activity from Visit 3.  
AEs for ZP4207 include: 
•
A clinically significant worsening of a concomitant illness
•
A clinical laboratory abnormality which is clinically significant, i.e., any abnormality that
suggests a disease and/or organ toxicity and is of a severity that requires active
management. Active management includes active treatment or further investigations,
for example, change of medicine dose or more frequent follow-up due to the
abnormality.
•
Hypoglycemic episodes  
•
Injection site reactions
The following should not be recorded as AEs, if recorded prior to randomization (on the 
Screening Form or the eCRF): 
•
Pre-planned procedure, unless the condition for which the procedure was planned has
worsened from the first trial-related activity from Visit 3. 
•
Pre-existing conditions found as a result of screening procedures (pre-existing
conditions should be reported as medical history or concomitant illness). 
For known (listed) AEs for Glucagon and Humalog, please refer to SPC for Glucagon and 
Humalog. 
10.1.1 
Follow-up of Adverse Events 
All AEs that are ongoing at the end of the patient’s participation in the trial will be followed-up 
until the event is resolved or reaches a satisfactory outcome as deemed by the Investigator. 
Follow-up actions for all serious adverse events (SAEs) will be performed according to 
appropriate clinical care practices and may depend on the nature of the event. These will be 
determined after internal review and/or Sponsor review. The follow-up information should only 
include new (updated and/or additional) information that reflects the situation at the time of the 
Investigator’s signature. 
Follow-up information on (S)AEs will be updated using the (S)AE Form. If a non-serious event 
becomes serious during the follow-up, the AE Form and SAE Form must be used and reporting 
timelines follow those of an SAE. 
The Investigator must forward follow-up information on SAEs, and if previously non-serious 
AEs become SAEs, to the Sponsor. 
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10.1.2 
Precautions 
Normal precautions taken for a human trial will be taken during this trial. Qualified and 
well-trained physicians and medical staff will instruct the patients. During a patient’s 
participation in the trial, the Investigator should ensure that adequate medical care is provided 
to the patient for any AEs, including clinically significant laboratory values related to the trial. 
The Investigator should inform the patient when medical care is needed for intercurrent 
illnesses of which the Investigator becomes aware.  
 
For further information on safety precautions for ZP4207, Lilly glucagon, Lilly Humalog, and 
the iPhone-based BP, please refer to the current version of the Investigator’s Brochure (IB) 
for ZP4207 (Zealand Pharma A/S, 2015, or any updates hereof), and the SPC for Glucagon 
(Eli Lilly, 2012) and Humalog (Eli Lilly, 2015), respectively. 
10.1.3 
Assessment of Adverse Events by the Investigator  
 
Intensity of an Adverse Event 
The maximum intensity (severity) of all AEs must be assessed by the Investigator and 
documented. Severity should be graded when the AE outcome is known: 
• 
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
• 
Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the patient. 
• 
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
 
A “severe” reaction does not necessarily deem the AE as “serious,” and an SAE may not be 
“severe” in nature. 
 
Causality Relationship to IMP 
Insulin (insulin lispro, Lilly Humalog), glucagon (glucagon for injection, Eli Lilly), and ZP4207 
are all regarded as IMP. 
 
The causality of each AE should be assessed by the Investigator according to the following 
classification: 
• 
Related: Good reason and sufficient documentation to assume a causal relationship. 
• 
Not related: No relationship to trial product can be established. 
 
Outcome of an Adverse Event 
The outcome of all AEs must be assessed by the Investigator and documented by his/her 
staff. The following definitions should be used: 
• 
Recovered/resolved: The patient has fully recovered, or by medical or surgical 
treatment the condition has returned to the level observed at the first trial-related 
activity from Visit 3. 
• 
Recovering/resolving: The condition is improving and the patient is expected to recover 
from the event. This term is only applicable if the patient has completed the trial. 
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• 
Recovered/resolved with sequelae: The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment, or procedure. If a sequela meets 
an SAE criterion, the AE must be reported as an SAE. 
• 
Not recovered/not resolved: The condition of the patient has not improved and the 
symptoms are unchanged, or the outcome is not known. 
• 
Fatal: This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he/she died should 
be assessed as “recovered/resolved,” “recovering/resolving,” “recovered/resolved with 
sequelae,” or “not recovered/not resolved.” An AE with a fatal outcome must be 
reported as an SAE. 
• 
Unknown: This term is only applicable if the patient is lost to follow-up. 
 
10.2 
Serious Adverse Events   
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death  
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Medically important 
 
Medical judgement must be exercised in deciding whether an AE is believed to be “medically 
important.” Medically important events may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above. 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is an AE fulfilling one of the criteria of seriousness and being assessed as related 
to an IMP, the nature or severity of which is not consistent with the applicable reference 
document (e.g., ZP4207 IB or package leaflet/SPC for an approved product). 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety, any life-threatening problem or 
death caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the application; or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. 
 
10.3 
Adverse Event Reporting – Procedures for Investigators  
The Principal Investigator and co-investigators will review any AEs and report any SAEs to 
the Sponsor as soon as possible and within 24 hours of obtaining knowledge of the event. The 
Principal Investigator and co-investigators will promptly report AEs to the Partner’s Institutional 
Review Board (IRB) and to the BU IRB (unless oversight is ceded by the BU IRB to the 
Partners IRB), in accordance with local requirements.  
 
Ed Damiano is the Sponsor of the Investigational Device Exception for the BP and Zealand 
Pharma A/S is the Sponsor of the IND for ZP4207.  
 
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 The following must be collected:  
• 
Initial information of the pregnancy  
• 
Information on the outcome of the pregnancy, including the health status of the 
newborn infant(s) at the age of 1 month 
• 
All AEs in connection with the pregnancy and pregnancy outcome must be reported 
on the pregnancy forms. It must be clear in the description if the event occurs in the 
patient/patient’s partner, the fetus, or the newborn infant. 
• 
All SAEs in connection with the pregnancy and pregnancy outcome must be reported 
on the pregnancy forms following the same timelines as required for other SAEs. It 
must be clear in the description if the event occurs in the patient/patient’s partner, the 
fetus, or the newborn infant.  
 
The SAEs that must be reported include abnormal outcome – such as congenital anomalies, 
fetal death, and termination of pregnancy (spontaneous or elective abortion), including any 
anomalies of the fetus observed at gross examination or during autopsy – as well as other 
pregnancy complications (ectopic pregnancy) fulfilling the criteria of an SAE. 
 
10.5 
Hypoglycemia 
Hypoglycemia will be regarded as an AE and will be recorded and documented on an AE 
Form. For the purposes of AE reporting, the following definitions of hypoglycemia will be used: 
• 
Symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia 
are accompanied by a BG concentration ≤70 mg/dL 
• 
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of 
hypoglycemia but with a BG concentration ≤50 mg/dL 
• 
Severe hypoglycemia: an event requiring assistance of another person to actively 
administer carbohydrates, glucagon, or take other corrective actions 
 
10.6 
Safety Monitoring 
10.6.1 
Data and Safety Monitoring Board 
An external DSMB will oversee the conduct of the trial, as set forth in the DSMB Charter. 
Additionally, the DSMB will be informed in the event of any serious and unexpected AEs. The 
DSMB will be informed if there are any changes to the trial protocol that could significantly 
impact the safety or scientific validity of the trial. A final DSMB meeting will convene after the 
completion of the trial. 
 
The participation of individual patients will be discontinued if they experience: 
• 
Seizure or unconsciousness associated with hypoglycemia and associated with 
participation in the trial  
• 
Persistent nausea and vomiting thought to be related to glucagon dosing associated 
with participation in the trial 
• 
Hospitalization associated with participation in the trial 
• 
Pregnancy 
• 
Diabetic ketoacidosis 
 
If more than 1 patient must be withdrawn from the trial for these reasons, the trial will stop and 
a vote of the DSMB will be required to restart it. All AEs that are serious and unexpected but 
related will be reported to the DSMB within 5 working days. 
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Note that patients may discontinue participation at any time. Patients may be removed from 
the trial for other reasons, for instance, failure to comply with trial procedures or intercurrent 
illness that is unrelated to the BP but that precludes safe participation. Discontinuation of 
participation for these reasons will not contribute to a decision to discontinue the trial.  
10.6.2 
Zealand Pharma Safety Committee 
The internal Zealand Pharma Safety Committee is constituted to perform ongoing safety 
surveillance of clinical trials within ZP4207, including this trial. 
If safety signals are observed either based on reported SAEs, periodic review of laboratory 
parameters, planned review of all AEs reported between the safety committee meetings, or 
on notification of significant findings, the Safety Committee will take appropriate measures to 
safeguard the patients. 
11 
STATISTICS 
11.1 
Analysis Populations 
The following analysis sets are defined in accordance with the ICH-E9 guidance: 
The Full Analysis Set is based on the intention-to-treat principle and includes all randomized 
patients. In exceptional cases, patients from the Full Analysis Set may be excluded (will be 
decided in the database review [DBR] meeting). In such cases, the exclusion will be justified 
and documented. Patients will contribute to the evaluation “as randomized.” 
The Per-Protocol Set includes all patients of the Full Analysis Set who completed the trial 
without any major protocol violations. Patients in the Per-Protocol Set will contribute to the 
evaluation “as treated.” This analysis will only be used if it is different than the Full Analysis 
Set. 
The Safety Analysis Set includes all patients receiving at least 1 dose of the IMP. Patients in 
the Safety Analysis Set will contribute to the evaluation “as treated.”  
Analyses of efficacy endpoints will be based on the Full Analysis Set (and the Per-Protocol 
Set if necessary). This decision will be made in the DBR meeting. The analysis of the safety 
endpoints will be based on the Safety Analysis Set.  
Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. At this time, it will be 
determined if patients and/or data should be excluded from the analysis. Furthermore, outliers 
will be identified by data review according to ICH-E9. 
Obviously erroneous data points may be excluded from the analyses or re-analyzed 
(e.g., serum concentrations). The decision to re-analyze or exclude data points from the 
statistical analysis is the joint responsibility of the Sponsor, the Principal Investigator, and the 
Trial Statistician. 
The patients or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to database release. The documentation 
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will be stored together with the remaining trial documentation. The patients and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report. 
 
11.2 
Statistical Methods  
Medpace will be responsible for the statistical analysis. The statistical planning and conduct 
of analyses of the data from this trial will follow the principles defined in relevant ICH guidelines 
and Medpace’s biostatistical standard operating procedures (SOPs). A general description of 
the statistical methods to be used is given in this section, specific details will be provided in 
the Statistical Analysis Plan (SAP), which will be prepared before database lock. All statistical 
analyses will be performed using SAS® (SAS Institute Inc., Cary, North Carolina, USA), 
version 9.4 or later.  
11.2.1 
Analysis of Safety 
The following variables will be evaluated according to treatment for safety purposes: 
 
Adverse Events 
All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). Individual AEs will be presented in a listing including relationship to trial 
product/device, severity, and treatment period at onset. If more than 20 treatment-emergent 
AEs (AEs with onset after [first] dosing at Visit 3 until the Follow-up Visit 6) are registered, a 
summary table including number of AEs, number of patients with at least 1 AE, and percentage 
of exposed patients with at least 1 AE will be made by system organ class and treatment 
period at onset. 
  
Local Tolerability 
Local tolerability at the injection site will be summarized using descriptive statistics as 
appropriate. 
 
Laboratory Safety Assessments 
Laboratory assessments will be summarized. A listing of abnormal values will be provided.  
 
Physical Examination 
A frequency table will show the number and percentage of physical examination results.  
 
Vital Signs 
Vital signs will be summarized using descriptive statistics. 
 
12-lead ECG 
The Investigator’s evaluations of 12-lead ECGs will be summarized and abnormal individual 
evaluations will be listed together with the Investigator’s comments. Changes in 12-lead ECG 
between measurements will be recorded as AEs if the Investigator judges them to be clinically 
significant.  
11.2.2 
Analysis of Efficacy 
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
 
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The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis, any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. Further details will be included in the 
SAP. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow.  
11.2.3 
Interim Analysis 
No interim analysis is planned. 
11.2.4 
Sample Size Determination 
No formal sample size calculations were made. It is expected that between 10 and 12 patients 
will be randomized in the trial. The sample size is based on a clinical rather than statistical 
rationale. The sample size is considered adequate to address the primary trial objective of 
exploring the safety of ZP4207 when used in the iPhone-based BP and with reference to Lilly 
glucagon used in the iPhone-based BP. 
12 
DATA MANAGEMENT AND RECORD KEEPING 
Data Management is the responsibility of Medpace. The complete Data Management process 
will be described in detail and agreed on in the Data Management Plan for this trial. 
12.1 
Data Handling 
Case Report Forms 
Electronic Case Report Forms will be used in this trial. The Data Management Department of 
Medpace will provide the eCRFs. All further information regarding the eCRFs and the data 
flow will be described and agreed on in the Data Management Plan. 
Device-Related Data 
During the trial, CGM data, calibration data, insulin dosing data, and glucagon dosing data will 
be automatically stored in the BP device (from which it will be downloaded at intervals), 
combined in a single database that will be compared against the primary data files for integrity, 
and ultimately transferred to Medpace.  
12.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
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12.3 
Data Entry 
Data must be recorded using the electronic data capture (EDC) system as the trial is in 
progress. The patient questionnaires will be transcribed into the EDC system by site 
personnel. All site personnel must log into the system using their secure user name and 
password in order to enter, review, or correct trial data. These procedures must comply with 
Title 21 of the Code of Federal Regulations (21 CFR Part 11) and other appropriate 
international regulations. All passwords will be strictly confidential. 
 
12.4 
Medical Information Coding  
Adverse events and medical history will be coded using the latest version of MedDRA. Prior 
and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. 
 
12.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, 
will be referred to the investigative site for resolution through data queries. 
 
The eCRFs must be reviewed and electronically signed by the Investigator. 
 
12.6 
Record Keeping 
Medpace will be responsible for hosting the TMF. Records of patients, source documents, 
monitoring visit logs, eCRFs, inventory of trial product, regulatory documents, and other 
Sponsor correspondence pertaining to the trial must be kept in the appropriate trial files at the 
site. Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
evaluation and reconstruction of the clinical trial. Source data are contained in source 
documents (original records or certified copies). These records will be retained in a secure file 
for the period as set forth in the Clinical Trial Agreement. Prior to transfer or destruction of 
these records, the Sponsor must be notified in writing and be given the opportunity to further 
store such records. 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
13.1 
Ethical Conduct of the Trial 
The trial will be conducted according to Medpace, MGH, and/or the Sponsor’s written 
instructions (SOPs, working instructions, or process descriptions). Content and definitions of 
the written instructions are based on the Declaration of Helsinki and the ICH GCP.  
 
13.2 
Institutional Review Board  
Written favorable opinion must be obtained from the responsible IRB prior to commencement 
of the trial. Clinical trial submission and reporting requirements before, during, and after 
completion of the trial will be performed in accordance with national law and local regulations.  
 
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All amendments that affect patient safety or the trial integrity (substantial amendments) must 
not be implemented before favorable opinion has been obtained, unless necessary to 
eliminate hazards to the patients. Non-substantial amendments do not require favorable 
opinion by the IRB, but the respective IRB will be notified according to local requirements.  
 
The Sponsor and Investigator must approve any amendment in writing before its 
implementation. 
 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
IRB. The records should be filed in the Sponsor’s Trial Master File (TMF). 
 
13.3 
Informed Consent  
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirement(s) and adhere to the ICH GCP guideline and the 
requirements in the Declaration of Helsinki. 
 
Prior to any trial-related activity, the Investigator must give the patient oral and written 
information in a form that the patient can read and understand about all aspects of the trial 
that are relevant to the patient’s decision to participate. The patient will be given ample time 
to decide whether or not to participate in the trial. 
 
The patient must be informed that his/her personal trial-related data will be used in accordance 
with the local data protection law. The level of disclosure must also be explained to the patient. 
 
The patient must be informed that his/her medical records may be examined by authorized 
monitors or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
 
A voluntary, personally signed and dated ICF must be obtained from the patient prior to any 
trial-related activity. The ICF must also be signed and dated by the physician or designee who 
conducted the informed consent procedure. A signed copy of the ICF and any additional 
patient information must be given to each patient.  
 
The responsibility for taking informed consent must remain with that of a research physician 
or designee. If information becomes available that may be relevant to the patient’s willingness 
to continue participating in the trial, the Investigator must inform the patient in a timely manner, 
and a revised written informed consent must be obtained. 
 
Should a protocol amendment become necessary, the ICF may need to be revised to reflect 
the changes to the protocol. It is the responsibility of the Sponsor to ensure that an amended 
consent form is reviewed and has received favorable opinion from IRB, and the Investigator 
must ensure that the amended consent form is signed by all patients subsequently entered 
into the trial and those currently in the trial, if affected by the amendment. 
 
13.4 
Trial Monitoring Requirements  
The monitoring procedures for this trial are described in detail in the Monitoring Manual. The 
objectives of the monitoring procedures are to ensure that (i) the safety and rights of the trial 
patients are respected, (ii) that accurate, valid, and complete data are collected, and (iii) that 
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the trial is conducted in accordance with the trial protocol, the principles of GCP, and local 
legislation, including drug accountability. 
The monitor must be given direct access to the investigational site files and source documents 
(original documents, data, and records). Direct access includes permission to examine, 
analyze, verify, and reproduce any record(s) and report(s) that are important to evaluation of 
the clinical trial. 
Key tasks of the monitor include verifying the presence of informed consent, the adherence to 
the inclusion/exclusion criteria, the documentation of SAEs, and the recording of all safety and 
efficacy variables. The monitor will also confirm the completeness of patient records, the 
adherence to the protocol, ICH GCP, and the progress in patient enrollment and perform drug 
accountability.  
Because no information that could reveal the identity of patients may ever be removed from 
the trial site, the monitor will visit the site at regular intervals to perform these monitoring tasks. 
Other contact between the Investigator and monitors will be maintained as required through 
telephone calls and e-mail. The Investigator and/or key members of staff involved in the trial 
must be available to assist the monitors during all visits.  
Site Initiation Visit 
During the Site Initiation Visit (SIV) the CRO, Sponsor, and/or monitors will go through 
information on the IMP, the protocol, the eCRFs, and other key aspects of the trial with the 
Investigator and the key members of staff involved in the trial. The topics of the SIV are 
documented in a SIV report made available to the Investigator. Documentation on the SIV 
(e.g., power point presentation) should be filed by both Investigator and Sponsor. 
13.5 
Disclosure of Data 
Data generated by this trial must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal 
physician or other appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the trial is confidential and disclosure to third 
parties other than those noted above is prohibited. 
13.6 
Retention of Records  
Massachusetts General Hospital will maintain the patient’s medical file according to local 
regulations. MGH will archive the documentation pertaining to the trial in an archive after 
completion or discontinuation of the trial if not otherwise notified. MGH should not destroy any 
documents without prior permission from the Sponsor. 
The documentation includes all the raw data generated during the clinical trial, the 
investigational site files, and a copy of the clinical trial report. The documents will be retained 
for a period of at least 15 years at archives by MGH, or its sub-contractor. After this period, 
the Sponsor will be contacted and their advice sought on the return or further retention of the 
trial records. 
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The Sponsor will maintain the documentation pertaining to the trial in accordance with national 
regulations. 
 
13.7 
Publication Policy  
The Principal Investigator of the trial will review and sign the clinical trial report. A summary of 
the final clinical trial report will be submitted to the IRB and Competent Authority. 
  
According to the Declaration of Helsinki Investigators and Sponsors “have ethical obligations 
with regard to the publication and dissemination of the results of research.” The trial design 
and results may be published as one or more original research manuscripts/abstracts and 
presented at a scientific meeting. The Investigator and Sponsor reserve the right to review any 
proposed presentation of the results of this trial before they are submitted for publication. 
Authorship on any publication(s) resulting from this clinical trial will be assigned according to 
the recommendations of the International Committee of Medicinal Journal Editors. 
 
Participating patients will not be identified by name in any published reports about the clinical 
trial.  
 
The Sponsor is responsible for trial registration at ClinicalTrials.gov (www.clinicaltrials.gov) 
according to the requirements from the FDA. 
  
13.8 
Legal Aspects  
An implicit or explicit approval must be obtained from the Competent Authority prior to 
commencement of the trial. Clinical trial submission and reporting requirements before, during, 
and after completion of the trial will be performed in accordance with national law and local 
regulations. 
 
An implicit or explicit approval will also be mandatory before implementation of substantial 
changes. Non-substantial amendments do not require approval from the Competent Authority 
but will be notified according to local requirements. 
 
The Sponsor and Investigator must approve the amendment in writing before its 
implementation. 
 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
Competent Authority. The records should be filed in the Sponsor’s TMF. 
  
Audits and Inspections  
In the event of an audit, representatives of the Sponsor or designee, or national and 
international regulatory authorities may request access to all trial records for inspection and 
copying. Such access must be stated in the ICF signed by the patient. 
 
13.9 
Sponsor Discontinuation Criteria  
The Sponsor, Investigator, or a pertinent regulatory authority may decide to stop the trial or 
part of the trial at any time but agreement on procedures to be followed must be obtained. 
Conditions that may warrant termination of the clinical trial include, but are not limited to: 
• 
Safety or administrative reasons 
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•
The discovery of an unexpected, relevant, or unacceptable risk to the patients enrolled
in the clinical trial
•
A decision of the Sponsor to suspend or discontinue investigation of the IMP
If the trial is prematurely terminated or suspended, the Investigator should promptly inform the 
patients and assure appropriate therapy and follow-up. Furthermore, the Sponsor should 
promptly inform the IRB and provide a detailed written explanation. The pertinent regulatory 
authorities should be informed according to national regulations. 
If after the termination of the trial the risk/benefit analysis has changed, the new evaluation 
should be provided to the IRB in case it will have an impact on the planned follow-up of the 
patients who have participated in the trial. Necessary actions needed to protect the patients 
should be described. 
13.10 
Patient Compensation 
Financial compensation will be provided to all patients who complete the Screening Visit. 
Patients will be paid $25 for completing the Screening Visit whether or not they are eligible to 
participate in the trial. Patients will be compensated $25 for completing the Training Visit. 
Patients will be compensated $100 for completing each of the 2 treatment visits, $25 for 
completing the phone call, and $25 for completing the Follow-up Visit. Thus, the total 
compensation for a patient who completes the trial would be $300. Patients who are unable 
to complete the trial or choose to stop participation will receive prorated compensation for 
each visit. In addition to the monetary compensation, the cost of the patients’ lunch meals 
during their participation in the trial, as well as the patients’ parking at each visit, will be covered 
by trial funds.  
14 
TRIAL ADMINISTRATIVE INFORMATION 
14.1 
Protocol Amendments  
Any amendments to the trial protocol will be communicated to the Investigators by Medpace 
or the Sponsor. All protocol amendments will undergo the same review and approval process 
as the original protocol. A protocol amendment may be implemented after it has been 
approved by the IRB, unless immediate implementation of the change is necessary for patient 
safety. In this case, the situation must be documented and reported to the IRB within 5 working 
days. 
14.2 
Address List 
14.2.1 
Sponsor 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Telephone: +45 88 77 36 00 
Facsimile: +45 88 77 38 98 
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Date: 17 August 2016
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APPENDIX A: SCHEDULE OF PROCEDURES 
Trial Visit 
Visit 1 [1]
Screening 
Visit 2
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5]
(2nd Treatment 
Visit) 
Visit 5
Phone Call [6] 
Visit 6
Follow-Up [7] 
Informed consent 
X 
Assess/confirm elig bility 
X 
X 
Demographics 
X
Medical, surgical, and social history; 
allergies  
X 
Concomitant illness 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Height, weight, physical examination, and 
vital signs including body temperature 
and blood pressure [8] 
X 
X [9] 
X [9] 
12-lead ECG 
X 
X [10] 
X [10] 
Urine HCG pregnancy test and menstrual 
history [11]   
X 
X 
X 
FSH [12] 
X 
Screening labs – HbA1c, optional 
fractionated metanephrines [13] 
X 
Safety lab sampling including chemistry 
and hematology 
X 
X [10] 
X [10] 
X 
Training on devices [14] 
X 
Monitored BP use 
X 
X 
Plasma glucose sampling [15] 
X 
X 
ZP4207/glucagon exposure sampling [16] 
X 
X 
Nausea and infusion site pain VAS and 
infusion site reaction Draize scale (visit 
start [17], hourly, & visit end) 
X 
X 
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Clinical Trial Protocol 
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Date: 17 August 2016
Zealand Pharma A/S 
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Trial Visit 
Visit 1 [1]
Screening 
Visit 2
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5]
(2nd Treatment 
Visit) 
Visit 5
Phone Call [6] 
Visit 6
Follow-Up [7] 
Standardized lunch [18] 
X 
X 
In-clinic exercise [19] 
X 
X 
Questionnaires (pre & post BP) 
X 
X 
ADA 
X [20] 
X 
Adverse event review 
X 
X 
X 
X 
1.
Once the patient has been enrolled and eligibility has been established, the order of the iPhone-based BP visits will be randomized in blocks of 2 patients.
2.
Each patient will participate in 2 treatment visits: one with the iPhone-based BP using ZP4207 and one with the iPhone-based BP using Lilly glucagon in a randomized order. Up to
2 patients may participate in the trial per day.
3.
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal skin and calibrate the sensor when prompted using the provided Nova StatStrip Xpress meter.
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the BP having fasted since 12 00 AM the night before (treatment with simple carbohydrate of up to 30 g
for a low is allowed). If the patient is not fasted, the visit will be rescheduled within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the visit window. If BG is
<50 mg/dL, treatment with simple carbohydrate is allowed. If the patient experiences persistent hypoglycemia, the visit will be rescheduled within the visit window.
4.
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 30 days after screening (Visit 1).
5.
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum of 3 weeks between Visit 3 and Visit 4.
6.
Visit 5 will take place 7 days ±3 days from Visit 4.
7.
Visit 6 will take place 25 days ±4 days from Visit 4.
8.
Height and physical examination will be measured at Visit 1 only.
9.
Vital signs including body temperature and blood pressure will be obtained at visit start and visit end.
10.
At visit start and visit end.
11.
Urine HCG pregnancy test only for women of childbearing potential. The date of the last menstrual period in female patients will be obtained at Visit 1 only.
12.
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year.
13.
If indicated by history.
14.
Patients will be trained in the insertion and calibration of the Dexcom G4 sensor, diabetes management (e.g., basal insulin rate adjustment by insulin pump) during fasting prior to and
between the treatment visits, and trial policies and procedures.
15.
Collected at least hourly. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will
be every 10 minutes.
16.
Collected at least hourly. If BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the Investigator.
17.
Once the infusion sites have been placed but no drug has yet been administered.
18.
Between approximately Hour 3 and Hour 4.
19.
Between approximately Hour 6 and Hour 7.
20.
Before the start of dosing.
ADA = anti-drug antibodies; BG = blood glucose; BP = bionic pancreas; CGM = continuous glucose monitor; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
HbA1c = hemoglobin A1c; HCG = human chorionic gonadotropin; VAS = visual analog scale.
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Clinical Trial Protocol 
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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Chemistry 
Alanine aminotransferase 
Aspartate aminotransferase 
Alkaline phosphatase 
Total protein 
Albumin 
Total and direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Creatinine 
Estimated glomerular filtration rate 
Blood urea nitrogen 
Uric acid
Bicarbonate 
Sodium 
Potassium 
Calcium 
Chloride 
Phosphorus 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell count 
White blood cell count and differential 
Platelets 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Pregnancy Test 
A urine HCG pregnancy test will be performed at screening, Visit 3, and Visit 4 only for 
women of childbearing potential. 
Anti-drug Antibody Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken prior to first dosing (Visit 3) and at the Follow-up Visit (Visit 6). 
ZP4207/Glucagon Exposure Sampling 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at 
the discretion of the Investigator. 
Screening Visit Only 
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year 
Optional fractionated plasma metanephrines (if indicated by history) 
Hemoglobin A1c 
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Clinical Trial Protocol 
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APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES 
Diabetes Treatment Satisfaction Questionnaire – Status (DTSQs) 
The DTSQs measures patient satisfaction with diabetes treatment. It consists of a 6 item scale 
for assessing treatment satisfaction and two additional items assessing perceived frequency 
of hyperglycemia and hypoglycemia. The DTSQs is meant for adults and older children. 
Dr. Clare Bradley has produced a version that is appropriate for bionic pancreas studies for 
this use, along with a version for younger children. It is administered before the intervention. 
The DTSQs is valid and reliable. Administration time is less than 5 minutes. 
Diabetes Treatment Satisfaction Questionnaire – Change (DTSQc) 
Although the DTSQ is responsive to treatment changes, ceiling effects are often seen with this 
instrument, where maximum or close-to-maximum scores at baseline provide little opportunity 
for registering improvement. The DTSQc contains the same items as the DTSQs version but 
asks patients to consider their satisfaction with their current treatment compared with their 
previous treatment. The DTSQc is meant for adults and older children. Dr. Clare Bradley has 
produced a version that is appropriate for bionic pancreas studies for our use, along with a 
version for younger children. It is administered during and at the end of the intervention. The 
DTSQc is valid and reliable. Administration time is less than 5 minutes. 
T1-Diabetes Distress Scale (T1-DDS) 
The T1-DDS is a 28-item survey that assesses seven sources of diabetes distress for type 1 
adults. It captures feelings of powerlessness; management distress; hypoglycemia distress; 
negative social perceptions by others; eating distress; physician (health care) distress; and 
friend/family distress. Items are scored on a 6-point scale from not a problem to a very serious 
problem. It is administered before, during, and at the end of the intervention. The scale is valid 
and reliable, and has been shown to be sensitive to change over time. Administration time is 
5 minutes. 
Problem Areas in Diabetes Survey (PAID) 
There are three versions of the PAID: Teen (PAID-T), Parent (PAID-P), and Child (PAID-C) 
versions. This measure of diabetes-specific emotional distress in youth with diabetes and their 
parents is 26 items. A total score is generated. It is administered before, during, and at the 
end of the intervention. The PAID-T and PAID-P are valid and reliable. Psychometric analysis 
of the PAID-C is in progress. Administration time is 5 minutes. 
Hypoglycemia Fear Survey (HFS) 
There are three versions of the HFS, Adult (HFS), Youth (HFS-Y) and Parent (HFS-P). The 
HFS measures several dimensions of fear of hypoglycemia among adults with type 1 diabetes. 
It consists of 23 items and produces two sub-scale scores; a Behavior sub-scale that 
measures behaviors involved in avoidance and/or over-treatment of hypoglycemia and a 
Worry sub-scale that measures anxiety and fear surrounding hypoglycemia. The HFS-Y 
consists of 25 items and the HFS-P consists of 26 items; both produce sub-scale scores 
similar to the Adult HFS. It is administered before, during, and at the end of the intervention. 
All versions of the HFS are valid and reliable. Administration time is 5-10 minutes. 
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Date: 17 August 2016 
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Impact of Daily Diabetes Demands (IDDD) 
There are four versions of the IDDD; Adult (IDDD-A), Youth (IDDD-Y), Parent (IDDD-P), and 
Significant Other (IDDD-SO). This instrument measures the burden related to the demands of 
the daily diabetes regimen and is 22 items. A total score is generated. It is administered before, 
during, and at the end of the intervention. Psychometric analysis of the IDDD-Y is in progress 
using the data from the second Bionic Pancreas Camp Study in pre-adolescent children, and 
of the IDDD-A is in progress using data from the Bionic Pancreas Multicenter Study in adults. 
Administration time is 5 minutes. 
Bionic Pancreas User Opinion Survey (BPUOS) 
There are four versions of the BPUOS; Adult (BPUOS-A), Youth (BPUOS-Y), Parent 
(BPUOS-P), and Significant Other (BPUOS-SO). This measure assessing both the benefits 
from, and difficulties with, use of the bionic pancreas, and consists of 38 items. A total score 
is generated. It is administered during and at the end of the intervention. Psychometric 
analysis of the BPUOS-Y is in progress using the data from the second Bionic Pancreas Camp 
Study in pre-adolescent children, and of the BPUOS -A is in progress using data from the 
Bionic Pancreas Multicenter Study in adults. Administration time is 10 minutes. 
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Summary of Changes, Amendment 2.0, ZP4207-16051 
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SUMMARY OF CHANGES DOCUMENT 
PROTOCOL NUMBER ZP4207-16051 
AMENDMENT NUMBER 2.0 
PROTOCOL TITLE: The iLet Feasibility Trial Testing the iLet, a Fully Integrated Bihormonal 
Bionic Pancreas with ZP4207 
AMENDMENT DATE: 03 August 2016 
SUMMARY AND JUSTIFICATION OF CHANGES: 
This amendment was developed to include additional clinical instructions regarding management 
of diabetes, low blood glucose (BG), and other medically significant findings during the trial. The 
main additions include statements that Investigators will instruct patients concerning diabetes 
management during fasting prior to and between the treatment visits; treatment with simple 
carbohydrates is allowed when a patient’s BG is <50 mg/dL; and a longer observation period at 
the trial site may be necessary if the patient experiences a medically significant event. In addition, 
the Exclusion Criteria was updated to exclude patients with a history of hypoglycemic 
unawareness in the last 12 months and patients with a history of severe hypersensitivity to milk 
proteins or lactose. The schedule of procedures was updated to reflect the changes specified in 
this document. 
SUMMARY OF CHANGES: 
The amended protocol sections and the details of the changes are summarized in the following 
sections. Revisions to the protocol are presented as strikethrough (ie, subject) for text that was 
removed and bold (ie, subject) for text that was added. 
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Section 1.5, Risk/Benefit, Page 20 
Original Text: 
Treatment with ZP4207 and marketed glucagon can result in undesired effects or complaints. 
Undesired effects and complaints such as gastrointestinal side effects including nausea, 
vomiting, and diarrhea are known side effects of glucagon administration at higher dose levels. 
The frequency of nausea associated with the administration of 1 mg of glucagon according to 
the Summary of Product Characteristics (SPC) for Glucagon is described to be between 1/10 
and 1/100. The frequency of vomiting is described to be between 1/100 and 1/1000 
(Novo Nordisk, 2015). Similar gastrointestinal side effects have also been observed to a limited 
degree in the 2 clinical trials conducted with ZP4207, again at higher dose levels. The individual 
doses of ZP4207 and Lilly glucagon delivered by the BP are expected to be significantly lower 
than doses typically associated with nausea. As with every novel drug substance, new and yet 
unknown side effects may also occur. 
New Text: 
Treatment with ZP4207 and marketed glucagon can result in undesired effects or complaints. 
Undesired effects and complaints such as gastrointestinal side effects including nausea, 
vomiting, and diarrhea are known side effects of glucagon administration at higher dose levels. 
The frequency of nausea associated with the administration of 1 mg of glucagon according to 
the Summary of Product Characteristics (SPC) for Glucagon is described to be between 1/10 
and 1/100. The frequency of vomiting is described to be between 1/100 and 1/1000 
(Novo Nordisk, 2015). Similar gastrointestinal side effects have also been observed to a limited 
degree in the 2 clinical trials conducted with ZP4207, again at higher dose levels. The individual 
doses of ZP4207 and Lilly glucagon delivered by the BP are expected to be significantly lower 
than doses typically associated with nausea. Episodes of low blood pressure have also 
been observed after administration of higher doses of glucagon and ZP4207. As with 
every novel drug substance, new and yet unknown side effects may also occur. 
Section 4.2, Exclusion Criteria, Page 24 
Original Text: 
19.
History of hypoglycemic seizures (grand-mal) or coma in the last 12 months
20.
History of pheochromocytoma: fractionated metanephrines will be tested in patients with
history increasing the risk for a catecholamine secreting tumor:
a. Episodic or treatment refractory (requiring 4 or more medications to achieve
normotension) hypertension
b. Paroxysms of tachycardia, pallor, or headache
c.
Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or
von Hippel-Lindau disease
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New Text: 
19.
History of hypoglycemic seizures (grand-mal) or coma in the last 12 months
20.
History of hypoglycemic unawareness in the last 12 months
20. 21. History of pheochromocytoma: fractionated metanephrines will be tested in patients with 
history increasing the risk for a catecholamine secreting tumor: 
a. Episodic or treatment refractory (requiring 4 or more medications to achieve
normotension) hypertension 
b. Paroxysms of tachycardia, pallor, or headache
c.
Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or
von Hippel-Lindau disease
Section 4.2, Exclusion Criteria, Page 25 
Original Text: 
26.
History of adverse reaction to glucagon (including allergy) besides nausea and vomiting
27.
Established history of allergy or severe reaction to adhesive or tape that must be used
in the trial
New Text: 
26.
History of adverse reaction to glucagon (including allergy) besides nausea and vomiting
27.
History of severe hypersensitivity to milk proteins or lactose
27. 28. Established history of allergy or severe reaction to adhesive or tape that must be used 
in the trial 
Section 7.2, Screening Visit (Visit 1), Page 29 
Original Text: 
All patients will have a Screening Visit to confirm eligibility. The patient will be interviewed and 
the electronic Case Report Form (eCRF) will be completed by trial staff to establish whether 
the patient is eligible. 
Once all of the results have been returned, a trial MD will review the eCRF to determine patient 
eligibility. If a patient is not eligible to continue in the trial, the results of abnormal tests will be 
reported to the patient and to a health care provider of their choosing. 
New Text: 
All patients will have a Screening Visit to confirm eligibility. The patient will be interviewed and 
the electronic Case Report Form (eCRF) will be completed by trial staff to establish whether 
the patient is eligible. 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits per 
the medical judgment of the Investigator. 
Once all of the results have been returned, a trial MD will review the eCRF to determine patient 
eligibility. If a patient is not eligible to continue in the trial, the results of abnormal tests will be 
reported to the patient and to a health care provider of their choosing. 
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Summary of Changes, Amendment 2.0, ZP4207-16051 
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Section 7.3, Training Visit (Visit 2), Page 30 
Original Text: 
A Training Visit will take place before the first treatment visit. Patients will be trained in the 
insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. Trial staff 
will verify that the patients have understood the material and are competent to participate safely 
in the trial. Concomitant medications will also be reviewed. 
New Text: 
A Training Visit will take place before the first treatment visit. Patients will be trained in the 
insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. Trial staff 
will verify that the patients have understood the material and are competent to participate safely 
in the trial. Patients will be instructed concerning diabetes management (e.g., basal 
insulin rate adjustment by insulin pump) during fasting prior to and between the 
treatment visits per the medical judgment of the Investigator. Concomitant medications 
will also be reviewed. 
Section 7.4, Treatment Visits (Visit 3 and Visit 4), Page 31 
Original Text: 

During the trial, patients will not use any recreational drugs or drugs of abuse. The need
to take prescription drugs that dull the sensorium, reduce sensitivity to symptoms of
hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion
from the trial or discontinuation of participation, a decision that will be made by the
Investigator.

Patients will not tamper with the BP, including changing any settings.
New Text: 

During the trial, patients will not use any recreational drugs or drugs of abuse. The need
to take prescription drugs that dull the sensorium, reduce sensitivity to symptoms of
hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion
from the trial or discontinuation of participation, a decision that will be made by the
Investigator.

Patients will be instructed concerning diabetes management (e.g., basal insulin
rate adjustment by insulin pump) during fasting prior to and between the
treatment visits per the medical judgment of the Investigator.

Patients will not tamper with the BP, including changing any settings.
Section 7.4.1, Visit Procedures, Page 31 
Original Text: 

Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the
BP having fasted since 12:00 AM the night before (treatment with simple carbohydrate
of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled
within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the visit
window.

Upon arrival to the visit, the patient’s weight and vital signs including body temperature
and blood pressure will be documented.
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Summary of Changes, Amendment 2.0, ZP4207-16051 
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New Text: 

Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the
BP having fasted since 12:00 AM the night before (treatment with simple carbohydrate
of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled
within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the visit
window. If BG is <50 mg/dL, treatment with simple carbohydrate is allowed. If the
patient experiences persistent hypoglycemia, the visit will be rescheduled within
the visit window. If the visit needs to be rescheduled due to hypoglycemia or
hyperglycemia, trial staff will assist the patient with insulin or medication
adjustments to address glycemic control. The patient will be instructed to contact
trial staff later in the day if his or her BG remains uncontrolled.

Upon arrival to the visit, the patient’s weight and vital signs including body temperature
and blood pressure will be documented.
Section 7.4.1, Visit Procedures, Page 32 
Original Text: 

Patients will be asked to rate any nausea and/or infusion site pain on 10 cm visual
analog scales (VAS) at the beginning of the visit once the infusion sites have been
placed but no drug has yet been administered, then approximately at the top of every
hour during the visit, and at the end of the visit. Trial staff will also evaluate their infusion
sites to document any erythema or edema at the same times. If moderate or severe
pain is reported or swelling or redness occurs at the infusion site, the infusion site will
be replaced in a different location. If moderate or severe pain, swelling, or redness
continues at the old site for more than 30 minutes after the infusion site is removed, or
if moderate or severe pain, swelling, or redness occurs at the new site, all infusion sites
will be removed and the patient will be discontinued from the study.

From the start of closed loop control until approximately Hour 3, the patients will
continue to fast.
New Text: 

Patients will be asked to rate any nausea and/or infusion site pain on 10 cm visual
analog scales (VAS) at the beginning of the visit once the infusion sites have been
placed but no drug has yet been administered, then approximately at the top of every
hour during the visit, and at the end of the visit. Trial staff will also evaluate their infusion
sites to document any erythema or edema at the same times. If moderate or severe
pain is reported or swelling or redness occurs at the infusion site, the infusion site will
be replaced in a different location. If moderate or severe pain, swelling, or redness
continues at the old site for more than 30 minutes after the infusion site is removed, or
if moderate or severe pain, swelling, or redness occurs at the new site, all infusion sites
will be removed and the patient will be discontinued from the study. Any such
symptoms will be followed until resolution.

From the start of closed loop control until approximately Hour 3, the patients will
continue to fast.
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Section 7.4.1, Visit Procedures, Page 33-34 
Original Text: 

After approximately Hour 8, but not earlier than at least 60 minutes after end of exercise,
the BP will be stopped and the patient will continue with their personal insulin pump.

The maximum amount of blood loss per study visit will be approximately 230 mL. The
total blood loss for the entire study will be up to 460 mL.

Patients will answer questionnaires (see Appendix C).

Chemistry and hematology samples will be collected at visit end (see Appendix B).

The BP and glucose meters will be collected and downloaded.

A trial MD will review the last several hours of insulin and glucagon dosing and assist
the patient in resuming their usual diabetes care. They will be instructed to call trial staff
with any questions, issues, or concerns.
New Text: 

After approximately Hour 8, but not earlier than at least 60 minutes after end of exercise,
the BP will be stopped and the patient will continue with their personal insulin pump.

If the patient experiences seizure or unconsciousness, persistent nausea or
vomiting, diabetic ketoacidosis, persistent hyperglycemia with ketonemia,
hemodynamic changes such as hypotension, or other medically significant
findings, a longer observation period at the trial site may be necessary until the
patient is considered stable for discharge. If the Investigator or trial staff
determines that the patient requires further observation or treatment, the patient
may be transferred to the emergency room for additional monitoring and/or
medical care. At discharge, patients will be provided with any necessary
instructions concerning personal insulin pump usage, food intake, and driving
arrangements.

The maximum amount of blood loss per study visit will be approximately 230 mL. The
total blood loss for the entire study will be up to 460 mL.

Patients will answer questionnaires (see Appendix C).

Chemistry and hematology samples will be collected at visit end (see Appendix B).

The BP and glucose meters will be collected and downloaded.

A trial MD will review the last several hours of insulin and glucagon dosing and assist
the patient in resuming their usual diabetes care. They A longer observation period
at the trial site may be necessary. Patients will be instructed to call trial staff with any
questions, issues, or concerns.
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Summary of Changes, Amendment 2.0, ZP4207-16051 
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Appendix A, Schedule of Procedures, Footnote 3, Page 57  
Original Text: 
3. 
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal 
skin and calibrate the sensor when prompted using the provided Nova StatStrip Xpress 
meter. Patients will be asked to arrive at the visit at least 1 hour in advance of the start 
of the BP having fasted since 12:00 AM the night before (treatment with simple 
carbohydrate of up to 30 g for a low is allowed). If the patient is not fasted, the visit will 
be rescheduled within the visit window. If BG is >250 mg/dL, the visit will be rescheduled 
within the visit window. 
New Text: 
3. 
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal 
skin and calibrate the sensor when prompted using the provided Nova StatStrip Xpress 
meter. Patients will be asked to arrive at the visit at least 1 hour in advance of the start 
of the BP having fasted since 12:00 AM the night before (treatment with simple 
carbohydrate of up to 30 g for a low is allowed). If the patient is not fasted, the visit will 
be rescheduled within the visit window. If BG is >250 mg/dL, the visit will be rescheduled 
within the visit window. If BG is <50 mg/dL, treatment with simple carbohydrate is 
allowed. If the patient experiences persistent hypoglycemia, the visit will be 
rescheduled within the visit window. 
Appendix A, Schedule of Procedures, Footnote 14, Page 57  
Original Text: 
14. 
Patients will be trained in the insertion and calibration of the Dexcom G4 sensor and 
trial policies and procedures. 
New Text: 
14. 
Patients will be trained in the insertion and calibration of the Dexcom G4 sensor, 
diabetes management (e.g., basal insulin rate adjustment by insulin pump) during 
fasting prior to and between the treatment visits, and trial policies and procedures. 
 
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Clinical Trial Protocol
ZP4207-16051
Version number: 3.0
Amendment 2.0
Date: 03 August 2016
Zealand Pharma A/S 
Confidential 
Page 3 of 60
INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary 
details for carrying out the trial as described. I will conduct this trial in accordance with the 
design and specific provision of this protocol and will make a reasonable effort to complete 
the trial within the time designated. I will provide copies of this protocol and access to all 
information furnished by Zealand Pharma A/S to trial personnel under my supervision. I will 
discuss this material with them to ensure they are fully informed about the trial product and 
trial procedures. I will let them know that this information is confidential and proprietary to 
Zealand Pharma A/S and that it may not be further disclosed to third parties. I understand that 
the trial may be terminated or enrollment suspended at any time by Zealand Pharma A/S, with 
or without cause, or by me if it becomes necessary to protect the best interests of the trial 
patients. 
I agree to conduct this trial in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations and ICH Guidelines for Good Clinical 
Practices. 
_
_______
____________________
Investigator’s Signature
Date
______________________________________________
Investigator’s Printed Name
Steven Russell, MD, PhD
8/3/2016
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SYNOPSIS 
TITLE: The iLet Feasibility Trial Testing the iLet, a Fully Integrated Bihormonal Bionic 
Pancreas with ZP4207 
 
PROTOCOL NUMBER: ZP4207-16051 
 
INVESTIGATIONAL PRODUCT: ZP4207 
 
PHASE: 2 
 
INDICATION: ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid 
formulation which is being studied to improve glycemic control in adults (and children) with 
type 1 diabetes mellitus (T1DM) as part of a bihormonal bionic pancreas (BP). 
 
OBJECTIVES: 
 
Primary: The primary objective is to conduct a trial testing the safety and tolerability of the 
iLet when used with ZP4207 in 10 adult (18 years of age) patients with T1DM. 
 
Secondary: The secondary objectives are to measure glycemic regulation, including 
hypoglycemia exposure (percent of time spent with continuous glucose monitor [CGM] 
glucose <60 mg/dL), evaluate BP device reliability, and to document the satisfaction of 
patients with the iLet with the goal of optimizing the functionality and user interface of the iLet. 
 
POPULATION: Up to 20 adult (18 years of age) patients who already manage their T1DM 
using continuous subcutaneous (SC) insulin infusion pump therapy can be enrolled. It is 
expected that up to 10 patients will complete the trial protocol. 
 
TRIAL DESIGN: This trial is a single-center, open-label, randomized cross-over trial. The trial 
will enroll adult patients with T1DM and will assess the safety and efficacy of the iLet using 
the glucagon analog ZP4207 versus the iLet using Lilly glucagon. The iLet will also administer 
insulin (insulin lispro, Lilly Humalog) using the same blood glucose (BG) control algorithm for 
both treatment arms. The trial will be conducted at a single center, the Massachusetts General 
Hospital Diabetes Center in Boston, MA. 
 
TRIAL TREATMENT: The trial involves SC administration of insulin lispro (Humalog, Lilly), 
which is commercially available by prescription and is indicated for patients with T1DM, but 
not for use in a BP. 
 
The trial also involves SC administration of Lilly glucagon in one iLet arm. Lilly glucagon is 
commercially available by prescription and is indicated for patients with T1DM in severe 
hypoglycemia, but not for use in a BP.  
 
The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, in the 
other iLet arm. ZP4207 will be made available by Zealand Pharma A/S, Denmark as liquid 
formulation in prefilled syringes of 0.6 mL. 
 
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PRIMARY ENDPOINT: 
The primary endpoint is the safety and tolerability of ZP4207 and the iLet as assessed by: 

Number and type of adverse events (AEs)

Clinical laboratory measurements

Vital signs

12-lead electrocardiogram (ECG)

Local tolerability and infusion site reactions as measured with the Draize scale

Immunogenicity as measured by anti-drug antibodies

Pain as measured on a 10 cm visual analog scale (VAS)

Nausea as measured on a 10 cm VAS
SECONDARY ENDPOINTS: 
The secondary endpoints for the iLet and ZP4207 include measurements of BP function as 
well as glycemic and non-glycemic measurements. 
Bionic Pancreas Function 
This endpoint data will be generated from the BP data during each treatment visit: 

Average percent insulin dose amounts calculated by the BP control algorithm that are
successfully delivered by the pump 

Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully delivered by the pump 

Average percent dose amounts successfully issued to the pump by the BP control
algorithm that are successfully delivered by the pump (calculated doses are not issued 
unless the pump is accessible and its delivery channel is available) 
o
Average percent insulin dose amounts successfully issued to the pump by the
BP control algorithm that are successfully delivered by the pump 
o
Average percent glucagon/ZP4207 dose amounts successfully issued to the
pump by the BP control algorithm that are successfully delivered by the pump 

Average percent dose amounts calculated by the BP algorithm that are successfully
issued to the pump by the BP (calculated doses are not issued unless the pump is 
accessible and its delivery channel is available) 
o
Average percent insulin dose amounts calculated by the BP control algorithm
that are successfully issued by the BP 
o
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully issued by the BP 

Average percent of 5-minute steps during which the BP is functioning nominally in all
respects based on real-time CGM data (new CGM glucose reading captured, dose 
calculated, and dose issued to pumps)  

Average percent of 5-minute steps during which the BP is functioning nominally with
or without a new CGM glucose reading captured (dose calculated and dose issued to 
pumps). If a CGM signal is not available, the dose calculated may be based on weight 
or historical basal rates. 

CGM reliability index, calculated as percent of possible values actually recorded by
CGM 

CGM Mean Absolute Relative Difference versus time-stamped BG values from meter
download 

List of technical faults associated with the BP including cause and resolution
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Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit. 

Fraction of time spent within each of the following glucose ranges:
o
<50 mg/dL
o
<60 mg/dL
o
<70 mg/dL
o
70-120 mg/dL
o
70-140 mg/dL
o
70-180 mg/dL
o
>180 mg/dL
o
>250 mg/dL
o
>300 mg/dL

Number of severe hypoglycemic events (patients unable to self-treat, requiring the
assistance of another person)

Number of episodes of symptomatic hypoglycemia

Number of carbohydrate interventions for hypoglycemia

Total grams of carbohydrates taken for hypoglycemia

Mean CGM glucose
Non-glycemic 

Glucagon/ZP4207 total delivery per kg of body mass

Insulin total delivery per kg of body mass

Number of unscheduled infusion set replacements

Number of unscheduled CGM sensor changes
EVALUATION OF TRIAL DATA: The following variables will be evaluated according to 
treatment for safety purposes: AEs, local tolerability, laboratory safety assessments, physical 
examination, vital signs, and 12-lead ECGs.  
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow. 
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SPONSOR: 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Tel: +45 88 77 36 00 
Fax: +45 88 77 38 98 
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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................... 2
INVESTIGATOR AGREEMENT ....................................................................................... 3
SYNOPSIS ....................................................................................................................... 4
TABLE OF CONTENTS ................................................................................................... 8
LIST OF FIGURES ..........................................................................................................11
LIST OF ABBREVIATIONS .............................................................................................12
1
INTRODUCTION AND BACKGROUND INFORMATION......................................14
1.1 
Background and Rationale .................................................................................... 14
1.2 
Bihormonal Bionic Pancreas System .................................................................... 15
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System ........................ 16
1.4 
ZP4207 ................................................................................................................. 18
1.5 
Risk/Benefit........................................................................................................... 19
2
TRIAL OBJECTIVES ............................................................................................22
2.1 
Primary Objective.................................................................................................. 22
2.2 
Secondary Objectives ........................................................................................... 22
3
TRIAL DESCRIPTION ..........................................................................................22
3.1 
Summary of Trial Design....................................................................................... 22
3.2 
Indication .............................................................................................................. 22
3.3 
Number of Patients ............................................................................................... 22
4
SELECTION AND WITHDRAWAL OF PATIENTS ...............................................23
4.1 
Inclusion Criteria ................................................................................................... 23
4.2 
Exclusion Criteria .................................................................................................. 23
4.3 
Target Population ................................................................................................. 25
4.4 
Withdrawal Criteria ................................................................................................ 25
5
ASSIGNMENT TO TREATMENT GROUPS .........................................................26
6
TRIAL TREATMENT .............................................................................................26
6.1 
Investigational Medicinal Products ........................................................................ 26
6.2 
Storage and Drug Accountability of IMPs .............................................................. 26
6.3 
Dispensing and Return of IMPs............................................................................. 27
6.4 
Doses ................................................................................................................... 27
6.5 
iLet Bionic Pancreas ............................................................................................. 27
6.6 
Other Trial Devices ............................................................................................... 28
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6.7 
Concomitant Medications ...................................................................................... 28
6.7.1 
Permitted Medications and/or Procedures ..................................................... 28
6.7.2 
Excluded Medications and/or Procedures ...................................................... 29
7
TRIAL PROCEDURES ..........................................................................................29
7.1 
Informed Consent ................................................................................................. 29
7.2 
Screening Visit (Visit 1) ......................................................................................... 29
7.2.1 
Data Collected at Screening .......................................................................... 30
7.3 
Training Visit (Visit 2) ............................................................................................ 30
7.4 
Treatment Visits (Visit 3 and Visit 4) ..................................................................... 30
7.4.1 
Visit Procedures ............................................................................................. 31
7.4.2 
Data Collected During the Treatment Visits ................................................... 34
7.4.3 
Response to Hypoglycemia ........................................................................... 35
7.4.4 
Response to Hyperglycemia .......................................................................... 35
7.4.5 
Response to Nausea/Vomiting ....................................................................... 35
7.4.6 
Response to Other Medical Needs ................................................................ 36
7.4.7 
Monitoring of Bionic Pancreas Performance .................................................. 36
7.4.8 
Supervision by Trial Staff ............................................................................... 36
7.5 
Phone Call (Visit 5) ............................................................................................... 36
7.6 
Follow-up Visit (Visit 6) ......................................................................................... 36
8
ENDPOINTS .........................................................................................................36
8.1 
Primary Endpoint .................................................................................................. 36
8.2 
Secondary Endpoints ............................................................................................ 36
8.2.1 
Bionic Pancreas Function .............................................................................. 36
8.2.2 
Glycemic ........................................................................................................ 37
8.2.3 
Non-glycemic ................................................................................................. 38
9
LABORATORY ASSESSMENTS .........................................................................38
9.1 
Safety Laboratory Assessments ............................................................................ 38
9.2 
Pharmacodynamic Assessments (Plasma Glucose) ............................................. 38
9.3 
Exposure Assessments (ZP4207 and Glucagon) .................................................. 38
9.4 
Anti-drug Antibody Assessments .......................................................................... 38
10 
SAFETY REPORTING ..........................................................................................38
10.1 
Adverse Events ..................................................................................................... 38
10.1.1 
Follow-up of Adverse Events ......................................................................... 39
10.1.2 
Precautions .................................................................................................... 39
10.1.3 
Assessment of Adverse Events by the Investigator ........................................ 40
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10.2 
Serious Adverse Events ........................................................................................ 41 
10.3 
Adverse Event Reporting – Procedures for Investigators ...................................... 41 
10.4 
Pregnancy Reporting ............................................................................................ 43 
10.5 
Hypoglycemia ....................................................................................................... 44 
10.6 
Safety Monitoring .................................................................................................. 44 
10.6.1 
Data and Safety Monitoring Board ................................................................. 44 
10.6.2 
Zealand Pharma Safety Committee ............................................................... 45 
11 
STATISTICS .........................................................................................................45 
11.1 
Analysis Populations ............................................................................................. 45 
11.2 
Statistical Methods ................................................................................................ 46 
11.2.1 
Analysis of Safety .......................................................................................... 46 
11.2.2 
Analysis of Efficacy ........................................................................................ 46 
11.2.3 
Interim Analysis ............................................................................................. 47 
11.2.4 
Sample Size Determination ............................................................................ 47 
12 
DATA MANAGEMENT AND RECORD KEEPING ................................................47 
12.1 
Data Handling ....................................................................................................... 47 
12.2 
Computer Systems ............................................................................................... 47 
12.3 
Data Entry ............................................................................................................. 47 
12.4 
Medical Information Coding .................................................................................. 48 
12.5 
Data Validation ..................................................................................................... 48 
12.6 
Record Keeping .................................................................................................... 48 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ...........................48 
13.1 
Ethical Conduct of the Trial ................................................................................... 48 
13.2 
Institutional Review Board ..................................................................................... 48 
13.3 
Informed Consent ................................................................................................. 49 
13.4 
Trial Monitoring Requirements .............................................................................. 49 
13.5 
Disclosure of Data................................................................................................. 50 
13.6 
Retention of Records ............................................................................................ 50 
13.7 
Publication Policy .................................................................................................. 50 
13.8 
Legal Aspects ....................................................................................................... 51 
13.9 
Sponsor Discontinuation Criteria ........................................................................... 51 
13.10 
Patient Compensation ....................................................................................... 52 
14 
TRIAL ADMINISTRATIVE INFORMATION ...........................................................52 
14.1 
Protocol Amendments ........................................................................................... 52 
14.2 
Address List .......................................................................................................... 52 
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14.2.1 
Sponsor ......................................................................................................... 52
14.2.2 
Supplier of Device .......................................................................................... 52
14.2.3 
Principal Investigator (Site) ............................................................................ 53
14.2.4 
Contract Research Organization (Including Monitoring) ................................. 53
14.2.5 
Medical Monitoring ......................................................................................... 53
14.2.6 
Pharmacovigilance ........................................................................................ 53
14.2.7 
Central Laboratory (Safety Laboratory and Plasma Glucose) ........................ 53
14.2.8 
Special Laboratory (ZP4207 Exposure and ADA Analyses) ........................... 54
14.2.9 
Special Laboratory (Glucagon Exposure) ....................................................... 54
15 
REFERENCES ......................................................................................................55
APPENDIX A: SCHEDULE OF PROCEDURES ..............................................................56
APPENDIX B: CLINICAL LABORATORY ANALYTES ..................................................58
APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES.......................................59
LIST OF FIGURES 
Figure 1. 
Outpatient Results Summarizing the Distribution of Mean CGM Glucose 
Levels and Hypoglycemia in the BP and Control Arms ............................ 17
Figure 2. 
Trial Design Schematic ................................................................................ 22
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
BG 
Blood glucose 
BP 
Bionic pancreas 
BU 
Boston University 
CFR 
Code of Federal Regulations 
CGM 
Continuous glucose monitor 
CRO 
Contract research organization 
DBR 
Database review 
DPP-4 
Dipeptidyl peptidase-4 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FHD 
First Human Dose 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HCG 
Human chorionic gonadotropin 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IV 
Intravenous 
MD 
Doctor of Medicine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH 
Massachusetts General Hospital 
MPC 
Model-predictive control 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
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Abbreviation 
Definition 
RN 
Registered nurse 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SGLT-2 
Sodium-glucose co-transporter-2 
SIV 
Site Initiation Visit 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 diabetes mellitus 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
 
 
 
 
 
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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background and Rationale 
To date, clinical trials conducted by Boston University (BU) and Massachusetts General 
Hospital (MGH) in patients with type 1 diabetes mellitus (T1DM) have demonstrated the 
practicality of a wearable automated bionic pancreas (BP) control system for robust glucose 
regulation using a continuous glucose monitor (CGM) to provide the input to the control 
system. Despite current technical limitations in CGMs and infusion pumps, the trials by 
BU/MGH have shown that a bihormonal BP is capable of achieving safe and effective blood 
glucose (BG) control automatically, with minimal hypoglycemia during 11 continuous days in 
the face of unrestrained meals and exercise and with trivial patient input (optional 
announcement of meals).  
The BP provides automatic BG regulation and reduces hypoglycemic episodes. Additionally, 
the system spares the wearer the relentless tasks of carbohydrate counting, frequent BG 
monitoring, estimating the effects of specific meals and exercise activity on BG levels, and 
manual drug administration, which are inexact, demanding, aggravating, and require 
continuous diligence and vigilance. The degree of glycemic control achieved by the BP is 
predicted to dramatically reduce the deleterious and debilitating complications of T1DM. 
In its last tested embodiment, the BP consisted of a Dexcom G4 CGM, and an iPhone that are 
hardwired together, with the iPhone running the control algorithm and communicating via 
Bluetooth with 2 Tandem t:slim pumps to dose insulin and glucagon. The connections are 
repeatedly lost among these 4 components throughout the day, an issue that has the potential 
to adversely impact BG control, whether due to missed CGM values or missed doses. In 
addition, the troubleshooting required to repair these recurring disconnections can be 
burdensome to the user. Integrating these components into a single device would establish 
seamless connectivity among them, which would eliminate the need for such troubleshooting. 
This would lead to a smoother device operation with fewer interruptions, which would enhance 
its user friendliness, optimize its BG control potential, and further improve the quality of life of 
its users.  
The BU Investigators have recently designed, built, and tested a proprietary first-generation 
of such a fully integrated BP system, referred to as the iLet and the iLet infusion set. The iLet 
is a dual-chamber infusion system that currently incorporates the Dexcom G4 CGM 
technology, a custom user interface with touchscreen display, and all of the mathematical 
dosing algorithms that were tested in and validated using the iPhone-based BP in outpatient 
studies over the past 3 years. The iLet infusion set provides 2 independent subcutaneous (SC) 
fluid pathways from the iLet to the patient (1 for insulin and the other for glucagon). One tube 
connects to the prefilled insulin cartridge and the other tube connects to the fillable (single-use) 
glucagon cartridge. 
In order to provide automatic BG regulation, the iLet has the ability to deliver both insulin and 
glucagon. However, currently available glucagon formulations have limited stability at room 
temperature, necessitating frequent changes to the glucagon infusion set. Therefore, the 
current trial is designed to test the glucagon analog ZP4207 in the iLet, as this peptide analog 
of human glucagon is provided in a liquid formulation stable at room temperature. 
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The current trial is a first feasibility trial designed to use the first-generation iLet and iLet 
infusion set to compare ZP4207 with marketed glucagon (Lilly). The trial is intended to 
demonstrate the safety and tolerability of ZP4207 in the iLet and the feasibility of achieving 
comparable autonomous glycemic control. It is not intended to comprehensively demonstrate 
the definitive efficacy of the iLet in extended, continuous daily use, but rather to demonstrate 
its functionality and accuracy in a practical, albeit very controlled, clinical setting. The trial is 
expected to provide practical information that will benefit the design of a next-generation iLet 
and iLet infusion set and help pave the way for a more comprehensive outpatient home-use 
Phase 2 trial and ultimately a pivotal trial where comprehensive safety and efficacy through 
continuous full daily use of the iLet with ZP4207 will be documented. 
 
The data derived from this trial will permit evaluation of the robustness of the iLet as well as 
the safety and efficacy of ZP4207 when used in conjunction with the iLet. The data obtained 
will be used to further improve the iLet and will allow BU/MGH to expand to larger outpatient 
trials using the iLet with ZP4207.  
 
1.2 
Bihormonal Bionic Pancreas System  
The BP is an autonomous, self-learning system that requires only the patient's weight for 
initialization, and then autonomously adapts, modestly or dramatically, as needed, to cope 
with the wide range of insulin requirements of adults, adolescents, and pre-adolescents with 
T1DM. The BP obviates the need for the patient to know, or even appreciate, their insulin 
requirements, and renders obsolete any need for patients or caregivers to know 
carbohydrate-to-insulin ratios, basal rates, or insulin correction factors. 
 
The core technology is a suite of control algorithms that orchestrate the automated dosing of 
insulin and glucagon to regulate BG levels. An insulin controller orchestrates all SC insulin 
dosing. At its centerpiece is a model-predictive control (MPC) algorithm, which bases insulin 
doses on the glucose data and insulin absorption kinetics, compensating for the slow 
absorption rate of SC insulin analogs (peak time in blood of 30-90 min, clearance in 4-8 hr). 
This enables the algorithm to refrain from stacking and overdosing insulin. Furthermore, the 
MPC algorithm automatically adjusts its insulin-dosing aggressiveness continuously and in 
real-time to different insulin needs between individuals and variable needs within the same 
individual. Running in parallel with the MPC algorithm is an algorithm that automatically 
modulates basal insulin delivery over multiple time scales, and another algorithm that 
automatically adapts insulin doses in response to optional meal announcements. Unlike 
current insulin pumps and the insulin-only control algorithms, the adaptive basal insulin 
algorithm obviates the need for the user to set, or even know, his or her “basal-rate profile.” 
Instead, it is capable of automatically adapting to, and compensating for, changes in an 
individual's basal insulin need, such as might occur over a period of hours, days, or weeks 
(e.g., circadian hormonal fluctuations, intercurrent illness, physical activity, or emotional state) 
or as might occur over a period of months or years due to developmental changes 
(e.g., hormonal changes that occur during puberty or menopause). The adaptive meal dose 
controller obviates the need for the user to set, or even know, his or her 
“carbohydrate-to-insulin ratios,” as it makes automatic adjustments based on dosing history 
for similar meal announcements made on previous days, and customizes the dose for each 
individual and for time of day.  
 
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The BP also includes a proportional-derivative algorithm governing SC micro-doses of 
glucagon to help prevent impending hypoglycemia. Glucagon dosing is based on the glucose 
level and rate of descent. It may occur preemptively even if glucose is above range, and it 
includes a feedback term to account for the pending effects of recent glucagon doses.  
Taken together, these mathematical algorithms provide a universal framework for a glycemic 
control strategy that requires no quantitative input from, or participation by, the user (besides 
entering body weight to initialize the system), but which automatically adapts insulin and 
glucagon dosing to meet the individual needs of each user. Another challenge met is enabling 
the technology to remain completely autonomous in managing insulin and glucagon delivery 
even when the CGM is offline. Specifically, when the CGM is offline, the BP invokes the 
high-resolution “basal rate profile” that it had recently learned and stored when the CGM was 
online. On the basis of what the system learned and stored about meal announcements when 
the CGM was online, it is able to respond to meal announcements in the same manner when 
the CGM is offline. Finally, it automatically responds to user-entered BG values when the CGM 
is offline by issuing a correction dose of insulin or glucagon based on what it learned about 
the user's insulin and glucagon needs when the CGM was online. Thus, the BP never relies 
on, or burdens the user with, the determination of subjective dosing decisions, which inevitably 
vary in quality and reliability among different users. The BP provides a turnkey solution for 
people with T1DM that comprehensively manages glycemia across a broad range of individual 
needs and across a large spectrum of circumstances and challenges to glycemic control. 
A significant challenge for the use of glucagon in a bihormonal BP is the lack of a commercially 
available glucagon formation that is stable and well-suited to infusion over several days in a 
pump reservoir. However, BU/MGH have proceeded with studies using a relatively unstable 
marketed formulation that must be reconstituted from a lyophilized powder on a daily basis. 
This allowed BU/MGH to proceed with studies of the bihormonal system while awaiting the 
production of stable glucagon formulations or stable glucagon analogs. 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System 
The BP hardware platform has evolved over the years from a laptop-driven system, which was 
used in all inpatient studies to the first truly mobile wearable iPhone-driven platform, which 
has been used in a number of outpatient studies. Using the iPhone-based BP system, 
>110 outpatient experiments of 5-11 days in duration in each subject have been conducted 
(>800 patient days or >2 patient years of data) across subjects ranging in age between 6 and 
76 years old and in body mass between 21 and 128 kg. The robust adaptation capabilities of 
the BP is evident in the fact that the average total daily dose of insulin among these subjects 
varied by over 13-fold (from 11 to 145 units/day). 
In November 2012, Food and Drug Administration (FDA) approval was obtained to conduct 
the first outpatient study testing the BP in adults 21 years or older with T1DM. This study, 
referred to as the Beacon Hill Study, followed a random-order cross-over design in which 
20 adults with T1DM participated in 5 days on the iPhone-based BP and 5 days of usual care 
in which they wore a CGM with blinded display and muted alarms. In the BP arm, subjects 
kept to a 3-square-mile geographic area centered around the Beacon Hill neighborhood in 
Boston. They ate as they chose at local restaurants, and exercised at will with access to 
2 gyms. Analysis was pre-specified to focus on Days 2-5, since glycemic control is more 
representative of BP performance after most of the adaptation by the BP occurs on Day 1 
(Russell, 2014). Results are summarized in Figure 1.  
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In April 2013, FDA approval was obtained to conduct the first outpatient study testing the BP 
in adolescents 12-20 years old with T1DM. This study, referred to as the 2013 Summer Camp 
Study, followed a random-order cross-over design in which 32 adolescents with T1DM 
participated in 5 days on the BP and 5 days of supervised camp care in which they wore a 
CGM with blinded display and muted alarms. Subjects were fully integrated into normal camp 
activities without restrictions on diet or exercise. The study used the same iPhone-based BP 
that was used in the Beacon Hill Study. Results are summarized in Figure 1 (Russell, 2014). 
In April 2014, FDA approval was obtained to conduct the first outpatient study testing the BP 
in pre-adolescents 6-11 years old with T1DM. This study, referred to as the 2014 Summer 
Camp Study, was similar in design to the 2013 Summer Camp Study. Results are summarized 
in Figure 1 (Russell, 2016).  
In April 2014, FDA approval was obtained to conduct the first multi-center study, which was 
also the first home study, to test the BP in adults 18 years or older with T1DM. This study, 
referred to as the Bionic Pancreas Multi-Center Study, followed a random-order cross-over 
design in which 39 adults participated in 11 days on the BP and 11 days of usual care. 
Participants went to work as usual, and lived and slept at home, all without clinical supervision. 
There were no restrictions placed on diet or exercise. The study included 4 medical centers 
(10 subjects per center), which included MGH, the University of Massachusetts Medical 
School, Stanford University, and the University of North Carolina at Chapel Hill. Results are 
summarized in Figure 1.  
All of these studies used marketed glucagon (glucagon for injection, Eli Lilly). Due to its limited 
stability, Lilly glucagon must be reconstituted immediately before use. Animal studies have 
previously shown that despite its limited chemical stability, Lilly glucagon maintains its 
biological activity for up to 7 days in solution. Using this data, an Investigational New Drug 
(IND) exemption was obtained from the FDA for its use in a pump for up to 27 hours. This 
allowed these studies to be performed by asking volunteers to reconstitute a new vial of 
glucagon and fill the glucagon pump at approximately the same time every day. However, 
marketed Lilly glucagon has no path forward for approval for chronic BP use. 
1.4 
ZP4207 
ZP4207 is a peptide analog of human glucagon that is being developed to treat hypoglycemia 
in patients with T1DM and type 2 diabetes mellitus. ZP4207 exhibits improved physical and 
chemical stability in aqueous media and is suitable for liquid formulation. ZP4207 is comprised 
of 29 amino acids and has 7 amino acid substitutions when compared to native glucagon.  
Two clinical Phase 1 trials have been conducted to establish safety and tolerability of ZP4207 
after single and multiple dosing to healthy patients and T1DM patients under insulin-induced 
hypoglycemic conditions. 
The First Human Dose (FHD) trial (ZP4207-14013) was finalized in April 2015. The trial was 
a randomized, double-blinded trial with the objectives to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of ZP4207 as compared to an active 
comparator. Part 1 included a single ascending dose in healthy volunteers in cohorts of 8. In 
each cohort, the patients were randomized 3:1 to ZP4207 (n=6) or Novo Nordisk GlucaGen® 
(n=2). Five cohorts with SC administration (0.01, 0.1, 0.3, 1.0, and 2.0 mg ZP4207 compared 
to 1 mg GlucaGen) and 3 cohorts with intramuscular (IM) administration (0.3, 1.0, and 2.0 mg 
ZP4207 compared to 1 mg GlucaGen) were included. Part 2 included 2 sequence groups of 
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10 hypoglycemic T1DM patients. The patients were treated with fixed single IM doses of 
0.7 mg ZP4207 and 1.0 mg GlucaGen in a sequential cross-over design in a randomized 
treatment order.  
 
The second clinical trial (ZP4207-15007) was a single-center, double-blind, Phase 1b trial 
investigating the safety and tolerability, PK and PD of ZP4207 following repeated 
administration in healthy volunteers compared to placebo. It was finalized in July 2015. Each 
of the 3 cohorts comprised 8 subjects, who received 5 repeated SC doses of ZP4207 or 
placebo in a 3:1 treatment allocation. The first cohort started with the lowest dose of 0.1 mg. 
Cohort 2 and 3 continued with 0.3 and 1.0 mg, respectively. 
 
The Phase 1 results did not give rise to specific safety concerns, beyond those related to the 
pharmacological effect of ZP4207. All adverse events (AEs) recorded in the trials were of mild 
or moderate severity. The most frequent systemic AE related to treatment with ZP4207 was 
nausea, which is a known side-effect following administration of glucagon. The most frequent 
injection site reaction was transient erythema, occurring in all ZP4207, glucagon, and placebo 
treatment groups, irrespective of dose. No anti-drug antibodies (ADA) incidences were 
observed. 
 
The observed PD response, in terms of increased plasma glucose, in insulin-induced 
hypoglycemic patients with T1DM following dosing with 0.7 mg ZP4207 administered IM was 
similar to that observed following IM dosing with 1.0 mg glucagon (GlucaGen, Novo Nordisk). 
An increase in plasma glucose of 20 mg/dL from hypoglycemic levels was achieved within 
30 minutes for all patients. 
 
In terms of PK, ZP4207 had a short half-life and high clearance and dose proportionality for 
both maximum plasma concentration and area under the concentration-time curve from 
time 0 to 300 minutes in the dose range 0.1 to 2.0 mg following SC administration. Following 
IM administration, dose proportionality was shown in the investigated dose range of 0.3 to 
2.0 mg. The PK properties of 0.7 mg ZP4207 IM were comparable with those of 1.0 mg 
glucagon (GlucaGen, Novo Nordisk) with IM administration. 
 
1.5 
Risk/Benefit   
While the potential risks are minimal, the findings of this trial may reveal information that can 
substantially improve medical care for persons with diabetes. Therefore, the overall 
risk/benefit for patients participating in this trial is assessed as acceptable. 
 
Potential Risks and Discomforts  
 
Trial patients will be informed by the Investigator of the potential risks of ZP4207 and other 
trial-related procedures before they enter the trial.  
 
In this trial, patients with T1DM will be included to test the safety and efficacy of the iLet using 
ZP4207 versus the iLet using Lilly glucagon. The cross-over design with inclusion of the same 
T1DM patients into the 2 treatment arms in a randomized order will allow for a direct 
comparison of the safety and efficacy of the 2 treatments, based on intra-patient variability 
only.  
  
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Patients may experience mild discomfort associated with the insertion of the infusion sets and 
sensor into the SC tissues. The risk of discomfort due to insertion of infusion sets and sensors 
is expected to be slightly greater than in their lives outside the trial because more infusion sets 
will be inserted and a CGM sensor will be inserted. Most patients will use only one infusion 
set and not all will use a CGM sensor in usual care.  
There is a potential risk of hypoglycemia, since recombinant insulin analog will be 
administered. Due to frequent monitoring of glucose and direct supervision by a registered 
nurse (RN) or Doctor of Medicine (MD) at all times, the risk of a hypoglycemic episodes leading 
to significant harm to patients is expected to be substantially lower than their risk during their 
usual therapy.  
There is a risk of hyperglycemia. This risk is expected to be less than the risk during the 
patients’ lives outside of the trial based on data from earlier BP trials and the design of this 
trial.  
Treatment with ZP4207 and marketed glucagon can result in undesired effects or complaints. 
Undesired effects and complaints such as gastrointestinal side effects including nausea, 
vomiting, and diarrhea are known side effects of glucagon administration at higher dose levels. 
The frequency of nausea associated with the administration of 1 mg of glucagon according to 
the Summary of Product Characteristics (SPC) for Glucagon is described to be between 1/10 
and 1/100. The frequency of vomiting is described to be between 1/100 and 1/1000 
(Novo Nordisk, 2015). Similar gastrointestinal side effects have also been observed to a 
limited degree in the 2 clinical trials conducted with ZP4207, again at higher dose levels. The 
individual doses of ZP4207 and Lilly glucagon delivered by the BP are expected to be 
significantly lower than doses typically associated with nausea. Episodes of low blood 
pressure have also been observed after administration of higher doses of glucagon and 
ZP4207. As with every novel drug substance, new and yet unknown side effects may also 
occur. 
There are limited data available to describe the immunogenic potential of glucagon products 
available on the market, but the data available indicate that marketed glucagon only has a 
small immunogenic potential. A Phase 1 trial performed with recombinant human glucagon 
and animal derived glucagon in 75 healthy patients did not show signs of ADA measured 
13 weeks after trial product administration (Eli Lilly, 2005). In the ZP4207 FHD trial, 
ZP4207-14013, no confirmed anti-ZP4207 or anti-glucagon antibodies were detected in any 
of the samples. In addition, the 5 sequential administrations of ZP4207, as applied in trial 
ZP4207-15007, were not associated with the development of antibodies against ZP4207 in 
the 18 subjects enrolled to receive ZP4207. The optimized formulation of ZP4207, as applied 
in the present trial is not expected to change the immunogenic potential of the Investigational 
Medicinal Product (IMP).  
In relation to diabetes therapy, development of insulin-antibodies is documented more 
substantially and route of administration has been shown to influence immunogenic potential 
of insulins. However, these antibodies against insulin generally do not have an impact on 
insulin action and are thus not clinically relevant. 
In terms of consequence, development of high titer antibodies against ZP4207 could, in theory 
reduce the activity of endogenous glucagon, which again, in theory could influence 
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hypoglycemic episodes. However, most patients with T1DM do not secrete glucagon normally 
in response to hypoglycemia, so they would be less likely to be negatively impacted by 
anti-glucagon antibodies. Limited suppression of glucagon would, however, not be considered 
critical, as low glucose levels can also be corrected by other means, including oral intake of 
glucose and by other endogenous hormones such as oxyntomodulin.  
 
Overall, ZP4207 is judged to be a low-risk molecule, based upon the available clinical data as 
well as the outcome of the risk-based approach to the immunogenicity assessment made. The 
present trial will include sampling for measurement of antibodies against ZP4207 prior to first 
dosing (Visit 3) and at the Follow-up Visit. In line with regulatory guidance documents, these 
samples will be appropriately analyzed and the results will be included in the overall 
assessment of the immunogenic potential of ZP4207 after completion of each trial and as the 
clinical development program advances. 
 
Administration of ZP4207 may be associated with a risk of allergic reactions similar to those 
observed for other therapeutic peptides or proteins. Patients with known or suspected allergies 
to the trial products or related products will be excluded from the trial. Mild or moderate allergic 
reactions may include symptoms of rash, fever, flu-like symptoms, nausea, headache, and 
myalgia. Acute generalized hypersensitivity reactions are usually very rare but may include 
symptoms of flushing, sweating, dizziness, change in blood pressure, and difficulties in 
breathing. The risk of acute hypersensitivity reactions is described to be less than 1/10,000 
for native glucagon. No severe acute hypersensitivity reactions have been observed in the 
2 clinical trials conducted with ZP4207.  
 
Potential Benefits 
 
Based on experiences from previous trials of the BP and the design of this trial, patients 
enrolled in the trial may benefit from a reduction in risk of hypoglycemia and hyperglycemia 
and a better mean glucose compared to their usual diabetes care during their short trial 
participation.  
 
The data derived from this trial will allow evaluation of safety and tolerability of ZP4207 in the 
iLet, and the robustness and effectiveness of the new BP control system. The data obtained 
will be used to further improve the iLet and will allow the expansion to larger outpatient trials 
using the iLet with ZP4207.  
 
This trial is a necessary step in preparing the BP with ZP4207 to become available to people 
with T1DM. Wide availability of the BP with ZP4207 could improve the medical care of adults 
and children with T1DM. 
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2 
TRIAL OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to conduct a trial testing the safety and tolerability of the iLet when 
used with ZP4207 in 10 adult (18 years of age) patients with T1DM. 
2.2 
Secondary Objectives 
The secondary objectives are to measure glycemic regulation, including hypoglycemia 
exposure (percent of time spent with CGM glucose <60 mg/dL), evaluate BP device reliability, 
and to document the satisfaction of patients with the iLet with the goal of optimizing the 
functionality and user interface of the iLet. 
3 
TRIAL DESCRIPTION 
3.1 
Summary of Trial Design 
This trial is a single-center, open-label, randomized cross-over trial. The trial will enroll adult 
patients with T1DM and will assess the safety and efficacy of the iLet using the glucagon 
analog ZP4207 versus the iLet using Lilly glucagon. The iLet will also administer insulin (insulin 
lispro, Lilly Humalog) using the same BG control algorithm for both treatment arms. The trial 
will be conducted at a single center, the MGH Diabetes Center in Boston, MA. 
The overall trial design schematic is displayed in Figure 2. 
Figure 2. 
Trial Design Schematic 
3.2 
Indication 
ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid formulation which 
is being studied to improve glycemic control in adults (and children) with T1DM as part of a 
bihormonal BP. 
3.3 
Number of Patients 
Up to 20 adult patients with T1DM can be enrolled. The upper bound is based on the 
expectation that some patients will be excluded after the Screening Visit and the possibility 
that some patients may have to be discontinued before completion (due to, for instance, 
inter-current illness or patient withdrawal). It is expected that up to 10 patients will complete 
the trial protocol. 
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4 
SELECTION AND WITHDRAWAL OF PATIENTS 
The trial will enroll patients who already manage their T1DM using continuous SC insulin 
infusion pump therapy. This requirement is imposed because multiple daily injection therapy 
involves the use of medium-acting or long-acting basal insulin that would require an extended 
washout period. 
4.1 
Inclusion Criteria 
1. Male and female patients with T1DM for at least 1 year, as defined by the American
Diabetes Association
2. Age 18 years
3. Diabetes managed using an insulin pump for 6 months
4. Prescription medication regimen stable for >1 month (except for medications that will
not affect the safety of the trial and are not expected to affect any outcome of the trial,
in the judgment of the Investigator)
5. Informed consent obtained before any trial-related activities (trial-related activities are
any procedure that would not have been performed during normal management of the
patient)
6. Patients in good health according to age (medical history, physical examination, vital
signs, 12-lead electrocardiograms [ECGs], laboratory assessments), as judged by the
Investigator
4.2 
Exclusion Criteria 
1. Unable to provide informed consent (e.g., impaired cognition or judgment)
2. Unable to safely comply with trial procedures and reporting requirements
(e.g., impairment of vision or dexterity that prevents safe operation of the BP, impaired
memory, unable to speak and read English)
3. Participation in another clinical trial of an investigational agent or device concurrently
or within 1 month (or 5 half-lives) prior to the Screening Visit
4. Previous exposure to ZP4207
5. Females of childbearing potential who are pregnant (positive urine human chorionic
gonadotropin [HCG]), breast feeding, plan to become pregnant in the immediate future,
or sexually active without using highly effective contraception methods (highly effective
methods are considered those with a failure rate less than 1% undesired pregnancies
per year including surgical sterilization, hormonal intrauterine devices [coil], oral
hormonal contraceptives, sexual abstinence, or a surgically sterilized partner) or
postmenopausal 
women 
amenorrheic 
for 
less 
than 
1 year 
with 
serum
follicle-stimulating hormone (FSH) level 40 IU/L and not using highly effective
contraceptive methods during the trial and until 1 month after last dosing in the trial
6. Male who is sexually active and not surgically sterilized who or whose partner(s) is not
using highly effective contraceptive methods (highly effective contraceptive measures
include surgical sterilization, hormonal intrauterine devices [coil], oral hormonal
contraceptives, each in combination with spermicide-coated condoms), or who is not
willing to refrain from sexual intercourse from the first dosing until 1 month after last
dosing in the trial
7. Current alcohol abuse (intake averaging >3 drinks daily in last 30 days) or use within
the last 6 months of controlled substances without a prescription (other than marijuana)
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8. New onset clinically significant illness within 4 weeks prior to screening, as judged by
the Investigator
9. Unwilling or unable to refrain on the treatment visits from:
a. Acetaminophen in any form
b. Use of drugs that may dull the sensorium, reduce sensitivity to symptoms of
hypoglycemia, or hinder decision making during the period of participation in
the trial (use of beta blockers will be allowed as long as the dose is stable and
the patient does not meet the criteria for hypoglycemia unawareness while
taking that stable dose, but use of benzodiazepines or narcotics, even if by
prescription, may be excluded according to the judgment of the Investigator)
10. History of liver disease that is expected to interfere with the anti-hypoglycemia action
of glucagon (e.g., liver failure or cirrhosis). Other liver disease (i.e., active hepatitis,
steatosis, active biliary disease, any tumor of the liver, hemochromatosis, glycogen
storage disease) may exclude the patient if it causes significant compromise to liver
function or may do so in an unpredictable fashion.
11. Aspartate aminotransferase >2  upper limit of normal (ULN), 
alanine
aminotransferase >2  ULN, or bilirubin >1.5  ULN on screening laboratories
12. Renal failure on dialysis or estimated glomerular filtration rate <30 mL/min/1.73 m2 on
screening laboratories
13. Hemoglobin <12 gm/dL for men and <11 gm/dL for women
14. Personal history of cystic fibrosis, pancreatitis, pancreatic tumor, or any other
pancreatic disease besides T1DM
15. Any known history of coronary artery disease including, but not limited to, history of
myocardial infarction, stress test showing ischemia, history of angina, or history of
intervention such as coronary artery bypass grafting, percutaneous coronary
intervention, or enzymatic lysis of a presumed coronary occlusion)
16. Congestive heart failure with New York Heart Association Functional Classification III
or IV
17. History of transient ischemic attack or stroke in the last 12 months
18. Seizure disorder, history of any non-hypoglycemic seizure within the last 2 years, or
ongoing treatment with anticonvulsants
19. History of hypoglycemic seizures (grand-mal) or coma in the last 12 months
20. History of hypoglycemic unawareness in the last 12 months
21. History of pheochromocytoma: fractionated metanephrines will be tested in patients
with history increasing the risk for a catecholamine secreting tumor:
a. Episodic or treatment refractory (requiring 4 or more medications to achieve
normotension) hypertension
b. Paroxysms of tachycardia, pallor, or headache
c.
Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or
von Hippel-Lindau disease
22. History of adrenal disease or tumor
23. Hypertension with systolic blood pressure 160 mm Hg or diastolic blood pressure
100 mm Hg despite treatment
24. Untreated or inadequately treated mental illness (indicators would include symptoms
such as psychosis, hallucinations, mania, and any psychiatric hospitalization in the last
year), or treatment with anti-psychotic medications that are known to affect glucose
regulation
25. Electrically powered implants (e.g., cochlear implants, neurostimulators) that might be
susceptible to radio frequency interference
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26. History of adverse reaction to glucagon (including allergy) besides nausea and
vomiting
27. History of severe hypersensitivity to milk proteins or lactose
28. Established history of allergy or severe reaction to adhesive or tape that must be used
in the trial
29. Use of oral anti-diabetic medications (e.g., thiazolidinediones, biguanides,
sulfonylureas, glitinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose
co-transporter-2 [SGLT-2] inhibitors)
30. Inadequate venous access as determined by trial nurse or physician at time of
screening
31. Any factors that, in the opinion of the Investigator, would interfere with trial endpoints
or the safe completion of the trial
4.3 
Target Population 
Patients who meet all of the inclusion and none of the exclusion criteria will be considered as 
candidates for this trial. Individuals who have previously inquired about participation in 
BU/MGH trials and have asked to have their contact information kept on file will be contacted. 
In addition, advertisements for the trial may be posted at the MGH Diabetes Center and other 
places, and may be distributed in the weekly broadcast e-mail of research studies seeking 
volunteers. A letter may be sent to adult endocrinologists in the Boston metropolitan as well 
as selected nearby endocrinologists informing them of the trial and asking them to refer any 
eligible patients who might be interested. Information will be posted about the trial along with 
contact 
information 
on 
the 
BU/MGH 
website 
www.bionicpancreas.org 
and 
on 
www.clinicaltrials.gov. 
4.4 
Withdrawal Criteria 
The participation of individual patients will be discontinued if they experience: 

Seizure or unconsciousness associated with hypoglycemia and associated with
participation in the trial 

Persistent nausea and vomiting thought to be related to glucagon dosing associated
with participation in the trial 

Hospitalization associated with participation in the trial

Pregnancy

Diabetic ketoacidosis
If more than 1 patient must be withdrawn from the trial for these reasons, the trial will stop and 
a vote of the Data and Safety Monitoring Board (DSMB) will be required to restart it. All AEs 
that are serious and unexpected but related will be reported to the DSMB within 5 working 
days. 
Note that patients may discontinue participation at any time. Patients may be removed from 
the trial for other reasons, for instance, failure to comply with trial procedures or intercurrent 
illness that is unrelated to the BP but that precludes safe participation. Discontinuation of 
participation for these reasons will not contribute to a decision to discontinue the trial.  
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5 
ASSIGNMENT TO TREATMENT GROUPS 
This trial is an open-label, randomized cross-over trial. Patients who have completed the 
Screening Visit and meet all of the inclusion and none of exclusion criteria will be enrolled into 
the trial. All patients will participate in two 1-day treatment arms in random order (iLet using 
ZP4207 and iLet using Lilly glucagon) according to a pre-generated randomization scheme. 
Up to 2 patients may participate in the trial per day. The order of the iLet visits will be 
randomized in blocks of 2 patients. 
6 
TRIAL TREATMENT 
6.1 
Investigational Medicinal Products 
Insulin: The trial involves SC administration of insulin lispro (Humalog, Lilly), which is 
commercially available by prescription and is indicated for patients with T1DM, but not for use 
in a BP. 
 
Glucagon: The trial also involves SC administration of Lilly glucagon in one iLet arm. Lilly 
glucagon is commercially available by prescription and is indicated for patients with T1DM in 
severe hypoglycemia, but not for use in a BP. 
  
ZP4207: The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, 
in the other iLet arm. ZP4207 will be made available by Zealand Pharma A/S, Denmark as 
liquid formulation in prefilled syringes of 0.6 mL. 
 
6.2 
Storage and Drug Accountability of IMPs 
All IMPs will be stored and handled in accordance with the Sponsor’s instructions and/or the 
product labelling at the Investigator’s site, e.g., refrigerated (+2ºC to +8ºC) and should not be 
exposed to excessive heat, direct sunlight and never be frozen. 
 
All used, partly used, and unused vials or prefilled syringes must be kept by the Investigator 
and stored between +2ºC and +8ºC (unused) or at room temperature (partly used and used). 
Used and unused pre-filled syringes must be stored separately.  
 
The Investigator must ensure the availability of proper storage conditions and record and 
evaluate the temperature. Temperature of the refrigerator used for drug storage is monitored 
continuously, an alarm system is established. The Investigator must inform the monitor 
immediately if any IMP has been stored outside specified conditions (e.g., outside temperature 
storage). Investigational Medicinal Product that has been stored improperly must not be 
dispensed to any patient before it has been re-evaluated and approved for further use. The 
Investigator must take appropriate action to ensure correct storage. 
  
For the IMP, the Investigator must keep an accurate record of all IMPs received and the 
products used for each patient in a Drug Accountability Record. Storage locations, batch 
numbers, and expiry dates are also documented in this form. 
 
The drug accountability must be performed in a timely manner by the monitor.  
 
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6.3 
Dispensing and Return of IMPs 
No IMPs may be dispensed to any person not enrolled in the trial. 
Upon completion of the trial, the Sponsor will be responsible for destruction or storage of IMPs 
(used, partially used, or unused). These duties can be delegated to a contract research 
organization (CRO) and must be documented in the trial files. 
6.4 
Doses 
The iLet can administer isolated insulin-glucagon doses once every 5 minutes. A single 
automated bolus of insulin will not exceed 3 units per 5-minute dose (30 µl of U-100 insulin) 
in both systems, and a single meal-priming dose, in response to a meal announcement made 
by the user, will not exceed 12 units (120 µl of U-100 insulin). A single bolus of glucagon will 
not exceed 80 µg (80 µl of 1 mg/mL Lilly glucagon or 1 mg/mL ZP4207). In prior studies, typical 
doses of glucagon were in the range of 0.005-0.04 mg per dose. The iLet is capable of 
administering as little as ~0.1 µl (0.011 units of U-100 insulin or 0.1 µg of 1 mg/mL ZP4207). 
It is expected that the mean total daily doses of glucagon/ZP4207 will be <1.0 mg daily as in 
previous studies. The mean daily glucagon dose in a previous 11-day outpatient trial was 
0.5 mg/day (range 0.2-0.9 mg/day). Currently, single doses of up to 2 mg ZP4207 have been 
administered in clinical trials. The recommended dose of marketed glucagon for adult patients 
suffering from severe hypoglycemia is 1 mg as a single injection. Mean glucagon levels in 
previous inpatient studies have been above the normal fasting range for glucagon only 1% of 
the time. Therefore, the glucagon exposure of patients is expected to be modest. 
6.5 
iLet Bionic Pancreas 
Infusion set: A novel, dual cannula infusion set has been designed specifically for use with 
the iLet. Patients will wear dual channel tubing that will be attached to 2 infusion sets with 
1 steel cannula each, one for insulin infusion and the other for glucagon infusion. The tubing 
and infusion sets will have undergone sterilization prior to being delivered in a sealed pouch. 
The steel cannulae will be inserted in the abdominal SC tissue. 
Continuous glucose monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to 
the controller. The sensor is powered by the battery within the transmitter that clips to the 
sensor and the whole assembly is held to the skin with an adhesive patch and communicates 
wirelessly with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM 
signal), it will be replaced promptly.  
Bionic Pancreas Control Unit: The iLet is being built according to Class III medical device 
standards, adheres to a comprehensive and robust quality system, and is fully compliant with 
International Organization for Standardization (ISO) 13485 standards and document control 
practices. The iLet is a fully-integrated dual-hormone BP system that integrates the CGM 
technology (currently the Dexcom G4 Share system) as well as 2 independent motor-drivetrain 
pumping assemblies, which independently actuate the delivery of insulin and glucagon from 
pre-filled cartridges that are separately loaded into the iLet housing. Each drivetrain assembly 
utilizes a lead screw, which is driven by a precision micromotor, a gear case assembly, and a 
motor controller unit, in a manner similar to what is commonly found in most insulin infusion 
pumps on the market today. The iLet has dosing accuracy that is comparable to 
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FDA-approved insulin pumps currently on the market. The iLet has a built-in Bluetooth Low 
Energy radio that also allows automatic communication with the paired CGM, as well as the 
Nova StatStrip® Xpress BG meter (Nova Biomedical). The iLet does not contain a cellular nor 
a WiFi radio, and does not accept input data from another mobile device (e.g., smartphone), 
other than the paired CGM and BG meter(s). 
 
The mathematical control algorithms (which are the same as those used in the iPhone-based 
BP), the CGM glucose engine (Dexcom), and the native user interface software, are all 
interconnected through controller framework software and reside as embedded systems on 
printed circuit boards contained within the device housing. The touchscreen-enabled, 
menu-driven user interface and onboard processor provide a comprehensive and standalone 
platform, which allows the iLet to operate independently of smartphones or other devices and 
without the need for internet support during routine operation. The graphical user interface of 
the iLet has the same user options and capabilities of the iPhone BP, including having its 
home screen password protected and its settings options only accessible to trial staff via a 
separate password. 
 
6.6 
Other Trial Devices  
YSI 2300 STAT Plus™ (Yellow Springs Instruments): The YSI 2300 STAT Plus is an 
FDA-approved glucose analyzer. Blood glucose measurements using the YSI 2300 STAT 
Plus will be obtained off of the IV line during both treatment visits.   
 
Nova Biomedical StatStrip Xpress Glucose Meter: The Nova StatStrip Xpress glucose 
meter is an FDA-approved glucose meter that is commercially available. Blood glucose 
measurements for CGM calibration will be obtained with the Nova StatStrip Xpress during both 
treatment visits if the YSI 2300 STAT Plus fails and via fingerstick with the Nova StatStrip 
Xpress during any periods when IV blood samples are not available for any reason or the IV 
fails. 
 
Exercise Bike: The trial will utilize a stationary exercise bike (ergometer) for the in-clinic 
exercise at the treatment visits. This bike will be stored at the Diabetes Research Center when 
not in use. 
 
6.7 
Concomitant Medications 
6.7.1 
Permitted Medications and/or Procedures  
Patients may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference with 
CGM sensing. All concomitant medications, including over-the-counter medications, should 
be recorded. 
 
Use of beta blockers will be allowed as long as the dose is stable and the patient does not 
meet the criteria for hypoglycemia unawareness while taking that stable dose. 
 
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911. 
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6.7.2 
Excluded Medications and/or Procedures  
During the trial, patients will not use any recreational drugs or drugs of abuse. The need to 
take prescription drugs that dull the sensorium, reduce sensitivity to symptoms of 
hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion from the 
trial or discontinuation of participation, a decision that will be made by the Investigator. 
 
Use of benzodiazepines or narcotics, even if by prescription, may be excluded according to 
the judgment of the Investigator. Use of oral anti-diabetic medications (e.g., thiazolidinediones, 
biguanides, sulfonylureas, glitinides, DPP-4 inhibitors, SGLT-2 inhibitors) will also be 
excluded. 
7 
TRIAL PROCEDURES  
7.1 
Informed Consent  
After potential patients have had time to review the consent document, and prior to any 
trial-related activities, they will meet with a trial MD or designee who will explain the trial, 
answer any questions, and administer informed consent. In the event that a volunteer is a 
patient of one of the trial MDs, another staff MD or designee will answer questions and 
administer consent. The patients will be fully informed of their responsibilities and their rights 
while participating in the trial as well as of the possible risks and potential benefits of 
participation in the trial. They will have the opportunity to discuss all questions and ample time 
to consider participation. 
 
Trial-related activities are any procedures that would not have been performed during normal 
management of the patient. Patients who wish to participate in the trial will be asked to 
personally date and sign an informed consent form (ICF). Likewise, the Investigator must also 
personally date and sign the ICF. All patients will be provided with a copy of their own signed 
and dated ICF. 
 
Trial staff will answer any questions that the patients may have during their participation. They 
will share any new information in a timely manner that may be relevant to the patient's 
willingness to continue participating in the trial. The patients may choose to discontinue their 
participation at any time.  
 
7.2 
Screening Visit (Visit 1) 
All patients will have a Screening Visit to confirm eligibility. The patient will be interviewed and 
the electronic Case Report Form (eCRF) will be completed by trial staff to establish whether 
the patient is eligible. 
 
Patients will be instructed concerning diabetes management (e.g., basal insulin rate 
adjustment by insulin pump) during fasting prior to and between the treatment visits per the 
medical judgment of the Investigator. 
 
Once all of the results have been returned, a trial MD will review the eCRF to determine patient 
eligibility. If a patient is not eligible to continue in the trial, the results of abnormal tests will be 
reported to the patient and to a health care provider of their choosing. 
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7.2.1 
Data Collected at Screening 

Age, sex, race, and ethnicity

Date of last menstrual period in female patients

Medical, surgical, and social history, allergies, and review of systems relevant to
inclusion and exclusion criteria, including:
o
Date of diabetes diagnosis
o
Duration of insulin pump use and type of insulin used in pump
o
Type/model of insulin pump
o
Insulin regimen (basal rate, sensitivity factor, and carbohydrate ratio)
o
Average total daily dose of insulin in the last 30 days as available (from pump
history)
o
Usage of CGM, if any (type of CGM, days per month worn, usage of data,
whether insulin is dosed based on CGM alone, alarm settings)

Concomitant illness (any illness present at screening)

Concomitant medications (prescription and non-prescription) and date of last change
in medication regimen

Height, weight, physical examination, and vital signs including body temperature and
blood pressure

12-lead ECG

Hemoglobin A1c

Chemistry and hematology samples (see Appendix B)

Urine HCG pregnancy test for women of childbearing potential

FSH level for postmenopausal women amenorrheic for less than 1 year

Fractionated plasma metanephrines (if indicated by history)
7.3 
Training Visit (Visit 2) 
A Training Visit will take place before the first treatment visit. Patients will be trained in the 
insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. Trial staff 
will verify that the patients have understood the material and are competent to participate 
safely in the trial. Patients will be instructed concerning diabetes management (e.g., basal 
insulin rate adjustment by insulin pump) during fasting prior to and between the treatment 
visits per the medical judgment of the Investigator. Concomitant medications will also be 
reviewed. 
7.4 
Treatment Visits (Visit 3 and Visit 4) 

Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than
30 days after screening (Visit 1).

There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum
of 3 weeks between Visit 3 and Visit 4.

Up to 2 patients may participate per day.

Each patient will participate in 2 treatment visits: one with the iLet using ZP4207 and
one with the iLet using Lilly glucagon in a randomized order.

The night before the treatment visit, patients will place a Dexcom G4 CGM sensor in
the abdominal skin and calibrate the sensor when prompted using the provided Nova
StatStrip Xpress meter. Patients will be instructed to call if they encounter any difficulty
with their CGM.
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
Patients will be responsible for their own medications other than insulin during the trial.
Any medical advice needed by the patients during their participation that is not directly
related to BG control should be obtained from them in their usual manner. Patients
may take any over-the-counter medications that they wish during the trial, with the
exception of any medication containing acetaminophen as that may cause interference
with CGM sensing. If patients experience urgent or emergent medical concerns
outside the scope of diabetes care and their primary care physicians, they will be taken
to the MGH walk-in clinic or emergency room, or if necessary call 911.

During the trial, patients will not use any recreational drugs or drugs of abuse. The
need to take prescription drugs that dull the sensorium, reduce sensitivity to symptoms
of hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion
from the trial or discontinuation of participation, a decision that will be made by the
Investigator.

Patients will be instructed concerning diabetes management (e.g., basal insulin rate
adjustment by insulin pump) during fasting prior to and between the treatment visits
per the medical judgment of the Investigator.

Patients will not tamper with the BP, including changing any settings.

Patients may not remove the BP during the trial unless the BP failed or they are
withdrawing from the trial.

The exact time of each procedure and assessment will be documented.
7.4.1 
Visit Procedures 

Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the
BP having fasted since 12:00 AM the night before (treatment with simple carbohydrate 
of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled 
within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the 
visit window. If BG is <50 mg/dL, treatment with simple carbohydrate is allowed. If the 
patient experiences persistent hypoglycemia, the visit will be rescheduled within the 
visit window. If the visit needs to be rescheduled due to hypoglycemia or 
hyperglycemia, trial staff will assist the patient with insulin or medication adjustments 
to address glycemic control. The patient will be instructed to contact trial staff later in 
the day if his or her BG remains uncontrolled. 

Upon arrival to the visit, the patient’s weight and vital signs including body temperature
and blood pressure will be documented. 

Patient reports of symptoms, any other complaints, and AEs will be reviewed.

Concomitant medications will be recorded.

Chemistry and hematology samples will be collected at visit start (see Appendix B).

ADA samples will be collected before the start of dosing (Visit 3 only).

A 12-lead ECG will be performed.

A urine HCG pregnancy test will be performed in female patients of childbearing
potential. If the test is positive, the patient will be informed of the result and the visit
will be ended.

Patients will complete a baseline survey about their attitudes and experience with their
usual diabetes care.

An intravenous (IV) catheter will be placed for blood sampling.
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
Trial staff will assist the patient to calibrate their CGM, review the trial procedures again
and assist with the setup of the BP system, including inserting and priming infusion
sets.

The control algorithm will be initialized only with the patient’s weight. Diagnostics will
be performed to ensure that the CGM device is appropriately calibrated and that all of
the components of the BP systems are in working order.

The basal rate of the patient’s own insulin infusion pump will be changed to be 2-fold
higher than weighted mean of the basal rate during the trial period. This is intended to
increase the usage of glucagon during the treatment visit.

The patients will continue to wear their own infusion pump infusing at the temporary
2-fold basal rate throughout the visit until the start of the structured exercise period, in
addition to the BP.

The staff will start the BP as close as possible to a minute divisible by 5 minutes
(i.e., on a 5-minute mark). The starting time will be considered Hour 0.

Additional calibrations will be performed at any of the BG checks throughout the day if
the CGM value does not meet the ISO standard (<15 mg/dL difference for BG values
<75 mg/dL; <20% absolute difference for BG values >75 mg/dL) at the time of the BG
measurement AND it is a good time to calibrate (the CGM trend arrow is flat and there
has been no carbohydrate intake in the last 30 minutes or glucagon boluses in the last
15 minutes).

Blood samples will be taken from the IV at least hourly and processed for plasma
ZP4207/glucagon. If BG is <150 mg/dL, more frequent samples for plasma
ZP4207/glucagon may be drawn at the discretion of the Investigator. The actual time
of sampling will be recorded in the eCRF.

Plasma glucose samples will be taken from the IV at least hourly in parallel with
ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT Plus.
If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes.
If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then
sampling will be every 10 minutes. The actual time of sampling will be recorded in the
eCRF.

Patients will be asked to rate any nausea and/or infusion site pain on 10 cm visual
analog scales (VAS) at the beginning of the visit once the infusion sites have been
placed but no drug has yet been administered, then approximately at the top of every
hour during the visit, and at the end of the visit. Trial staff will also evaluate their infusion
sites to document any erythema or edema at the same times. If moderate or severe
pain is reported or swelling or redness occurs at the infusion site, the infusion site will
be replaced in a different location. If moderate or severe pain, swelling, or redness
continues at the old site for more than 30 minutes after the infusion site is removed, or
if moderate or severe pain, swelling, or redness occurs at the new site, all infusion
sites will be removed and the patient will be discontinued from the study. Any such
symptoms will be followed until resolution.

From the start of closed loop control until approximately Hour 3, the patients will
continue to fast.

Between approximately Hour 3 and Hour 4, patients will be provided with a lunch meal
of their choice in the Diabetes Research Center from a menu of choices from nearby
restaurants. They will be asked to choose a meal that is a “typical meal” for them. The
content of their meal will not be restricted in any way, with the exception that the
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number of carbohydrates should be in the “typical” range for them at lunch, and that 
they must eat the same meal at the same time during both visits. 

At approximately 15 minutes before the meal, patients will administer a bolus for the
meal with their own insulin pump based on the carbohydrate count for the meal.

After lunch is completed, the patients will not be allowed any carbohydrate intake
(non-caloric drinks will be permitted) until the trial is completed (except as necessary
to treat hypoglycemia), to allow the BP to control the post-prandial BG without further
interruption.

Between approximately Hour 6 and Hour 7, the patients will start a period of structured
exercise.

At the start of the exercise period, patients will restore their normal basal insulin profile
so that they will not have elevated insulin levels at the end of the study period when
they are to transition back to their usual care.

Patients will exercise on a stationary bike with a heart rate from 120-140 beats per
minute for a total of 4,000 heart beats (approximately 30 minutes). Patients will rate
their exercise intensity using the Borg scale every 5 minutes, with the target intensity
level between 12 and 14. Heart rate will be measured every 5 minutes.

BG measurements will be obtained off of the IV line every 10 minutes. If BG is
<80 mg/dL, BG measurements will be obtained off of the IV line every 5 minutes.
o
Carbohydrates will be given for any BG <50 mg/dL according to the following
protocol: Dextrose (g) = BSA (m2)/[1.7 m2 (women) or 1.9 m2 (men)] *15 g.
o
Repeat treatments will be given at 15-minute intervals as long as BG remains
<50 mg/dL.

If there is an interruption in the Dexcom CGM output, trial staff will assist the patient in
recovering CGM data streaming. If this requires replacement of the CGM sensor, BGs
will be checked every 10 minutes (every 5 minutes if BG is <80 mg/dL) using blood
from the IV until the CGM is able to be calibrated again. These BGs will be entered
into the BP, which will treat them as CGM values and dose insulin and/or glucagon
appropriately.

If there is a complete failure of the BP operation, patients will take over their own BG
control using their personal insulin pump until the BP can be brought back online. If BP
control cannot be promptly resumed (e.g., within 30 minutes), the patient may be asked
to repeat that trial day once.

Patients may choose to withdraw from the trial at any time. If they withdraw from the
trial, they should alert a provider immediately.

Just prior to the end of the study visit, vital signs including body temperature and blood
pressure will be obtained and a 12-lead ECG will be performed.

After approximately Hour 8, but not earlier than at least 60 minutes after end of
exercise, the BP will be stopped and the patient will continue with their personal insulin
pump.
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
If the patient experiences seizure or unconsciousness, persistent nausea or vomiting,
diabetic ketoacidosis, persistent hyperglycemia with ketonemia, hemodynamic
changes such as hypotension, or other medically significant findings, a longer
observation period at the trial site may be necessary until the patient is considered
stable for discharge. If the Investigator or trial staff determines that the patient requires
further observation or treatment, the patient may be transferred to the emergency room
for additional monitoring and/or medical care. At discharge, patients will be provided
with any necessary instructions concerning personal insulin pump usage, food intake,
and driving arrangements.

The maximum amount of blood loss per study visit will be approximately 230 mL. The
total blood loss for the entire study will be up to 460 mL.

Patients will answer questionnaires (see Appendix C).

Chemistry and hematology samples will be collected at visit end (see Appendix B).

The BP and glucose meters will be collected and downloaded.

A trial MD will review the last several hours of insulin and glucagon dosing and assist
the patient in resuming their usual diabetes care. A longer observation period at the
trial site may be necessary. Patients will be instructed to call trial staff with any
questions, issues, or concerns.
7.4.2 
Data Collected During the Treatment Visits 

CGM glucose every 5 minutes from the Dexcom G4 Platinum CGM

All BG measurements taken

Insulin total dose by the BP and the patient’s own insulin pump

Glucagon total dose

Timing and content of the meal eaten and carbohydrate amount

Timing of meal announcement and size of meal announced

Timing and glucose values at calibrations

Timing and amount of carbohydrates taken for hypoglycemia

Data from a questionnaire about attitudes and expectations regarding the BP before
and after each treatment arm (see Appendix C)

Time patients were not under BP control for any reason

List of technical faults associated with the BP including cause and resolution

ZP4207/glucagon sampling will be collected at least hourly. If BG is <150 mg/dL, more
frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the
Investigator.

Plasma glucose sampling will be collected at least hourly in parallel with
ZP4207/glucagon exposure sampling. If BG is <150 mg/dL, then sampling will be every
30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is
<80 mg/dL, then sampling will be every 10 minutes.

Nausea and infusion site pain on a VAS at visit start (after insertion and before any
drug administration), hourly, and at visit end

Infusion site reaction according to the Draize scale at visit start (after insertion and
before any drug administration), hourly, and at visit end

Patient reports of symptoms, any other complaints, and AEs

Vital signs including body temperature and blood pressure (at visit start and visit end)
and weight

Concomitant medications
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
Chemistry and hematology samples (see Appendix B) at visit start and visit end

ADA (Visit 3 only)

12-lead ECG at visit start and visit end

Urine HCG pregnancy test for women of childbearing potential
7.4.3 
Response to Hypoglycemia  

Patients are encouraged to check their BG for any symptoms of hypoglycemia.

Patients will be permitted to take 15 grams of carbohydrates for any BG value
<60 mg/dL. Trial staff will ensure proper functioning of the BP, infusion set, and insulin
pump, and will encourage the patient to wait for the BP to treat the low blood sugar for
as long as they feel comfortable.

Patients will be required to take 15 grams of carbohydrates for any BG value
<50 mg/dL. After treatment of hypoglycemia, a follow-up measurement will be taken
15 minutes later. Repeated measurements will be taken every 15 minutes until the
BG is >60 mg/dL. Treatment will be repeated if subsequent BG values are still
<50 mg/dL. All carbohydrate treatments for hypoglycemia will be documented by trial
staff (amount and time).

Trial staff will check the infusion site, BP, and insulin pump for normal operation any
time hypoglycemia occurs. If there is any suspicion of infusion set malfunction, the site
should be replaced. Trial staff will check the BP for any malfunction and correct any
problems that are found.

If no correctable fault is found, but there is doubt regarding the correct function of the
BP system, an entirely new backup BP system may be started.

If a patient experiences a seizure or unconsciousness associated with hypoglycemia,
his or her participation in the trial will be discontinued.
7.4.4 
Response to Hyperglycemia  

Trial staff will check the infusion site, BP, and insulin pump for normal operation any
time BG is >300 mg/dL. If there is any suspicion of infusion set malfunction, the site 
should be replaced. Trial staff will check the BP for any malfunction and correct any 
problems that are found. If the BG remains >300 mg/dL for 2 hours despite 
troubleshooting, blood ketones will be measured. If the blood ketone result is 
>1.5 mmol/L, the visit will be stopped and rescheduled. The patient will be provided 
with insulin and a syringe to give an injection based on their correction factor. 

If a patient experiences diabetic ketoacidosis, his or her participation in the trial will be
discontinued. 

If no correctable fault is found, but there is doubt regarding the correct function of the
BP system, the treatment visit may be stopped and the visit rescheduled. 
7.4.5 
Response to Nausea/Vomiting 
If significant nausea (e.g., that prevents the patient from eating normally) or any vomiting 
occurs, trial staff will notify the Investigator. Trial staff will assist the patient in troubleshooting, 
such as checking BG and the calibration of the CGM (excessive glucagon dosing may occur 
if the CGM is reading lower than the true BG). If a patient experiences persistent nausea and 
vomiting thought to be related to glucagon dosing, his or her participation in the trial will be 
discontinued. 
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7.4.6 
Response to Other Medical Needs 
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911.  
7.4.7 
Monitoring of Bionic Pancreas Performance  
Bionic pancreas inventors and developers 
, 
, and/or an 
engineer trained by them will be readily available by phone for consultation for the trial staff at 
all times during the course of the trial.  
7.4.8 
Supervision by Trial Staff 
A trial MD will be on call at all times during the course of the trial. An RN or MD will be with 
the trial patients in the Diabetes Research Center at all times. 
7.5 
Phone Call (Visit 5) 
A phone call will be conducted 7 days ±3 days following the last day of dosing (Visit 4) to 
review AEs and concomitant medications. 
7.6 
Follow-up Visit (Visit 6) 
Patients will return for a Follow-up Visit 25 days ±4 days following the last day of dosing 
(Visit 4), for chemistry, hematology, and ADA sampling, and a review of AEs and concomitant 
medications.  
8 
ENDPOINTS 
8.1 
Primary Endpoint 
The primary endpoint is the safety and tolerability of ZP4207 and the iLet as assessed by: 

Number and type of AEs

Clinical laboratory measurements

Vital signs

12-lead ECG

Local tolerability and infusion site reactions as measured with the Draize scale

Immunogenicity as measured by ADA

Pain as measured on a 10 cm VAS

Nausea as measured on a 10 cm VAS
8.2 
Secondary Endpoints 
The secondary endpoints for the iLet and ZP4207 include measurements of BP function as 
well as glycemic and non-glycemic measurements. 
8.2.1 
Bionic Pancreas Function 
This endpoint data will be generated from the BP data during each treatment visit: 

Average percent insulin dose amounts calculated by the BP control algorithm that are
successfully delivered by the pump 

Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully delivered by the pump 
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
Average percent dose amounts successfully issued to the pump by the BP control
algorithm that are successfully delivered by the pump (calculated doses are not issued
unless the pump is accessible and its delivery channel is available)
o
Average percent insulin dose amounts successfully issued to the pump by the
BP control algorithm that are successfully delivered by the pump
o
Average percent glucagon/ZP4207 dose amounts successfully issued to the
pump by the BP control algorithm that are successfully delivered by the pump

Average percent dose amounts calculated by the BP algorithm that are successfully
issued to the pump by the BP (calculated doses are not issued unless the pump is
accessible and its delivery channel is available)
o
Average percent insulin dose amounts calculated by the BP control algorithm
that are successfully issued by the BP
o
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully issued by the BP

Average percent of 5-minute steps during which the BP is functioning nominally in all
respects based on real-time CGM data (new CGM glucose reading captured, dose
calculated, and dose issued to pumps)

Average percent of 5-minute steps during which the BP is functioning nominally with
or without a new CGM glucose reading captured (dose calculated and dose issued to
pumps). If a CGM signal is not available, the dose calculated may be based on weight
or historical basal rates.

CGM reliability index, calculated as percent of possible values actually recorded by
CGM

CGM Mean Absolute Relative Difference versus time-stamped BG values from meter
download

List of technical faults associated with the BP including cause and resolution
8.2.2 
Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit. 

Fraction of time spent within each of the following glucose ranges:
o
<50 mg/dL
o
<60 mg/dL
o
<70 mg/dL
o
70-120 mg/dL
o
70-140 mg/dL
o
70-180 mg/dL
o
>180 mg/dL
o
>250 mg/dL
o
>300 mg/dL

Number of severe hypoglycemic events (patients unable to self-treat, requiring the
assistance of another person)

Number of episodes of symptomatic hypoglycemia

Number of carbohydrate interventions for hypoglycemia

Total grams of carbohydrates taken for hypoglycemia

Mean CGM glucose
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8.2.3 
Non-glycemic 

Glucagon/ZP4207 total delivery per kg of body mass

Insulin total delivery per kg of body mass

Number of unscheduled infusion set replacements

Number of unscheduled CGM sensor changes
9 
LABORATORY ASSESSMENTS 
Descriptions of sample handling and sample processing, storage, and shipment at the site will 
be included in the laboratory manual. 
The responsible laboratories are listed in the address list. 
9.1 
Safety Laboratory Assessments 
Chemistry and hematology samples will be collected at specified time points. See Appendix A 
for the schedule of procedures and Appendix B for a list of clinical laboratory analytes. 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) 
At Visit 3 and Visit 4, plasma glucose samples will be taken from the IV at least hourly in 
parallel with ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT 
Plus. If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for 
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is 
<100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will 
be every 10 minutes. The actual time of sampling will be recorded in the eCRF. 
9.3 
Exposure Assessments (ZP4207 and Glucagon) 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the 
discretion of the Investigator. The actual time of sampling will be recorded in the eCRF. 
Bioanalytical Reports will be prepared. 
9.4 
Anti-drug Antibody Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken at Visit 3 and the Follow-up Visit 6. 
A Bioanalytical Report will be prepared. 
10 
SAFETY REPORTING 
10.1 
Adverse Events 
An AE is any untoward medical occurrence in a trial patient administered an IMP and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be 
any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not considered related to 
the IMP. Patients should be instructed to report any AE they experience to the Investigator. 
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Note: This includes events from the first trial-related activity from Visit 3. 
AEs for ZP4207 include: 

A clinically significant worsening of a concomitant illness

A clinical laboratory abnormality which is clinically significant, i.e., any abnormality that
suggests a disease and/or organ toxicity and is of a severity that requires active
management. Active management includes active treatment or further investigations,
for example, change of medicine dose or more frequent follow-up due to the
abnormality.

Hypoglycemic episodes

Injection site reactions
The following should not be recorded as AEs, if recorded prior to randomization (on the 
Screening Form or the eCRF): 

Pre-planned procedure, unless the condition for which the procedure was planned has
worsened from the first trial-related activity from Visit 3. 

Pre-existing conditions found as a result of screening procedures (pre-existing
conditions should be reported as medical history or concomitant illness). 
For known (listed) AEs for Glucagon and Humalog, please refer to SPC for Glucagon and 
Humalog. 
10.1.1 
Follow-up of Adverse Events 
All AEs that are ongoing at the end of the patient’s participation in the trial will be followed-up 
until the event is resolved or reaches a satisfactory outcome as deemed by the Investigator. 
Follow-up actions for all serious adverse events (SAEs) will be performed according to 
appropriate clinical care practices and may depend on the nature of the event. These will be 
determined after internal review and/or Sponsor review. The follow-up information should only 
include new (updated and/or additional) information that reflects the situation at the time of the 
Investigator’s signature. 
Follow-up information on (S)AEs will be updated using the (S)AE Form. If a non-serious event 
becomes serious during the follow-up, the AE Form and SAE Form must be used and reporting 
timelines follow those of an SAE. 
The Investigator must forward follow-up information on SAEs, and if previously non-serious 
AEs become SAEs, to the Sponsor. 
10.1.2 
Precautions 
Normal precautions taken for a human trial will be taken during this trial. Qualified and 
well-trained physicians and medical staff will instruct the patients. During a patient’s 
participation in the trial, the Investigator should ensure that adequate medical care is provided 
to the patient for any AEs, including clinically significant laboratory values related to the trial. 
The Investigator should inform the patient when medical care is needed for intercurrent 
illnesses of which the Investigator becomes aware.  
For further information on safety precautions for ZP4207, Lilly glucagon, Lilly Humalog, and 
the iLet, please refer to the current version of the Investigator’s Brochure (IB) for ZP4207 
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(Zealand Pharma A/S, 2015, or any updates hereof), and the SPC for Glucagon (Eli Lilly, 
2012) and Humalog (Eli Lilly, 2015), respectively. 
10.1.3 
Assessment of Adverse Events by the Investigator 
Intensity of an Adverse Event 
The maximum intensity (severity) of all AEs must be assessed by the Investigator and 
documented. Severity should be graded when the AE outcome is known: 

Mild: A type of AE that is usually transient and may require only minimal treatment or
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 

Moderate: A type of AE that is usually alleviated with additional specific therapeutic
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the patient. 

Severe: A type of AE that interrupts usual activities of daily living, or significantly affects
clinical status, or may require intensive therapeutic intervention. 
A “severe” reaction does not necessarily deem the AE as “serious,” and an SAE may not be 
“severe” in nature. 
Causality Relationship to IMP 
Insulin (insulin lispro, Lilly Humalog), glucagon (glucagon for injection, Eli Lilly), and ZP4207 
are all regarded as IMP. 
The causality of each AE should be assessed by the Investigator according to the following 
classification: 

Related: Good reason and sufficient documentation to assume a causal relationship.

Not related: No relationship to trial product can be established.
Outcome of an Adverse Event 
The outcome of all AEs must be assessed by the Investigator and documented by his/her 
staff. The following definitions should be used: 

Recovered/resolved: The patient has fully recovered, or by medical or surgical
treatment the condition has returned to the level observed at the first trial-related 
activity from Visit 3. 

Recovering/resolving: The condition is improving and the patient is expected to recover
from the event. This term is only applicable if the patient has completed the trial.

Recovered/resolved with sequelae: The patient has recovered from the condition, but
with lasting effect due to a disease, injury, treatment, or procedure. If a sequela meets
an SAE criterion, the AE must be reported as an SAE.

Not recovered/not resolved: The condition of the patient has not improved and the
symptoms are unchanged, or the outcome is not known.

Fatal: This term is only applicable if the patient died from a condition related to the
reported AE. Outcomes of other reported AEs in a patient before he/she died should
be assessed as “recovered/resolved,” “recovering/resolving,” “recovered/resolved with
sequelae,” or “not recovered/not resolved.” An AE with a fatal outcome must be
reported as an SAE.

Unknown: This term is only applicable if the patient is lost to follow-up.
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10.2 
Serious Adverse Events   
An SAE is any untoward medical occurrence that at any dose: 

Results in death

Is life-threatening

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability or incapacity

Is a congenital anomaly or birth defect

Medically important
Medical judgement must be exercised in deciding whether an AE is believed to be “medically 
important.” Medically important events may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above. 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is an AE fulfilling one of the criteria of seriousness and being assessed as related 
to an IMP, the nature or severity of which is not consistent with the applicable reference 
document (e.g., ZP4207 IB or package leaflet/SPC for an approved product). 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety, any life-threatening problem or 
death caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the application; or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. 
10.3 
Adverse Event Reporting – Procedures for Investigators 
The Principal Investigator and co-investigators will review any AEs and report any SAEs to 
the Sponsor as soon as possible and within 24 hours of obtaining knowledge of the event. The 
Principal Investigator and co-investigators will promptly report AEs to the Partner’s Institutional 
Review Board (IRB) and to the BU IRB (unless oversight is ceded by the BU IRB to the 
Partners IRB), in accordance with local requirements.  
Ed Damiano is the Sponsor of the Investigational Device Exception for the BP and Zealand 
Pharma A/S is the Sponsor of the IND for ZP4207.  
Reports of AEs will be submitted to the FDA in compliance with the terms of the Code of 
Federal Regulations. 
All events meeting the definition of an AE must be collected and reported from the first 
trial-related activity from Visit 3 until the end of the post-treatment follow-up period. At each 
contact with the site (visit or telephone, excluding safety visits, where the patient is not seeing 
the Investigator or staff [e.g., visits to the laboratory], the patient must be asked about AEs. 
All AEs, either observed by the Investigator or reported by the patient, must be recorded by 
the Investigator and evaluated. 
The Investigator should record the diagnosis, if possible. If no diagnosis can be made, the 
Investigator should record each sign and symptom as individual AEs. 
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 
All SAEs in connection with the pregnancy and pregnancy outcome must be reported 
on the pregnancy forms following the same timelines as required for other SAEs. It 
must be clear in the description if the event occurs in the patient/patient’s partner, the 
fetus, or the newborn infant.  
 
The SAEs that must be reported include abnormal outcome – such as congenital anomalies, 
fetal death, and termination of pregnancy (spontaneous or elective abortion), including any 
anomalies of the fetus observed at gross examination or during autopsy – as well as other 
pregnancy complications (ectopic pregnancy) fulfilling the criteria of an SAE. 
 
10.5 
Hypoglycemia 
Hypoglycemia will be regarded as an AE and will be recorded and documented on an AE 
Form. For the purposes of AE reporting, the following definitions of hypoglycemia will be used: 
 
Symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia 
are accompanied by a BG concentration 70 mg/dL 
 
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of 
hypoglycemia but with a BG concentration 50 mg/dL 
 
Severe hypoglycemia: an event requiring assistance of another person to actively 
administer carbohydrates, glucagon, or take other corrective actions 
 
10.6 
Safety Monitoring 
10.6.1 
Data and Safety Monitoring Board 
An external DSMB will oversee the conduct of the trial, as set forth in the DSMB Charter. 
Additionally, the DSMB will be informed in the event of any serious and unexpected AEs. The 
DSMB will be informed if there are any changes to the trial protocol that could significantly 
impact the safety or scientific validity of the trial. A final DSMB meeting will convene after the 
completion of the trial. 
 
The participation of individual patients will be discontinued if they experience: 
 
Seizure or unconsciousness associated with hypoglycemia and associated with 
participation in the trial  
 
Persistent nausea and vomiting thought to be related to glucagon dosing associated 
with participation in the trial 
 
Hospitalization associated with participation in the trial 
 
Pregnancy 
 
Diabetic ketoacidosis 
 
If more than 1 patient must be withdrawn from the trial for these reasons, the trial will stop and 
a vote of the DSMB will be required to restart it. All AEs that are serious and unexpected but 
related will be reported to the DSMB within 5 working days. 
 
Note that patients may discontinue participation at any time. Patients may be removed from 
the trial for other reasons, for instance, failure to comply with trial procedures or intercurrent 
illness that is unrelated to the BP but that precludes safe participation. Discontinuation of 
participation for these reasons will not contribute to a decision to discontinue the trial.  
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10.6.2 
Zealand Pharma Safety Committee 
The internal Zealand Pharma Safety Committee is constituted to perform ongoing safety 
surveillance of clinical trials within ZP4207, including this trial. 
If safety signals are observed either based on reported SAEs, periodic review of laboratory 
parameters, planned review of all AEs reported between the safety committee meetings, or 
on notification of significant findings, the Safety Committee will take appropriate measures to 
safeguard the patients. 
11 
STATISTICS 
11.1 
Analysis Populations 
The following analysis sets are defined in accordance with the ICH-E9 guidance: 
The Full Analysis Set is based on the intention-to-treat principle and includes all randomized 
patients. In exceptional cases, patients from the Full Analysis Set may be excluded (will be 
decided in the database review [DBR] meeting). In such cases, the exclusion will be justified 
and documented. Patients will contribute to the evaluation “as randomized.” 
The Per-Protocol Set includes all patients of the Full Analysis Set who completed the trial 
without any major protocol violations. Patients in the Per-Protocol Set will contribute to the 
evaluation “as treated.” This analysis will only be used if it is different than the Full Analysis 
Set. 
The Safety Analysis Set includes all patients receiving at least 1 dose of the IMP. Patients in 
the Safety Analysis Set will contribute to the evaluation “as treated.”  
Analyses of efficacy endpoints will be based on the Full Analysis Set (and the Per-Protocol 
Set if necessary). This decision will be made in the DBR meeting. The analysis of the safety 
endpoints will be based on the Safety Analysis Set.  
Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. At this time, it will be 
determined if patients and/or data should be excluded from the analysis. Furthermore, outliers 
will be identified by data review according to ICH-E9. 
Obviously erroneous data points may be excluded from the analyses or re-analyzed 
(e.g., serum concentrations). The decision to re-analyze or exclude data points from the 
statistical analysis is the joint responsibility of the Sponsor, the Principal Investigator, and the 
Trial Statistician. 
The patients or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to database release. The documentation 
will be stored together with the remaining trial documentation. The patients and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report. 
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11.2 
Statistical Methods 
Medpace will be responsible for the statistical analysis. The statistical planning and conduct 
of analyses of the data from this trial will follow the principles defined in relevant ICH guidelines 
and Medpace’s biostatistical standard operating procedures (SOPs). A general description of 
the statistical methods to be used is given in this section, specific details will be provided in 
the Statistical Analysis Plan (SAP), which will be prepared before database lock. All statistical 
analyses will be performed using SAS® (SAS Institute Inc., Cary, North Carolina, USA), 
version 9.4 or later.  
11.2.1 
Analysis of Safety 
The following variables will be evaluated according to treatment for safety purposes: 
Adverse Events 
All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). Individual AEs will be presented in a listing including relationship to trial 
product/device, severity, and treatment period at onset. If more than 20 treatment-emergent 
AEs (AEs with onset after [first] dosing at Visit 3 until the Follow-up Visit 6) are registered, a 
summary table including number of AEs, number of patients with at least 1 AE, and percentage 
of exposed patients with at least 1 AE will be made by system organ class and treatment 
period at onset. 
Local Tolerability 
Local tolerability at the injection site will be summarized using descriptive statistics as 
appropriate. 
Laboratory Safety Assessments 
Laboratory assessments will be summarized. A listing of abnormal values will be provided. 
Physical Examination 
A frequency table will show the number and percentage of physical examination results. 
Vital Signs 
Vital signs will be summarized using descriptive statistics. 
12-lead ECG 
The Investigator’s evaluations of 12-lead ECGs will be summarized and abnormal individual 
evaluations will be listed together with the Investigator’s comments. Changes in 12-lead ECG 
between measurements will be recorded as AEs if the Investigator judges them to be clinically 
significant.  
11.2.2 
Analysis of Efficacy 
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
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A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis, any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. Further details will be included in the 
SAP. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow.  
11.2.3 
Interim Analysis 
No interim analysis is planned. 
11.2.4 
Sample Size Determination 
No formal sample size calculations were made. It is expected that between 10 and 12 patients 
will be randomized in the trial. The sample size is based on a clinical rather than statistical 
rationale. The sample size is considered adequate to address the primary trial objective of 
exploring the safety of ZP4207 when used in the iLet and with reference to Lilly glucagon used 
in the iLet. 
12 
DATA MANAGEMENT AND RECORD KEEPING 
Data Management is the responsibility of Medpace. The complete Data Management process 
will be described in detail and agreed on in the Data Management Plan for this trial. 
12.1 
Data Handling 
Case Report Forms 
Electronic Case Report Forms will be used in this trial. The Data Management Department of 
Medpace will provide the eCRFs. All further information regarding the eCRFs and the data 
flow will be described and agreed on in the Data Management Plan. 
Device-Related Data 
During the trial, CGM data, calibration data, insulin dosing data, and glucagon dosing data will 
be automatically stored in the BP device (from which it will be downloaded at intervals), 
combined in a single database that will be compared against the primary data files for integrity, 
and ultimately transferred to Medpace.  
12.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
12.3 
Data Entry 
Data must be recorded using the electronic data capture (EDC) system as the trial is in 
progress. The patient questionnaires will be transcribed into the EDC system by site 
personnel. All site personnel must log into the system using their secure user name and 
password in order to enter, review, or correct trial data. These procedures must comply with 
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Title 21 of the Code of Federal Regulations (21 CFR Part 11) and other appropriate 
international regulations. All passwords will be strictly confidential. 
12.4 
Medical Information Coding 
Adverse events and medical history will be coded using the latest version of MedDRA. Prior 
and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. 
12.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, 
will be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
12.6 
Record Keeping 
Medpace will be responsible for hosting the TMF. Records of patients, source documents, 
monitoring visit logs, eCRFs, inventory of trial product, regulatory documents, and other 
Sponsor correspondence pertaining to the trial must be kept in the appropriate trial files at the 
site. Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
evaluation and reconstruction of the clinical trial. Source data are contained in source 
documents (original records or certified copies). These records will be retained in a secure file 
for the period as set forth in the Clinical Trial Agreement. Prior to transfer or destruction of 
these records, the Sponsor must be notified in writing and be given the opportunity to further 
store such records. 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
13.1 
Ethical Conduct of the Trial 
The trial will be conducted according to Medpace, MGH, and/or the Sponsor’s written 
instructions (SOPs, working instructions, or process descriptions). Content and definitions of 
the written instructions are based on the Declaration of Helsinki and the ICH GCP.  
13.2 
Institutional Review Board 
Written favorable opinion must be obtained from the responsible IRB prior to commencement 
of the trial. Clinical trial submission and reporting requirements before, during, and after 
completion of the trial will be performed in accordance with national law and local regulations. 
All amendments that affect patient safety or the trial integrity (substantial amendments) must 
not be implemented before favorable opinion has been obtained, unless necessary to 
eliminate hazards to the patients. Non-substantial amendments do not require favorable 
opinion by the IRB, but the respective IRB will be notified according to local requirements.  
The Sponsor and Investigator must approve any amendment in writing before its 
implementation. 
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The Sponsor must maintain an accurate and complete record of all submissions made to the 
IRB. The records should be filed in the Sponsor’s Trial Master File (TMF). 
13.3 
Informed Consent 
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirement(s) and adhere to the ICH GCP guideline and the 
requirements in the Declaration of Helsinki. 
Prior to any trial-related activity, the Investigator must give the patient oral and written 
information in a form that the patient can read and understand about all aspects of the trial 
that are relevant to the patient’s decision to participate. The patient will be given ample time 
to decide whether or not to participate in the trial. 
The patient must be informed that his/her personal trial-related data will be used in accordance 
with the local data protection law. The level of disclosure must also be explained to the patient. 
The patient must be informed that his/her medical records may be examined by authorized 
monitors or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
A voluntary, personally signed and dated ICF must be obtained from the patient prior to any 
trial-related activity. The ICF must also be signed and dated by the physician or designee who 
conducted the informed consent procedure. A signed copy of the ICF and any additional 
patient information must be given to each patient.  
The responsibility for taking informed consent must remain with that of a research physician 
or designee. If information becomes available that may be relevant to the patient’s willingness 
to continue participating in the trial, the Investigator must inform the patient in a timely manner, 
and a revised written informed consent must be obtained. 
Should a protocol amendment become necessary, the ICF may need to be revised to reflect 
the changes to the protocol. It is the responsibility of the Sponsor to ensure that an amended 
consent form is reviewed and has received favorable opinion from IRB, and the Investigator 
must ensure that the amended consent form is signed by all patients subsequently entered 
into the trial and those currently in the trial, if affected by the amendment. 
13.4 
Trial Monitoring Requirements 
The monitoring procedures for this trial are described in detail in the Monitoring Manual. The 
objectives of the monitoring procedures are to ensure that (i) the safety and rights of the trial 
patients are respected, (ii) that accurate, valid, and complete data are collected, and (iii) that 
the trial is conducted in accordance with the trial protocol, the principles of GCP, and local 
legislation, including drug accountability. 
The monitor must be given direct access to the investigational site files and source documents 
(original documents, data, and records). Direct access includes permission to examine, 
analyze, verify, and reproduce any record(s) and report(s) that are important to evaluation of 
the clinical trial. 
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Key tasks of the monitor include verifying the presence of informed consent, the adherence to 
the inclusion/exclusion criteria, the documentation of SAEs, and the recording of all safety and 
efficacy variables. The monitor will also confirm the completeness of patient records, the 
adherence to the protocol, ICH GCP, and the progress in patient enrollment and perform drug 
accountability.  
Because no information that could reveal the identity of patients may ever be removed from 
the trial site, the monitor will visit the site at regular intervals to perform these monitoring tasks. 
Other contact between the Investigator and monitors will be maintained as required through 
telephone calls and e-mail. The Investigator and/or key members of staff involved in the trial 
must be available to assist the monitors during all visits.  
Site Initiation Visit 
During the Site Initiation Visit (SIV) the CRO, Sponsor, and/or monitors will go through 
information on the IMP, the protocol, the eCRFs, and other key aspects of the trial with the 
Investigator and the key members of staff involved in the trial. The topics of the SIV are 
documented in a SIV report made available to the Investigator. Documentation on the SIV 
(e.g., power point presentation) should be filed by both Investigator and Sponsor. 
13.5 
Disclosure of Data 
Data generated by this trial must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal 
physician or other appropriate medical personnel responsible for their welfare. 
Patient medical information obtained during the trial is confidential and disclosure to third 
parties other than those noted above is prohibited. 
13.6 
Retention of Records 
Massachusetts General Hospital will maintain the patient’s medical file according to local 
regulations. MGH will archive the documentation pertaining to the trial in an archive after 
completion or discontinuation of the trial if not otherwise notified. MGH should not destroy any 
documents without prior permission from the Sponsor. 
The documentation includes all the raw data generated during the clinical trial, the 
investigational site files, and a copy of the clinical trial report. The documents will be retained 
for a period of at least 15 years at archives by MGH, or its sub-contractor. After this period, 
the Sponsor will be contacted and their advice sought on the return or further retention of the 
trial records. 
The Sponsor will maintain the documentation pertaining to the trial in accordance with national 
regulations. 
13.7 
Publication Policy  
The Principal Investigator of the trial will review and sign the clinical trial report. A summary of 
the final clinical trial report will be submitted to the IRB and Competent Authority. 
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According to the Declaration of Helsinki Investigators and Sponsors “have ethical obligations 
with regard to the publication and dissemination of the results of research.” The trial design 
and results may be published as one or more original research manuscripts/abstracts and 
presented at a scientific meeting. The Investigator and Sponsor reserve the right to review any 
proposed presentation of the results of this trial before they are submitted for publication. 
Authorship on any publication(s) resulting from this clinical trial will be assigned according to 
the recommendations of the International Committee of Medicinal Journal Editors. 
Participating patients will not be identified by name in any published reports about the clinical 
trial. 
The Sponsor is responsible for trial registration at ClinicalTrials.gov (www.clinicaltrials.gov) 
according to the requirements from the FDA. 
13.8 
Legal Aspects 
An implicit or explicit approval must be obtained from the Competent Authority prior to 
commencement of the trial. Clinical trial submission and reporting requirements before, during, 
and after completion of the trial will be performed in accordance with national law and local 
regulations. 
An implicit or explicit approval will also be mandatory before implementation of substantial 
changes. Non-substantial amendments do not require approval from the Competent Authority 
but will be notified according to local requirements. 
The Sponsor and Investigator must approve the amendment in writing before its 
implementation. 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
Competent Authority. The records should be filed in the Sponsor’s TMF. 
Audits and Inspections  
In the event of an audit, representatives of the Sponsor or designee, or national and 
international regulatory authorities may request access to all trial records for inspection and 
copying. Such access must be stated in the ICF signed by the patient. 
13.9 
Sponsor Discontinuation Criteria 
The Sponsor, Investigator, or a pertinent regulatory authority may decide to stop the trial or 
part of the trial at any time but agreement on procedures to be followed must be obtained. 
Conditions that may warrant termination of the clinical trial include, but are not limited to: 

Safety or administrative reasons

The discovery of an unexpected, relevant, or unacceptable risk to the patients enrolled
in the clinical trial

A decision of the Sponsor to suspend or discontinue investigation of the IMP
If the trial is prematurely terminated or suspended, the Investigator should promptly inform the 
patients and assure appropriate therapy and follow-up. Furthermore, the Sponsor should 
promptly inform the IRB and provide a detailed written explanation. The pertinent regulatory 
authorities should be informed according to national regulations. 
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If after the termination of the trial the risk/benefit analysis has changed, the new evaluation 
should be provided to the IRB in case it will have an impact on the planned follow-up of the 
patients who have participated in the trial. Necessary actions needed to protect the patients 
should be described. 
13.10 
Patient Compensation 
Financial compensation will be provided to all patients who complete the Screening Visit. 
Patients will be paid $25 for completing the Screening Visit whether or not they are eligible to 
participate in the trial. Patients will be compensated $25 for completing the Training Visit. 
Patients will be compensated $100 for completing each of the 2 treatment visits, $25 for 
completing the phone call, and $25 for completing the Follow-up Visit. Thus, the total 
compensation for a patient who completes the trial would be $300. Patients who are unable 
to complete the trial or choose to stop participation will receive prorated compensation for 
each visit. In addition to the monetary compensation, the cost of the patients’ lunch meals 
during their participation in the trial, as well as the patients’ parking at each visit, will be covered 
by trial funds.  
14 
TRIAL ADMINISTRATIVE INFORMATION 
14.1 
Protocol Amendments 
Any amendments to the trial protocol will be communicated to the Investigators by Medpace 
or the Sponsor. All protocol amendments will undergo the same review and approval process 
as the original protocol. A protocol amendment may be implemented after it has been 
approved by the IRB, unless immediate implementation of the change is necessary for patient 
safety. In this case, the situation must be documented and reported to the IRB within 5 working 
days. 
14.2 
Address List 
14.2.1 
Sponsor 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Telephone: +45 88 77 36 00 
Facsimile: +45 88 77 38 98 
14.2.2 
Supplier of Device 
, PhD 
Beta Bionics, Inc. 
Business Innovation Center, Photonics Center 
8 Saint Mary’s Street, Suite 936 
Boston, Massachusetts 02215-2421 
United States 
Tel: 
 
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15 
REFERENCES 
1.
Russell SJ, El-Khatib FH, Sinha M, et al. Outpatient glycemic control with a bionic
pancreas in type 1 diabetes. N Engl J Med. 2014;371(4):313-325.
2.
Russell SJ, Hillard MA, Balliro C, et al. Day and night glycemic control with a bionic
pancreas versus conventional insulin pump therapy in preadolescent children with type
1 
diabetes: 
a 
randomized 
crossover 
trial. 
Lancet 
Diabetes 
Endocrinol.
2016;4(3):233-243.
3.
Summary of Product Characteristics. GlucaGen Hypokit 1 mg. Bagsværd, Denmark;
Novo Nordisk:2015.
4.
Glucagon 
Results. 
http://lillytrials.com/results/glucagon.pdf. 
Eli 
Lilly 
and 
Company:2005.
5.
Garcia A, Rack-Gomer AL, Bhavaraju NC, et al. Dexcom G4AP: an advanced
continuous glucose monitor for the artificial pancreas. J Diabetes Sci Technol.
2013;7(6):1436-1445.
6.
Zealand Pharma A/S. Investigator’s Brochure for ZP4207. Edition No. 2, 14 December
2015. 
7.
Summary of Product Characteristics. Glucagon for Injection. Indianapolis, IN, USA; Eli
Lilly and Company:2012.
8.
Summary of Product Characteristics. Humalog (insulin lispro injection). Indianapolis,
IN, USA; Eli Lilly and Company:2015.
9.
ICH Harmonised Tripartite Guideline. Statistical Principles for Clinical Trials E9. 
http://www.ich.org/fileadmin/Public Web Site/ICH Products/Guidelines/Efficacy/E9/
Step4/E9 Guideline.pdf. 5 February 1998.
10.
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R1). 
http://www.ich.org/fileadmin/Public Web Site/ICH Products/Guidelines/Efficacy/E6/
E6 R1 Guideline.pdf. 10 June 1996.
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APPENDIX A: SCHEDULE OF PROCEDURES 
Trial Visit 
Visit 1 [1] 
Screening 
Visit 2 
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5] 
(2nd Treatment 
Visit) 
Visit 5 
Phone Call [6] 
Visit 6 
Follow-Up [7] 
Informed consent 
X 
Assess/confirm eligibility 
X 
X 
Demographics 
X 
Medical, surgical, and social history; 
allergies  
X 
Concomitant illness 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Height, weight, physical examination, and 
vital signs including body temperature 
and blood pressure [8] 
X 
X [9] 
X [9] 
12-lead ECG 
X 
X [10] 
X [10] 
Urine HCG pregnancy test and menstrual 
history [11]   
X 
X 
X 
FSH [12] 
X 
Screening labs – HbA1c, optional 
fractionated metanephrines [13] 
X 
Safety lab sampling including chemistry 
and hematology 
X 
X [10] 
X [10] 
X 
Training on devices [14] 
X 
Monitored BP use 
X 
X 
Plasma glucose sampling [15] 
X 
X 
ZP4207/glucagon exposure sampling [16] 
X 
X 
Nausea and infusion site pain VAS and 
infusion site reaction Draize scale (visit 
start [17], hourly, & visit end) 
X 
X 
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Trial Visit 
Visit 1 [1] 
Screening 
Visit 2 
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5] 
(2nd Treatment 
Visit) 
Visit 5 
Phone Call [6] 
Visit 6 
Follow-Up [7] 
Standardized lunch [18] 
X 
X 
In-clinic exercise [19] 
X 
X 
Questionnaires (pre & post BP) 
X 
X 
ADA 
X [20] 
X 
Adverse event review 
X 
X 
X 
X 
1.
Once the patient has been enrolled and eligibility has been established, the order of the iLet visits will be randomized in blocks of 2 patients.
2.
Each patient will participate in 2 treatment visits: one with the iLet using ZP4207 and one with the iLet using Lilly glucagon in a randomized order. Up to 2 patients may participate in the 
trial per day.
3.
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal skin and calibrate the sensor when prompted using the provided Nova StatStrip Xpress meter.
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the BP having fasted since 12 00 AM the night before (treatment with simple carbohydrate of up to 30 g
for a low is allowed). If the patient is not fasted, the visit will be rescheduled within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the visit window. If BG is
<50 mg/dL, treatment with simple carbohydrate is allowed. If the patient experiences persistent hypoglycemia, the visit will be rescheduled within the visit window.
4.
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 30 days after screening (Visit 1).
5.
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum of 3 weeks between Visit 3 and Visit 4.
6.
Visit 5 will take place 7 days ±3 days from Visit 4.
7.
Visit 6 will take place 25 days ±4 days from Visit 4.
8.
Height and physical examination will be measured at Visit 1 only.
9.
Vital signs including body temperature and blood pressure will be obtained at visit start and visit end.
10.
At visit start and visit end.
11.
Urine HCG pregnancy test only for women of childbearing potential. The date of the last menstrual period in female patients will be obtained at Visit 1 only.
12.
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year.
13.
If indicated by history.
14.
Patients will be trained in the insertion and calibration of the Dexcom G4 sensor, diabetes management (e.g., basal insulin rate adjustment by insulin pump) during fasting prior to and
between the treatment visits, and trial policies and procedures.
15.
Collected at least hourly. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will
be every 10 minutes.
16.
Collected at least hourly. If BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the Investigator.
17.
Once the infusion sites have been placed but no drug has yet been administered.
18.
Between approximately Hour 3 and Hour 4.
19.
Between approximately Hour 6 and Hour 7.
20.
Before the start of dosing.
ADA = anti-drug antibodies; BG = blood glucose; BP = bionic pancreas; CGM = continuous glucose monitor; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
HbA1c = hemoglobin A1c; HCG = human chorionic gonadotropin; VAS = visual analog scale. 
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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Chemistry 
Alanine aminotransferase 
Aspartate aminotransferase 
Alkaline phosphatase 
Total protein 
Albumin 
Total and direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Creatinine 
Estimated glomerular filtration rate 
Blood urea nitrogen 
Uric acid 
Bicarbonate 
Sodium 
Potassium 
Calcium 
Chloride 
Phosphorus 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell count 
White blood cell count and differential 
Platelets 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Pregnancy Test 
A urine HCG pregnancy test will be performed at screening, Visit 3, and Visit 4 only for 
women of childbearing potential. 
Anti-drug Antibody Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken prior to first dosing (Visit 3) and at the Follow-up Visit (Visit 6). 
ZP4207/Glucagon Exposure Sampling 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at 
the discretion of the Investigator. 
Screening Visit Only 
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year 
Optional fractionated plasma metanephrines (if indicated by history) 
Hemoglobin A1c 
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APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES 
Diabetes Treatment Satisfaction Questionnaire - Status (DTSQs) 
The DTSQs measures patient satisfaction with diabetes treatment. It consists of a 6 item scale 
for assessing treatment satisfaction and two additional items assessing perceived frequency 
of hyperglycemia and hypoglycemia. The DTSQs is meant for adults and older children. 
Dr. Clare Bradley has produced a version that is appropriate for bionic pancreas studies for 
this use, along with a version for younger children. It is administered before the intervention. 
The DTSQs is valid and reliable. Administration time is less than 5 minutes. 
Diabetes Treatment Satisfaction Questionnaire – Change (DTSQc) 
Although the DTSQ is responsive to treatment changes, ceiling effects are often seen with this 
instrument, where maximum or close-to-maximum scores at baseline provide little opportunity 
for registering improvement. The DTSQc contains the same items as the DTSQs version but 
asks patients to consider their satisfaction with their current treatment compared with their 
previous treatment. The DTSQc is meant for adults and older children. Dr. Clare Bradley has 
produced a version that is appropriate for bionic pancreas studies for our use, along with a 
version for younger children. It is administered during and at the end of the intervention. The 
DTSQc is valid and reliable. Administration time is less than 5 minutes. 
T1-Diabetes Distress Scale (T1-DDS) 
The T1-DDS is a 28-item survey that assesses seven sources of diabetes distress for type 1 
adults. It captures feelings of powerlessness; management distress; hypoglycemia distress; 
negative social perceptions by others; eating distress; physician (health care) distress; and 
friend/family distress. Items are scored on a 6-point scale from not a problem to a very serious 
problem. It is administered before, during, and at the end of the intervention. The scale is valid 
and reliable, and has been shown to be sensitive to change over time. Administration time is 
5 minutes. 
Problem Areas in Diabetes Survey (PAID) 
There are three versions of the PAID: Teen (PAID-T), Parent (PAID-P), and Child (PAID-C) 
versions. This measure of diabetes-specific emotional distress in youth with diabetes and their 
parents is 26 items. A total score is generated. It is administered before, during, and at the 
end of the intervention. The PAID-T and PAID-P are valid and reliable. Psychometric analysis 
of the PAID-C is in progress. Administration time is 5 minutes. 
Hypoglycemia Fear Survey (HFS) 
There are three versions of the HFS, Adult (HFS), Youth (HFS-Y) and Parent (HFS-P). The 
HFS measures several dimensions of fear of hypoglycemia among adults with type 1 diabetes. 
It consists of 23 items and produces two sub-scale scores; a Behavior sub-scale that 
measures behaviors involved in avoidance and/or over-treatment of hypoglycemia and a 
Worry sub-scale that measures anxiety and fear surrounding hypoglycemia. The HFS-Y 
consists of 25 items and the HFS-P consists of 26 items; both produce sub-scale scores 
similar to the Adult HFS. It is administered before, during, and at the end of the intervention. 
All versions of the HFS are valid and reliable. Administration time is 5-10 minutes. 
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Impact of Daily Diabetes Demands (IDDD) 
There are four versions of the IDDD; Adult (IDDD-A), Youth (IDDD-Y), Parent (IDDD-P), and 
Significant Other (IDDD-SO). This instrument measures the burden related to the demands of 
the daily diabetes regimen and is 22 items. A total score is generated. It is administered before, 
during, and at the end of the intervention. Psychometric analysis of the IDDD-Y is in progress 
using the data from the second Bionic Pancreas Camp Study in pre-adolescent children, and 
of the IDDD-A is in progress using data from the Bionic Pancreas Multicenter Study in adults. 
Administration time is 5 minutes. 
Bionic Pancreas User Opinion Survey (BPUOS) 
There are four versions of the BPUOS; Adult (BPUOS-A), Youth (BPUOS-Y), Parent 
(BPUOS-P), and Significant Other (BPUOS-SO). This measure assessing both the benefits 
from, and difficulties with, use of the bionic pancreas, and consists of 38 items. A total score 
is generated. It is administered during and at the end of the intervention. Psychometric 
analysis of the BPUOS-Y is in progress using the data from the second Bionic Pancreas Camp 
Study in pre-adolescent children, and of the BPUOS -A is in progress using data from the 
Bionic Pancreas Multicenter Study in adults. Administration time is 10 minutes. 
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SUMMARY OF CHANGES DOCUMENT 
PROTOCOL NUMBER ZP4207-16051 
AMENDMENT NUMBER 1.0 
PROTOCOL TITLE: The iLet Feasibility Trial Testing the iLet, a Fully Integrated Bihormonal 
Bionic Pancreas with ZP4207 
AMENDMENT DATE: 28 June 2016 
SUMMARY AND JUSTIFICATION OF CHANGES: 
This amendment was developed to include additional safety language and measures and to 
improve clarity and consistency within the study protocol. The main additions include the 
maximum blood volume drawn per study visit and for the entire study; blood glucose (BG) checks 
every 30 minutes if blood glucose is <150 mg/dL; the discontinuation of patients from the trial who 
experience diabetic ketoacidosis; and blood ketones measurement if the BG remains >300 mg/dL 
for 2 hours despite troubleshooting. If the blood ketone result is >1.5 mmol/L, the visit will be 
stopped and rescheduled. The patient will be provided with insulin and a syringe to give an 
injection based on their correction factor. Blood pressure will be measured at screening as well 
as Visit 3 and Visit 4. The timing around visit windows was updated, and other minor edits were 
made throughout the protocol to provide greatly clarity and consistency. The schedule of 
procedures was updated to reflect the changes specified in this document. 
SUMMARY OF CHANGES: 
The amended protocol sections and the details of the changes are summarized in the following 
sections. Revisions to the protocol are presented as strikethrough (ie, subject) for text that was 
removed and bold (ie, subject) for text that was added. 
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Synopsis, Population, Page 4 
Original Text: 
Up to 20 adult (≥18 years of age) patients who already manage their T1DM using continuous 
subcutaneous (SC) insulin infusion pump therapy can be enrolled. 
New Text: 
Up to 20 adult (≥18 years of age) patients who already manage their T1DM using continuous 
subcutaneous (SC) insulin infusion pump therapy can be enrolled. It is expected that up to 
10 patients will complete the trial protocol. 
Section 3.3, Number of Patients, Page 22 
Original Text: 
Up to 20 adult patients with T1DM can be enrolled. The upper bound is based on the 
expectation that some patients will be excluded after the Screening Visit and the possibility that 
some patients may have to be discontinued before completion (due to, for instance, 
inter-current illness or patient withdrawal). Eligible patients will be randomized until 10 patients 
have completed the trial protocol. It is expected that between 10 and 12 patients will be 
randomized. 
New Text: 
Up to 20 adult patients with T1DM can be enrolled. The upper bound is based on the 
expectation that some patients will be excluded after the Screening Visit and the possibility that 
some patients may have to be discontinued before completion (due to, for instance, 
inter-current illness or patient withdrawal). Eligible patients will be randomized until It is 
expected that up to 10 patients have completed will complete the trial protocol. It is expected 
that between 10 and 12 patients will be randomized. 
Section 4.4, Withdrawal Criteria, Page 25; Section 10.6.1, Data and Safety Monitoring 
Board, Page 43 
Original Text: 
The participation of individual patients will be discontinued if they experience: 

Seizure or unconsciousness associated with hypoglycemia and associated with
participation in the trial 

Persistent nausea and vomiting thought to be related to glucagon dosing associated
with participation in the trial 

Hospitalization associated with participation in the trial

Pregnancy
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New Text: 
The participation of individual patients will be discontinued if they experience: 

Seizure or unconsciousness associated with hypoglycemia and associated with
participation in the trial 

Persistent nausea and vomiting thought to be related to glucagon dosing associated
with participation in the trial 

Hospitalization associated with participation in the trial

Pregnancy

Diabetic ketoacidosis
Section 7.2, Screening Visit (Visit 1), Page 29 
Original Text: 
7.2 
Screening Visit (Visit 1, up to 30 days prior to Visit 2) 
New Text: 
7.2 
Screening Visit (Visit 1, up to 30 days prior to Visit 2) 
Section 7.3, Training Visit (Visit 2), Page 30 
Original Text: 
7.3 
Training Visit (Visit 2) (Day 1) 
New Text: 
7.3 
Training Visit (Visit 2) (Day 1) 
Section 7.4, Treatment Visits (Visit 3 and Visit 4), Page 30  
Original Text: 
7.4 
Treatment Visits (Visit 3 [Day 8 ±3] and Visit 4 [Day 15 ±3]) 

Up to 2 patients may participate per day.

Each patient will participate in 2 treatment visits: one with the iLet using ZP4207 and
one with the iLet using Lilly glucagon in a randomized order.
New Text: 
7.4 
Treatment Visits (Visit 3 [Day 8 ±3] and Visit 4 [Day 15 ±3]) 

Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than
30 days after screening (Visit 1).

There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a
maximum of 3 weeks between Visit 3 and Visit 4.

Up to 2 patients may participate per day.

Each patient will participate in 2 treatment visits: one with the iLet using ZP4207 and
one with the iLet using Lilly glucagon in a randomized order.
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Section 7.4.1, Visit Procedures, Page 31 
Original Text: 

Upon arrival to the visit, the patient’s weight and vital signs including body temperature
will be documented.

Patient reports of symptoms, any other complaints, and AEs will be reviewed.
New Text: 

Upon arrival to the visit, the patient’s weight and vital signs including body temperature
and blood pressure will be documented.

Patient reports of symptoms, any other complaints, and AEs will be reviewed.
Section 7.4.1, Visit Procedures, Page 32 
Original Text: 

Blood samples will be taken from the IV at least hourly and processed for plasma
ZP4207/glucagon. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG
is <80 mg/dL, then sampling will be every 10 minutes. The actual time of sampling will
be recorded in the eCRF.

Plasma glucose samples will be taken from the IV at least hourly in parallel with
ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT Plus. If
the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for
glucose measurements. If BG is <100 mg/dL, then sampling will be every 20 minutes.
If BG is <80 mg/dL, then sampling will be every 10 minutes. The actual time of sampling
will be recorded in the eCRF.
New Text: 

Blood samples will be taken from the IV at least hourly and processed for plasma
ZP4207/glucagon. If BG is <100150 mg/dL, then sampling will more frequent samples
for plasma ZP4207/glucagon may be every 20 minutes. If BG is <80 mg/dL, then
sampling will be every 10 minutes drawn at the discretion of the Investigator. The
actual time of sampling will be recorded in the eCRF.

Plasma glucose samples will be taken from the IV at least hourly in parallel with
ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT Plus. If
the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for
glucose measurements. If BG is <150 mg/dL, then sampling will be every
30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is
<80 mg/dL, then sampling will be every 10 minutes. The actual time of sampling will be
recorded in the eCRF.
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Section 7.4.1, Visit Procedures, Page 33 
Original Text: 

Patients may choose to withdraw from the trial at any time. If they withdraw from the
trial, they should alert a provider immediately.

Just prior to the end of the study visit, vital signs including body temperature will be
obtained and a 12-lead ECG will be performed.

After approximately Hour 8, but not earlier than at least 60 minutes after end of exercise,
the BP will be stopped and the patient will continue with their personal insulin pump.

Patients will answer questionnaires (see Appendix C).
New Text: 

Patients may choose to withdraw from the trial at any time. If they withdraw from the
trial, they should alert a provider immediately.

Just prior to the end of the study visit, vital signs including body temperature and blood
pressure will be obtained and a 12-lead ECG will be performed.

After approximately Hour 8, but not earlier than at least 60 minutes after end of exercise,
the BP will be stopped and the patient will continue with their personal insulin pump.

The maximum amount of blood loss per study visit will be approximately 230 mL.
The total blood loss for the entire study will be up to 460 mL.

Patients will answer questionnaires (see Appendix C).
Section 7.4.2, Data Collected During the Treatment Visits, Page 33-34 
Original Text: 

ZP4207/glucagon sampling collected at least hourly. If BG is <100 mg/dL, then sampling
will be every 20 minutes. If BG is <80 mg/dL, then sampling will be every 10 minutes.

Plasma glucose sampling will be collected at least hourly in parallel with
ZP4207/glucagon exposure sampling. If BG is <100 mg/dL, then sampling will be every
20 minutes. If BG is <80 mg/dL, then sampling will be every 10 minutes.
New Text: 

ZP4207/glucagon sampling will be collected at least hourly. If BG is <100150 mg/dL,
then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will more
frequent samples for plasma ZP4207/glucagon may be every 10 minutes drawn at
the discretion of the Investigator.

Plasma glucose sampling will be collected at least hourly in parallel with
ZP4207/glucagon exposure sampling. If BG is <150 mg/dL, then sampling will be
every 30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG
is <80 mg/dL, then sampling will be every 10 minutes.
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Section 7.4.2, Data Collected During the Treatment Visits, Page 34 
Original Text: 

Patient reports of symptoms, any other complaints, and AEs

Vital signs including body temperature (at visit start and visit end) and weight
New Text: 

Patient reports of symptoms, any other complaints, and AEs

Vital signs including body temperature and blood pressure (at visit start and visit end)
and weight
Section 7.4.4, Response to Hyperglycemia, Page 34-35 
Original Text: 

Trial staff will check the infusion site, BP, and insulin pump for normal operation any
time BG is >300 mg/dL. If there is any suspicion of infusion set malfunction, the site
should be replaced. Trial staff will check the BP for any malfunction and correct any
problems that are found.

If no correctable fault is found, but there is doubt regarding the correct function of the
BP system, the treatment visit may be stopped and the visit rescheduled.
New Text: 

Trial staff will check the infusion site, BP, and insulin pump for normal operation any
time BG is >300 mg/dL. If there is any suspicion of infusion set malfunction, the site
should be replaced. Trial staff will check the BP for any malfunction and correct any
problems that are found. If the BG remains >300 mg/dL for 2 hours despite
troubleshooting, blood ketones will be measured. If the blood ketone result is
>1.5 mmol/L, the visit will be stopped and rescheduled. The patient will be
provided with insulin and a syringe to give an injection based on their correction
factor.

If a patient experiences diabetic ketoacidosis, his or her participation in the trial
will be discontinued.

If no correctable fault is found, but there is doubt regarding the correct function of the
BP system, the treatment visit may be stopped and the visit rescheduled.
Section 7.5, Phone Call (Visit 5), Page 35 
Original Text: 
7.5 
Phone Call (Visit 5) (Day 22 ±3) 
A phone call will be conducted 1 week following the last day of dosing (Visit 4) to review AEs 
and concomitant medications. 
New Text: 
7.5 
Phone Call (Visit 5) (Day 22 ±3) 
A phone call will be conducted 1 week 7 days ±3 days following the last day of dosing (Visit 4) 
to review AEs and concomitant medications. 
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Section 7.6, Follow-up Visit (Visit 6), Page 35 
Original Text: 
7.6 
Follow-up Visit (Visit 6) (Day 40 ±3) 
Three to 4 weeks following the last day of dosing (Visit 4), patients will return for a Follow-up 
Visit for chemistry, hematology, and ADA sampling, and a review of AEs and concomitant 
medications.  
New Text: 
7.6 
Follow-up Visit (Visit 6) (Day 40 ±3) 
Three to Patients will return for a Follow-up Visit 25 days ±4 weeks days following the last 
day of dosing (Visit 4), patients will return for a Follow up Visit 4), for chemistry, hematology, 
and ADA sampling, and a review of AEs and concomitant medications.  
Section 9.2, Pharmacodynamic Assessments (Plasma Glucose), Page 37 
Original Text: 
At Visit 3 and Visit 4, plasma glucose samples will be taken from the IV at least hourly in parallel 
with ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT Plus. If the 
YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for glucose 
measurements. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is 
<80 mg/dL, then sampling will be every 10 minutes. The actual time of sampling will be recorded 
in the eCRF. 
New Text: 
At Visit 3 and Visit 4, plasma glucose samples will be taken from the IV at least hourly in parallel 
with ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT Plus. If the 
YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for glucose 
measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is 
<100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will be 
every 10 minutes. The actual time of sampling will be recorded in the eCRF. 
Section 9.3, Exposure Assessments (ZP4207 and Glucagon), Page 37; Appendix B, 
Clinical Laboratory Analytes, Page 57 
Original Text: 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling 
will be every 10 minutes.  
New Text: 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <100 150 mg/dL, then sampling will more frequent samples for plasma 
ZP4207/glucagon may be every 20 minutes. If BG is <80 mg/dL, then sampling will be every 
10 minutes drawn at the discretion of the Investigator. 
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Appendix A, Schedule of Procedures, Page 55-56 
Original Text: 
APPENDIX A: SCHEDULE OF PROCEDURES 
Trial Visit 
Visit 1 [1] 
Screening 
Visit 2 
Training 
Visit 3 [2] [3] 
Treatment 
Visit 4 [2] [3] 
Treatment 
Visit 5 
Phone Call 
Visit 6 
Follow-Up 
Trial Day 
Up to 30 days 
prior to Visit 2 
Day 1 
Day 8 
(±3 days) 
Day 15 
(±3 days) 
Day 22 
(±3 days) 
Day 40 
(±3 days) 
Informed consent 
X 
Assess/confirm eligibility 
X 
X 
Demographics 
X 
Medical, surgical, and social history; 
allergies  
X 
Concomitant illness 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Height, weight, physical examination, 
and vital signs including body 
temperature and blood pressure [4] 
X 
X [5] 
X [5] 
12-lead ECG 
X 
X [6] 
X [6] 
Urine HCG pregnancy test and 
menstrual history [7]   
X 
X 
X 
FSH [8] 
X 
Screening labs – HbA1c, optional 
fractionated metanephrines [9] 
X 
Safety lab sampling including 
chemistry and hematology 
X 
X [6] 
X [6] 
X 
Training on devices [10] 
X 
Monitored BP use 
X 
X 
Plasma glucose sampling [11] 
X 
X 
ZP4207/glucagon exposure sampling 
[12] 
X 
X 
Nausea and infusion site pain VAS 
and infusion site reaction Draize scale 
(visit start [11], hourly, & visit end) 
X 
X 
Standardized lunch [13] 
X 
X 
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Trial Visit 
Visit 1 [1] 
Screening 
Visit 2 
Training 
Visit 3 [2] [3] 
Treatment 
Visit 4 [2] [3] 
Treatment 
Visit 5 
Phone Call 
Visit 6 
Follow-Up 
Trial Day 
Up to 30 days 
prior to Visit 2 
Day 1 
Day 8 
(±3 days) 
Day 15 
(±3 days) 
Day 22 
(±3 days) 
Day 40 
(±3 days) 
In-clinic exercise [14] 
X 
X 
Questionnaires (pre & post BP) 
X 
X 
ADA 
X [15] 
X 
Adverse event review 
X 
X 
X 
X 
1.
Once the patient has been enrolled and eligibility has been established, the order of the iLet visits will be randomized in blocks of 2 patients.
2.
Each patient will participate in 2 treatment visits: one with the iLet using ZP4207 and one with the iLet using Lilly glucagon in a randomized order. Up to 2 patients can
par icipate in the trial per day.
3.
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal skin and calibrate the sensor when prompted using the provided Nova StatStrip
Xpress meter. Pa ients will arrive at the visit at least 1 hour in advance of the start of the BP having fasted since 12:00 AM the night before (treatment with simple
carbohydrate of up to 30 g for a low is allowed). If the patient is not fasted, he visit will be rescheduled within the visit window. If BG is >250 mg/dL, the visit will be
rescheduled within the visit window.
4.
Height, blood pressure, and physical examination will be measured at Visit 1 only.
5.
Vital signs including body temperature will be obtained at visit start and visit end.
6.
At visit start and visit end.
7.
Urine HCG pregnancy test only for women of childbearing poten ial. The date of the last menstrual period in female patients will be obtained at Visit 1 only.
8.
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year.
9.
If indicated by history.
10.
Patients will be trained in the insertion and calibration of the Dexcom G4 sensor and trial policies and procedures.
11.
Collected at least hourly. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will be every 10 minutes.
12.
Once the infusion sites have been placed but no drug has yet been administered.
13.
Between approximately Hour 3 and Hour 4.
14.
Between approximately Hour 6 and Hour 7.
15.
Before the start of dosing.
ADA = anti-drug antibodies; BG = blood glucose; BP = bionic pancreas; CGM = continuous glucose monitor; ECG = electrocardiogram; FSH = follicle-stimula ing hormone; 
HbA1c = hemoglobin A1c; HCG = human chorionic gonadotropin; VAS = visual analog scale. 
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New Text: 
APPENDIX A: SCHEDULE OF PROCEDURES 
Trial Visit 
Visit 1 [1] 
Screening 
Visit 2 
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5] 
(2nd Treatment 
Visit) 
Visit 5 
Phone Call 
[6] 
Visit 6 
Follow-Up [7] 
Trial Day 
Up to 30 days 
prior to Visit 2 
Day 1 
Day 8 
(±3 days) 
Day 15 
(±3 days) 
Day 22 
(±3 days) 
Day 40 
(±3 days) 
Informed consent 
X 
Assess/confirm eligibility 
X 
X 
Demographics 
X 
Medical, surgical, and social history; 
allergies  
X 
Concomitant illness 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Height, weight, physical examination, 
and vital signs including body 
temperature and blood pressure [48] 
X 
X [59] 
X [59] 
12-lead ECG 
X 
X [610] 
X [610] 
Urine HCG pregnancy test and 
menstrual history [711]   
X 
X 
X 
FSH [812] 
X 
Screening labs – HbA1c, optional 
fractionated metanephrines [913] 
X 
Safety lab sampling including 
chemistry and hematology 
X 
X [610] 
X [610] 
X 
Training on devices [1014] 
X 
Monitored BP use 
X 
X 
Plasma glucose sampling [1115] 
X 
X 
ZP4207/glucagon exposure sampling 
[1216] 
X 
X 
Nausea and infusion site pain VAS 
and infusion site reaction Draize scale 
(visit start [1117], hourly, & visit end) 
X 
X 
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Trial Visit 
Visit 1 [1] 
Screening 
Visit 2 
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5] 
(2nd Treatment 
Visit) 
Visit 5 
Phone Call 
[6] 
Visit 6 
Follow-Up [7] 
Trial Day 
Up to 30 days 
prior to Visit 2 
Day 1 
Day 8 
(±3 days) 
Day 15 
(±3 days) 
Day 22 
(±3 days) 
Day 40 
(±3 days) 
Standardized lunch [1318] 
X 
X 
In-clinic exercise [1419] 
X 
X 
Questionnaires (pre & post BP) 
X 
X 
ADA 
X [1520] 
X 
Adverse event review 
X 
X 
X 
X 
1.
Once the patient has been enrolled and eligibility has been established, the order of the iLet visits will be randomized in blocks of 2 patients.
2.
Each patient will participate in 2 treatment visits: one with the iLet using ZP4207 and one with the iLet using Lilly glucagon in a randomized order. Up to 2 patients can may 
participate in the trial per day.
3.
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal skin and calibrate the sensor when prompted using the provided Nova StatStrip
Xpress meter. Pa ients will be asked to arrive at the visit at least 1 hour in advance of the start of the BP having fasted since 12:00 AM the night before (treatment with simple
carbohydrate of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled within the visit window. If BG is >250 mg/dL, the visit will be
rescheduled within the visit window.
4.
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 30 days after screening (Visit 1).
5.
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum of 3 weeks between Visit 3 and Visit 4.
6.
Visit 5 will take place 7 days ±3 days from Visit 4.
7.
Visit 6 will take place 25 days ±4 days from Visit 4.
48.
Height, blood pressure, and physical examination will be measured at Visit 1 only.
59.
Vital signs including body temperature and blood pressure will be obtained at visit start and visit end.
610. At visit start and visit end. 
711. Urine HCG pregnancy test only for women of childbearing poten ial. The date of the last menstrual period in female patients will be obtained at Visit 1 only. 
812. Test for FSH level only for postmenopausal women amenorrheic for less than 1 year. 
913. If indicated by history. 
1014. Patients will be trained in the insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. 
1115. Collected at least hourly. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, 
then sampling will be every 10 minutes. 
16.
Collected at least hourly. If BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the Investigator.
1217. Once the infusion sites have been placed but no drug has yet been administered. 
1318. Between approximately Hour 3 and Hour 4. 
1419. Between approximately Hour 6 and Hour 7. 
1520. Before the start of dosing. 
ADA = anti-drug antibodies; BG = blood glucose; BP = bionic pancreas; CGM = continuous glucose monitor; ECG = electrocardiogram; FSH = follicle-stimula ing hormone; 
HbA1c = hemoglobin A1c; HCG = human chorionic gonadotropin; VAS = visual analog scale. 
Zealand Pharma A/S 
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Clinical Trial Protocol 
ZP4207-16051 
Version number: 2.0 
Amendment 1.0 
Date: 28 June 2016 
Zealand Pharma A/S 
Confidential 
Page 1 of 59 
CLINICAL TRIAL PROTOCOL 
The iLet Feasibility Trial Testing the iLet, a Fully Integrated Bihormonal Bionic 
Pancreas with ZP4207 
Investigational Product: ZP4207 
Protocol Number: ZP4207-16051 
IND Number: 129980 
Phase: 2  
Principal Investigator: 
Steven J. Russell, MD, PhD1 
Co-Investigator: 
, MD1 
1Diabetes Research Center, Massachusetts General Hospital, Boston, Massachusetts 
Sponsor: 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Tel: +45 88 77 36 00 
Fax: +45 88 77 38 98 
Original Version: 03 May 2016 
Amendment Number: 1.0 
Protocol Version Number: 2.0 
Date: 28 June 2016 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Zealand Pharma A/S except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical trial for Zealand Pharma A/S. 
You are allowed to disclose the contents of this document only to your Institutional Review 
Board (IRB) and trial personnel directly involved with conducting this protocol. Persons to 
whom the information is disclosed must be informed that the information is confidential and 
proprietary to Zealand Pharma A/S and that it may not be further disclosed to third parties. 
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Clinical Trial Protocol 
ZP4207-16051 
 
 
Version number: 2.0 
Amendment 1.0 
Date: 28 June 2016 
 
Zealand Pharma A/S 
Confidential 
Page 4 of 59 
SYNOPSIS 
TITLE: The iLet Feasibility Trial Testing the iLet, a Fully Integrated Bihormonal Bionic 
Pancreas with ZP4207 
 
PROTOCOL NUMBER: ZP4207-16051 
 
INVESTIGATIONAL PRODUCT: ZP4207 
 
PHASE: 2 
 
INDICATION: ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid 
formulation which is being studied to improve glycemic control in adults (and children) with 
type 1 diabetes mellitus (T1DM) as part of a bihormonal bionic pancreas (BP). 
 
OBJECTIVES: 
 
Primary: The primary objective is to conduct a trial testing the safety and tolerability of the 
iLet when used with ZP4207 in 10 adult (≥18 years of age) patients with T1DM. 
 
Secondary: The secondary objectives are to measure glycemic regulation, including 
hypoglycemia exposure (percent of time spent with continuous glucose monitor [CGM] 
glucose <60 mg/dL), evaluate BP device reliability, and to document the satisfaction of 
patients with the iLet with the goal of optimizing the functionality and user interface of the iLet. 
 
POPULATION: Up to 20 adult (≥18 years of age) patients who already manage their T1DM 
using continuous subcutaneous (SC) insulin infusion pump therapy can be enrolled. It is 
expected that up to 10 patients will complete the trial protocol. 
 
TRIAL DESIGN: This trial is a single-center, open-label, randomized cross-over trial. The trial 
will enroll adult patients with T1DM and will assess the safety and efficacy of the iLet using 
the glucagon analog ZP4207 versus the iLet using Lilly glucagon. The iLet will also administer 
insulin (insulin lispro, Lilly Humalog) using the same blood glucose (BG) control algorithm for 
both treatment arms. The trial will be conducted at a single center, the Massachusetts General 
Hospital Diabetes Center in Boston, MA. 
 
TRIAL TREATMENT: The trial involves SC administration of insulin lispro (Humalog, Lilly), 
which is commercially available by prescription and is indicated for patients with T1DM, but 
not for use in a BP. 
 
The trial also involves SC administration of Lilly glucagon in one iLet arm. Lilly glucagon is 
commercially available by prescription and is indicated for patients with T1DM in severe 
hypoglycemia, but not for use in a BP.  
 
The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, in the 
other iLet arm. ZP4207 will be made available by Zealand Pharma A/S, Denmark as liquid 
formulation in prefilled syringes of 0.6 mL. 
 
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Clinical Trial Protocol 
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Date: 28 June 2016 
Zealand Pharma A/S 
Confidential 
Page 5 of 59 
PRIMARY ENDPOINT: 
The primary endpoint is the safety and tolerability of ZP4207 and the iLet as assessed by: 
•
Number and type of adverse events (AEs)
•
Clinical laboratory measurements
•
Vital signs
•
12-lead electrocardiogram (ECG)
•
Local tolerability and infusion site reactions as measured with the Draize scale
•
Immunogenicity as measured by anti-drug antibodies
•
Pain as measured on a 10 cm visual analog scale (VAS)
•
Nausea as measured on a 10 cm VAS
SECONDARY ENDPOINTS: 
The secondary endpoints for the iLet and ZP4207 include measurements of BP function as 
well as glycemic and non-glycemic measurements. 
Bionic Pancreas Function 
This endpoint data will be generated from the BP data during each treatment visit: 
•
Average percent insulin dose amounts calculated by the BP control algorithm that are
successfully delivered by the pump
•
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully delivered by the pump
•
Average percent dose amounts successfully issued to the pump by the BP control
algorithm that are successfully delivered by the pump (calculated doses are not issued
unless the pump is accessible and its delivery channel is available)
o
Average percent insulin dose amounts successfully issued to the pump by the
BP control algorithm that are successfully delivered by the pump
o
Average percent glucagon/ZP4207 dose amounts successfully issued to the
pump by the BP control algorithm that are successfully delivered by the pump
•
Average percent dose amounts calculated by the BP algorithm that are successfully
issued to the pump by the BP (calculated doses are not issued unless the pump is
accessible and its delivery channel is available)
o
Average percent insulin dose amounts calculated by the BP control algorithm
that are successfully issued by the BP
o
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully issued by the BP
•
Average percent of 5-minute steps during which the BP is functioning nominally in all
respects based on real-time CGM data (new CGM glucose reading captured, dose
calculated, and dose issued to pumps)
•
Average percent of 5-minute steps during which the BP is functioning nominally with
or without a new CGM glucose reading captured (dose calculated and dose issued to
pumps). If a CGM signal is not available, the dose calculated may be based on weight
or historical basal rates.
•
CGM reliability index, calculated as percent of possible values actually recorded by
CGM
•
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter
download
•
List of technical faults associated with the BP including cause and resolution
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Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit. 
•
Fraction of time spent within each of the following glucose ranges:
o
<50 mg/dL
o
<60 mg/dL
o
<70 mg/dL
o
70-120 mg/dL
o
70-140 mg/dL
o
70-180 mg/dL
o
>180 mg/dL
o
>250 mg/dL
o
>300 mg/dL
•
Number of severe hypoglycemic events (patients unable to self-treat, requiring the
assistance of another person)
•
Number of episodes of symptomatic hypoglycemia
•
Number of carbohydrate interventions for hypoglycemia
•
Total grams of carbohydrates taken for hypoglycemia
•
Mean CGM glucose
Non-glycemic 
•
Glucagon/ZP4207 total delivery per kg of body mass
•
Insulin total delivery per kg of body mass
•
Number of unscheduled infusion set replacements
•
Number of unscheduled CGM sensor changes
EVALUATION OF TRIAL DATA: The following variables will be evaluated according to 
treatment for safety purposes: AEs, local tolerability, laboratory safety assessments, physical 
examination, vital signs, and 12-lead ECGs.  
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow. 
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SPONSOR: 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Tel: +45 88 77 36 00 
Fax: +45 88 77 38 98 
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TABLE OF CONTENTS 
SIGNATURE PAGE ............................................................................................................. 2 
INVESTIGATOR AGREEMENT .......................................................................................... 3 
SYNOPSIS ........................................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................... 8 
LIST OF FIGURES ............................................................................................................ 11 
LIST OF ABBREVIATIONS .............................................................................................. 12 
1 
INTRODUCTION AND BACKGROUND INFORMATION ...................................... 14 
1.1 
Background and Rationale ..................................................................................... 14 
1.2 
Bihormonal Bionic Pancreas System ..................................................................... 15 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System ........................ 16 
1.4 
ZP4207 ................................................................................................................... 18 
1.5 
Risk/Benefit ............................................................................................................ 19 
2 
TRIAL OBJECTIVES .............................................................................................. 22 
2.1 
Primary Objective ................................................................................................... 22 
2.2 
Secondary Objectives ............................................................................................. 22 
3 
TRIAL DESCRIPTION ............................................................................................ 22 
3.1 
Summary of Trial Design ........................................................................................ 22 
3.2 
Indication ................................................................................................................ 22 
3.3 
Number of Patients ................................................................................................. 22 
4 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................ 23 
4.1 
Inclusion Criteria ..................................................................................................... 23 
4.2 
Exclusion Criteria .................................................................................................... 23 
4.3 
Target Population ................................................................................................... 25 
4.4 
Withdrawal Criteria ................................................................................................. 25 
5 
ASSIGNMENT TO TREATMENT GROUPS........................................................... 26 
6 
TRIAL TREATMENT .............................................................................................. 26 
6.1 
Investigational Medicinal Products ......................................................................... 26 
6.2 
Storage and Drug Accountability of IMPs ............................................................... 26 
6.3 
Dispensing and Return of IMPs .............................................................................. 27 
6.4 
Doses ..................................................................................................................... 27 
6.5 
iLet Bionic Pancreas ............................................................................................... 27 
6.6 
Other Trial Devices ................................................................................................. 28 
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6.7 
Concomitant Medications ....................................................................................... 28 
6.7.1 
Permitted Medications and/or Procedures ...................................................... 28 
6.7.2 
Excluded Medications and/or Procedures ....................................................... 29 
7 
TRIAL PROCEDURES ........................................................................................... 29 
7.1 
Informed Consent ................................................................................................... 29 
7.2 
Screening Visit (Visit 1) .......................................................................................... 29 
7.2.1 
Data Collected at Screening ............................................................................ 29 
7.3 
Training Visit (Visit 2) .............................................................................................. 30 
7.4 
Treatment Visits (Visit 3 and Visit 4) ....................................................................... 30 
7.4.1 
Visit Procedures .............................................................................................. 31 
7.4.2 
Data Collected During the Treatment Visits .................................................... 33 
7.4.3 
Response to Hypoglycemia ............................................................................. 34 
7.4.4 
Response to Hyperglycemia ........................................................................... 34 
7.4.5 
Response to Nausea/Vomiting ........................................................................ 35 
7.4.6 
Response to Other Medical Needs ................................................................. 35 
7.4.7 
Monitoring of Bionic Pancreas Performance ................................................... 35 
7.4.8 
Supervision by Trial Staff ................................................................................ 35 
7.5 
Phone Call (Visit 5) ................................................................................................. 35 
7.6 
Follow-up Visit (Visit 6) ........................................................................................... 35 
8 
ENDPOINTS ........................................................................................................... 35 
8.1 
Primary Endpoint .................................................................................................... 35 
8.2 
Secondary Endpoints ............................................................................................. 36 
8.2.1 
Bionic Pancreas Function ................................................................................ 36 
8.2.2 
Glycemic .......................................................................................................... 36 
8.2.3 
Non-glycemic ................................................................................................... 37 
9 
LABORATORY ASSESSMENTS ........................................................................... 37 
9.1 
Safety Laboratory Assessments ............................................................................. 37 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) .............................................. 37 
9.3 
Exposure Assessments (ZP4207 and Glucagon) ................................................... 37 
9.4 
Anti-drug Antibody Assessments ............................................................................ 37 
10 
SAFETY REPORTING ............................................................................................ 38 
10.1 
Adverse Events ...................................................................................................... 38 
10.1.1 
Follow-up of Adverse Events ........................................................................... 38 
10.1.2 
Precautions ..................................................................................................... 39 
10.1.3 
Assessment of Adverse Events by the Investigator ........................................ 39 
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10.2 
Serious Adverse Events ......................................................................................... 40 
10.3 
Adverse Event Reporting – Procedures for Investigators ....................................... 40 
10.4 
Pregnancy Reporting .............................................................................................. 42 
10.5 
Hypoglycemia ......................................................................................................... 43 
10.6 
Safety Monitoring .................................................................................................... 43 
10.6.1 
Data and Safety Monitoring Board .................................................................. 43 
10.6.2 
Zealand Pharma Safety Committee ................................................................ 44 
11 
STATISTICS ........................................................................................................... 44 
11.1 
Analysis Populations .............................................................................................. 44 
11.2 
Statistical Methods ................................................................................................. 45 
11.2.1 
Analysis of Safety ............................................................................................ 45 
11.2.2 
Analysis of Efficacy ......................................................................................... 45 
11.2.3 
Interim Analysis ............................................................................................... 46 
11.2.4 
Sample Size Determination ............................................................................. 46 
12 
DATA MANAGEMENT AND RECORD KEEPING ................................................ 46 
12.1 
Data Handling ......................................................................................................... 46 
12.2 
Computer Systems ................................................................................................. 46 
12.3 
Data Entry ............................................................................................................... 47 
12.4 
Medical Information Coding .................................................................................... 47 
12.5 
Data Validation ....................................................................................................... 47 
12.6 
Record Keeping ...................................................................................................... 47 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ........................... 47 
13.1 
Ethical Conduct of the Trial .................................................................................... 47 
13.2 
Institutional Review Board ...................................................................................... 47 
13.3 
Informed Consent ................................................................................................... 48 
13.4 
Trial Monitoring Requirements ............................................................................... 48 
13.5 
Disclosure of Data .................................................................................................. 49 
13.6 
Retention of Records .............................................................................................. 49 
13.7 
Publication Policy ................................................................................................... 50 
13.8 
Legal Aspects ......................................................................................................... 50 
13.9 
Sponsor Discontinuation Criteria ............................................................................ 50 
13.10 
Patient Compensation ......................................................................................... 51 
14 
TRIAL ADMINISTRATIVE INFORMATION ............................................................ 51 
14.1 
Protocol Amendments ............................................................................................ 51 
14.2 
Address List ............................................................................................................ 51 
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14.2.1 
Sponsor ........................................................................................................... 51 
14.2.2 
Supplier of Device ........................................................................................... 52 
14.2.3 
Principal Investigator (Site) ............................................................................. 52 
14.2.4 
Contract Research Organization (Including Monitoring) ................................. 52 
14.2.5 
Medical Monitoring .......................................................................................... 52 
14.2.6 
Pharmacovigilance .......................................................................................... 52 
14.2.7 
Central Laboratory (Safety Laboratory and Plasma Glucose) ......................... 53 
14.2.8 
Special Laboratory (ZP4207 Exposure and ADA Analyses) ........................... 53 
14.2.9 
Special Laboratory (Glucagon Exposure) ....................................................... 53 
15 
REFERENCES ........................................................................................................ 54 
APPENDIX A: SCHEDULE OF PROCEDURES ............................................................... 55 
APPENDIX B: CLINICAL LABORATORY ANALYTES ................................................... 57 
APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES ....................................... 58 
 
LIST OF FIGURES 
Figure 1. 
Outpatient Results Summarizing the Distribution of Mean CGM Glucose 
Levels and Hypoglycemia in the BP and Control Arms ............................. 17 
Figure 2. 
Trial Design Schematic ................................................................................. 22 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
BG 
Blood glucose 
BP 
Bionic pancreas 
BU 
Boston University 
CFR 
Code of Federal Regulations 
CGM 
Continuous glucose monitor 
CRO 
Contract research organization 
DBR 
Database review 
DPP-4 
Dipeptidyl peptidase-4 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FHD 
First Human Dose 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HCG 
Human chorionic gonadotropin 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IV 
Intravenous 
MD 
Doctor of Medicine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH 
Massachusetts General Hospital 
MPC 
Model-predictive control 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
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Abbreviation 
Definition 
RN 
Registered nurse 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SGLT-2 
Sodium-glucose co-transporter-2 
SIV 
Site Initiation Visit 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 diabetes mellitus 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background and Rationale 
To date, clinical trials conducted by Boston University (BU) and Massachusetts General 
Hospital (MGH) in patients with type 1 diabetes mellitus (T1DM) have demonstrated the 
practicality of a wearable automated bionic pancreas (BP) control system for robust glucose 
regulation using a continuous glucose monitor (CGM) to provide the input to the control 
system. Despite current technical limitations in CGMs and infusion pumps, the trials by 
BU/MGH have shown that a bihormonal BP is capable of achieving safe and effective blood 
glucose (BG) control automatically, with minimal hypoglycemia during 11 continuous days in 
the face of unrestrained meals and exercise and with trivial patient input (optional 
announcement of meals).  
 
The BP provides automatic BG regulation and reduces hypoglycemic episodes. Additionally, 
the system spares the wearer the relentless tasks of carbohydrate counting, frequent BG 
monitoring, estimating the effects of specific meals and exercise activity on BG levels, and 
manual drug administration, which are inexact, demanding, aggravating, and require 
continuous diligence and vigilance. The degree of glycemic control achieved by the BP is 
predicted to dramatically reduce the deleterious and debilitating complications of T1DM. 
 
In its last tested embodiment, the BP consisted of a Dexcom G4 CGM, and an iPhone that are 
hardwired together, with the iPhone running the control algorithm and communicating via 
Bluetooth with 2 Tandem t:slim pumps to dose insulin and glucagon. The connections are 
repeatedly lost among these 4 components throughout the day, an issue that has the potential 
to adversely impact BG control, whether due to missed CGM values or missed doses. In 
addition, the troubleshooting required to repair these recurring disconnections can be 
burdensome to the user. Integrating these components into a single device would establish 
seamless connectivity among them, which would eliminate the need for such troubleshooting. 
This would lead to a smoother device operation with fewer interruptions, which would enhance 
its user friendliness, optimize its BG control potential, and further improve the quality of life of 
its users.  
 
The BU Investigators have recently designed, built, and tested a proprietary first-generation 
of such a fully integrated BP system, referred to as the iLet and the iLet infusion set. The iLet 
is a dual-chamber infusion system that currently incorporates the Dexcom G4 CGM 
technology, a custom user interface with touchscreen display, and all of the mathematical 
dosing algorithms that were tested in and validated using the iPhone-based BP in outpatient 
studies over the past 3 years. The iLet infusion set provides 2 independent subcutaneous (SC) 
fluid pathways from the iLet to the patient (1 for insulin and the other for glucagon). One tube 
connects to the prefilled insulin cartridge and the other tube connects to the fillable (single-use) 
glucagon cartridge. 
 
In order to provide automatic BG regulation, the iLet has the ability to deliver both insulin and 
glucagon. However, currently available glucagon formulations have limited stability at room 
temperature, necessitating frequent changes to the glucagon infusion set. Therefore, the 
current trial is designed to test the glucagon analog ZP4207 in the iLet, as this peptide analog 
of human glucagon is provided in a liquid formulation stable at room temperature. 
 
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The current trial is a first feasibility trial designed to use the first-generation iLet and iLet 
infusion set to compare ZP4207 with marketed glucagon (Lilly). The trial is intended to 
demonstrate the safety and tolerability of ZP4207 in the iLet and the feasibility of achieving 
comparable autonomous glycemic control. It is not intended to comprehensively demonstrate 
the definitive efficacy of the iLet in extended, continuous daily use, but rather to demonstrate 
its functionality and accuracy in a practical, albeit very controlled, clinical setting. The trial is 
expected to provide practical information that will benefit the design of a next-generation iLet 
and iLet infusion set and help pave the way for a more comprehensive outpatient home-use 
Phase 2 trial and ultimately a pivotal trial where comprehensive safety and efficacy through 
continuous full daily use of the iLet with ZP4207 will be documented. 
The data derived from this trial will permit evaluation of the robustness of the iLet as well as 
the safety and efficacy of ZP4207 when used in conjunction with the iLet. The data obtained 
will be used to further improve the iLet and will allow BU/MGH to expand to larger outpatient 
trials using the iLet with ZP4207.  
1.2 
Bihormonal Bionic Pancreas System 
The BP is an autonomous, self-learning system that requires only the patient's weight for 
initialization, and then autonomously adapts, modestly or dramatically, as needed, to cope 
with the wide range of insulin requirements of adults, adolescents, and pre-adolescents with 
T1DM. The BP obviates the need for the patient to know, or even appreciate, their insulin 
requirements, and renders obsolete any need for patients or caregivers to know 
carbohydrate-to-insulin ratios, basal rates, or insulin correction factors. 
The core technology is a suite of control algorithms that orchestrate the automated dosing of 
insulin and glucagon to regulate BG levels. An insulin controller orchestrates all SC insulin 
dosing. At its centerpiece is a model-predictive control (MPC) algorithm, which bases insulin 
doses on the glucose data and insulin absorption kinetics, compensating for the slow 
absorption rate of SC insulin analogs (peak time in blood of 30-90 min, clearance in 4-8 hr). 
This enables the algorithm to refrain from stacking and overdosing insulin. Furthermore, the 
MPC algorithm automatically adjusts its insulin-dosing aggressiveness continuously and in 
real-time to different insulin needs between individuals and variable needs within the same 
individual. Running in parallel with the MPC algorithm is an algorithm that automatically 
modulates basal insulin delivery over multiple time scales, and another algorithm that 
automatically adapts insulin doses in response to optional meal announcements. Unlike 
current insulin pumps and the insulin-only control algorithms, the adaptive basal insulin 
algorithm obviates the need for the user to set, or even know, his or her “basal-rate profile.” 
Instead, it is capable of automatically adapting to, and compensating for, changes in an 
individual's basal insulin need, such as might occur over a period of hours, days, or weeks 
(e.g., circadian hormonal fluctuations, intercurrent illness, physical activity, or emotional state) 
or as might occur over a period of months or years due to developmental changes 
(e.g., hormonal changes that occur during puberty or menopause). The adaptive meal dose 
controller obviates the need for the user to set, or even know, his or her 
“carbohydrate-to-insulin ratios,” as it makes automatic adjustments based on dosing history 
for similar meal announcements made on previous days, and customizes the dose for each 
individual and for time of day.  
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The BP also includes a proportional-derivative algorithm governing SC micro-doses of 
glucagon to help prevent impending hypoglycemia. Glucagon dosing is based on the glucose 
level and rate of descent. It may occur preemptively even if glucose is above range, and it 
includes a feedback term to account for the pending effects of recent glucagon doses.  
Taken together, these mathematical algorithms provide a universal framework for a glycemic 
control strategy that requires no quantitative input from, or participation by, the user (besides 
entering body weight to initialize the system), but which automatically adapts insulin and 
glucagon dosing to meet the individual needs of each user. Another challenge met is enabling 
the technology to remain completely autonomous in managing insulin and glucagon delivery 
even when the CGM is offline. Specifically, when the CGM is offline, the BP invokes the 
high-resolution “basal rate profile” that it had recently learned and stored when the CGM was 
online. On the basis of what the system learned and stored about meal announcements when 
the CGM was online, it is able to respond to meal announcements in the same manner when 
the CGM is offline. Finally, it automatically responds to user-entered BG values when the CGM 
is offline by issuing a correction dose of insulin or glucagon based on what it learned about 
the user's insulin and glucagon needs when the CGM was online. Thus, the BP never relies 
on, or burdens the user with, the determination of subjective dosing decisions, which inevitably 
vary in quality and reliability among different users. The BP provides a turnkey solution for 
people with T1DM that comprehensively manages glycemia across a broad range of individual 
needs and across a large spectrum of circumstances and challenges to glycemic control. 
A significant challenge for the use of glucagon in a bihormonal BP is the lack of a commercially 
available glucagon formation that is stable and well-suited to infusion over several days in a 
pump reservoir. However, BU/MGH have proceeded with studies using a relatively unstable 
marketed formulation that must be reconstituted from a lyophilized powder on a daily basis. 
This allowed BU/MGH to proceed with studies of the bihormonal system while awaiting the 
production of stable glucagon formulations or stable glucagon analogs. 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System 
The BP hardware platform has evolved over the years from a laptop-driven system, which was 
used in all inpatient studies to the first truly mobile wearable iPhone-driven platform, which 
has been used in a number of outpatient studies. Using the iPhone-based BP system, 
>110 outpatient experiments of 5-11 days in duration in each subject have been conducted 
(>800 patient days or >2 patient years of data) across subjects ranging in age between 6 and 
76 years old and in body mass between 21 and 128 kg. The robust adaptation capabilities of 
the BP is evident in the fact that the average total daily dose of insulin among these subjects 
varied by over 13-fold (from 11 to 145 units/day). 
In November 2012, Food and Drug Administration (FDA) approval was obtained to conduct 
the first outpatient study testing the BP in adults 21 years or older with T1DM. This study, 
referred to as the Beacon Hill Study, followed a random-order cross-over design in which 
20 adults with T1DM participated in 5 days on the iPhone-based BP and 5 days of usual care 
in which they wore a CGM with blinded display and muted alarms. In the BP arm, subjects 
kept to a 3-square-mile geographic area centered around the Beacon Hill neighborhood in 
Boston. They ate as they chose at local restaurants, and exercised at will with access to 
2 gyms. Analysis was pre-specified to focus on Days 2-5, since glycemic control is more 
representative of BP performance after most of the adaptation by the BP occurs on Day 1 
(Russell, 2014). Results are summarized in Figure 1.  
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In April 2013, FDA approval was obtained to conduct the first outpatient study testing the BP 
in adolescents 12-20 years old with T1DM. This study, referred to as the 2013 Summer Camp 
Study, followed a random-order cross-over design in which 32 adolescents with T1DM 
participated in 5 days on the BP and 5 days of supervised camp care in which they wore a 
CGM with blinded display and muted alarms. Subjects were fully integrated into normal camp 
activities without restrictions on diet or exercise. The study used the same iPhone-based BP 
that was used in the Beacon Hill Study. Results are summarized in Figure 1 (Russell, 2014). 
In April 2014, FDA approval was obtained to conduct the first outpatient study testing the BP 
in pre-adolescents 6-11 years old with T1DM. This study, referred to as the 2014 Summer 
Camp Study, was similar in design to the 2013 Summer Camp Study. Results are summarized 
in Figure 1 (Russell, 2016).  
In April 2014, FDA approval was obtained to conduct the first multi-center study, which was 
also the first home study, to test the BP in adults 18 years or older with T1DM. This study, 
referred to as the Bionic Pancreas Multi-Center Study, followed a random-order cross-over 
design in which 39 adults participated in 11 days on the BP and 11 days of usual care. 
Participants went to work as usual, and lived and slept at home, all without clinical supervision. 
There were no restrictions placed on diet or exercise. The study included 4 medical centers 
(10 subjects per center), which included MGH, the University of Massachusetts Medical 
School, Stanford University, and the University of North Carolina at Chapel Hill. Results are 
summarized in Figure 1.  
All of these studies used marketed glucagon (glucagon for injection, Eli Lilly). Due to its limited 
stability, Lilly glucagon must be reconstituted immediately before use. Animal studies have 
previously shown that despite its limited chemical stability, Lilly glucagon maintains its 
biological activity for up to 7 days in solution. Using this data, an Investigational New Drug 
(IND) exemption was obtained from the FDA for its use in a pump for up to 27 hours. This 
allowed these studies to be performed by asking volunteers to reconstitute a new vial of 
glucagon and fill the glucagon pump at approximately the same time every day. However, 
marketed Lilly glucagon has no path forward for approval for chronic BP use. 
1.4 
ZP4207 
ZP4207 is a peptide analog of human glucagon that is being developed to treat hypoglycemia 
in patients with T1DM and type 2 diabetes mellitus. ZP4207 exhibits improved physical and 
chemical stability in aqueous media and is suitable for liquid formulation. ZP4207 is comprised 
of 29 amino acids and has 7 amino acid substitutions when compared to native glucagon.  
Two clinical Phase 1 trials have been conducted to establish safety and tolerability of ZP4207 
after single and multiple dosing to healthy patients and T1DM patients under insulin-induced 
hypoglycemic conditions. 
The First Human Dose (FHD) trial (ZP4207-14013) was finalized in April 2015. The trial was 
a randomized, double-blinded trial with the objectives to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of ZP4207 as compared to an active 
comparator. Part 1 included a single ascending dose in healthy volunteers in cohorts of 8. In 
each cohort, the patients were randomized 3:1 to ZP4207 (n=6) or Novo Nordisk GlucaGen® 
(n=2). Five cohorts with SC administration (0.01, 0.1, 0.3, 1.0, and 2.0 mg ZP4207 compared 
to 1 mg GlucaGen) and 3 cohorts with intramuscular (IM) administration (0.3, 1.0, and 2.0 mg 
ZP4207 compared to 1 mg GlucaGen) were included. Part 2 included 2 sequence groups of 
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10 hypoglycemic T1DM patients. The patients were treated with fixed single IM doses of 
0.7 mg ZP4207 and 1.0 mg GlucaGen in a sequential cross-over design in a randomized 
treatment order.  
 
The second clinical trial (ZP4207-15007) was a single-center, double-blind, Phase 1b trial 
investigating the safety and tolerability, PK and PD of ZP4207 following repeated 
administration in healthy volunteers compared to placebo. It was finalized in July 2015. Each 
of the 3 cohorts comprised 8 subjects, who received 5 repeated SC doses of ZP4207 or 
placebo in a 3:1 treatment allocation. The first cohort started with the lowest dose of 0.1 mg. 
Cohort 2 and 3 continued with 0.3 and 1.0 mg, respectively. 
 
The Phase 1 results did not give rise to specific safety concerns, beyond those related to the 
pharmacological effect of ZP4207. All adverse events (AEs) recorded in the trials were of mild 
or moderate severity. The most frequent systemic AE related to treatment with ZP4207 was 
nausea, which is a known side-effect following administration of glucagon. The most frequent 
injection site reaction was transient erythema, occurring in all ZP4207, glucagon, and placebo 
treatment groups, irrespective of dose. No anti-drug antibodies (ADA) incidences were 
observed. 
 
The observed PD response, in terms of increased plasma glucose, in insulin-induced 
hypoglycemic patients with T1DM following dosing with 0.7 mg ZP4207 administered IM was 
similar to that observed following IM dosing with 1.0 mg glucagon (GlucaGen, Novo Nordisk). 
An increase in plasma glucose of ≥20 mg/dL from hypoglycemic levels was achieved within 
30 minutes for all patients. 
 
In terms of PK, ZP4207 had a short half-life and high clearance and dose proportionality for 
both maximum plasma concentration and area under the concentration-time curve from 
time 0 to 300 minutes in the dose range 0.1 to 2.0 mg following SC administration. Following 
IM administration, dose proportionality was shown in the investigated dose range of 0.3 to 
2.0 mg. The PK properties of 0.7 mg ZP4207 IM were comparable with those of 1.0 mg 
glucagon (GlucaGen, Novo Nordisk) with IM administration. 
 
1.5 
Risk/Benefit   
While the potential risks are minimal, the findings of this trial may reveal information that can 
substantially improve medical care for persons with diabetes. Therefore, the overall 
risk/benefit for patients participating in this trial is assessed as acceptable. 
 
Potential Risks and Discomforts  
 
Trial patients will be informed by the Investigator of the potential risks of ZP4207 and other 
trial-related procedures before they enter the trial.  
 
In this trial, patients with T1DM will be included to test the safety and efficacy of the iLet using 
ZP4207 versus the iLet using Lilly glucagon. The cross-over design with inclusion of the same 
T1DM patients into the 2 treatment arms in a randomized order will allow for a direct 
comparison of the safety and efficacy of the 2 treatments, based on intra-patient variability 
only.  
  
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Patients may experience mild discomfort associated with the insertion of the infusion sets and 
sensor into the SC tissues. The risk of discomfort due to insertion of infusion sets and sensors 
is expected to be slightly greater than in their lives outside the trial because more infusion sets 
will be inserted and a CGM sensor will be inserted. Most patients will use only one infusion 
set and not all will use a CGM sensor in usual care.  
There is a potential risk of hypoglycemia, since recombinant insulin analog will be 
administered. Due to frequent monitoring of glucose and direct supervision by a registered 
nurse (RN) or Doctor of Medicine (MD) at all times, the risk of a hypoglycemic episodes leading 
to significant harm to patients is expected to be substantially lower than their risk during their 
usual therapy.  
There is a risk of hyperglycemia. This risk is expected to be less than the risk during the 
patients’ lives outside of the trial based on data from earlier BP trials and the design of this 
trial.  
Treatment with ZP4207 and marketed glucagon can result in undesired effects or complaints. 
Undesired effects and complaints such as gastrointestinal side effects including nausea, 
vomiting, and diarrhea are known side effects of glucagon administration at higher dose levels. 
The frequency of nausea associated with the administration of 1 mg of glucagon according to 
the Summary of Product Characteristics (SPC) for Glucagon is described to be between 1/10 
and 1/100. The frequency of vomiting is described to be between 1/100 and 1/1000 
(Novo Nordisk, 2015). Similar gastrointestinal side effects have also been observed to a 
limited degree in the 2 clinical trials conducted with ZP4207, again at higher dose levels. The 
individual doses of ZP4207 and Lilly glucagon delivered by the BP are expected to be 
significantly lower than doses typically associated with nausea. As with every novel drug 
substance, new and yet unknown side effects may also occur. 
There are limited data available to describe the immunogenic potential of glucagon products 
available on the market, but the data available indicate that marketed glucagon only has a 
small immunogenic potential. A Phase 1 trial performed with recombinant human glucagon 
and animal derived glucagon in 75 healthy patients did not show signs of ADA measured 
13 weeks after trial product administration (Eli Lilly, 2005). In the ZP4207 FHD trial, 
ZP4207-14013, no confirmed anti-ZP4207 or anti-glucagon antibodies were detected in any 
of the samples. In addition, the 5 sequential administrations of ZP4207, as applied in trial 
ZP4207-15007, were not associated with the development of antibodies against ZP4207 in 
the 18 subjects enrolled to receive ZP4207. The optimized formulation of ZP4207, as applied 
in the present trial is not expected to change the immunogenic potential of the Investigational 
Medicinal Product (IMP).  
In relation to diabetes therapy, development of insulin-antibodies is documented more 
substantially and route of administration has been shown to influence immunogenic potential 
of insulins. However, these antibodies against insulin generally do not have an impact on 
insulin action and are thus not clinically relevant. 
In terms of consequence, development of high titer antibodies against ZP4207 could, in theory 
reduce the activity of endogenous glucagon, which again, in theory could influence 
hypoglycemic episodes. However, most patients with T1DM do not secrete glucagon normally 
in response to hypoglycemia, so they would be less likely to be negatively impacted by 
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anti-glucagon antibodies. Limited suppression of glucagon would, however, not be considered 
critical, as low glucose levels can also be corrected by other means, including oral intake of 
glucose and by other endogenous hormones such as oxyntomodulin.  
Overall, ZP4207 is judged to be a low-risk molecule, based upon the available clinical data as 
well as the outcome of the risk-based approach to the immunogenicity assessment made. The 
present trial will include sampling for measurement of antibodies against ZP4207 prior to first 
dosing (Visit 3) and at the Follow-up Visit. In line with regulatory guidance documents, these 
samples will be appropriately analyzed and the results will be included in the overall 
assessment of the immunogenic potential of ZP4207 after completion of each trial and as the 
clinical development program advances. 
Administration of ZP4207 may be associated with a risk of allergic reactions similar to those 
observed for other therapeutic peptides or proteins. Patients with known or suspected allergies 
to the trial products or related products will be excluded from the trial. Mild or moderate allergic 
reactions may include symptoms of rash, fever, flu-like symptoms, nausea, headache, and 
myalgia. Acute generalized hypersensitivity reactions are usually very rare but may include 
symptoms of flushing, sweating, dizziness, change in blood pressure, and difficulties in 
breathing. The risk of acute hypersensitivity reactions is described to be less than 1/10,000 
for native glucagon. No severe acute hypersensitivity reactions have been observed in the 
2 clinical trials conducted with ZP4207.  
Potential Benefits 
Based on experiences from previous trials of the BP and the design of this trial, patients 
enrolled in the trial may benefit from a reduction in risk of hypoglycemia and hyperglycemia 
and a better mean glucose compared to their usual diabetes care during their short trial 
participation.  
The data derived from this trial will allow evaluation of safety and tolerability of ZP4207 in the 
iLet, and the robustness and effectiveness of the new BP control system. The data obtained 
will be used to further improve the iLet and will allow the expansion to larger outpatient trials 
using the iLet with ZP4207.  
This trial is a necessary step in preparing the BP with ZP4207 to become available to people 
with T1DM. Wide availability of the BP with ZP4207 could improve the medical care of adults 
and children with T1DM. 
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2 
TRIAL OBJECTIVES  
2.1 
Primary Objective 
The primary objective is to conduct a trial testing the safety and tolerability of the iLet when 
used with ZP4207 in 10 adult (≥18 years of age) patients with T1DM. 
2.2 
Secondary Objectives 
The secondary objectives are to measure glycemic regulation, including hypoglycemia 
exposure (percent of time spent with CGM glucose <60 mg/dL), evaluate BP device reliability, 
and to document the satisfaction of patients with the iLet with the goal of optimizing the 
functionality and user interface of the iLet. 
3 
TRIAL DESCRIPTION 
3.1 
Summary of Trial Design 
This trial is a single-center, open-label, randomized cross-over trial. The trial will enroll adult 
patients with T1DM and will assess the safety and efficacy of the iLet using the glucagon 
analog ZP4207 versus the iLet using Lilly glucagon. The iLet will also administer insulin (insulin 
lispro, Lilly Humalog) using the same BG control algorithm for both treatment arms. The trial 
will be conducted at a single center, the MGH Diabetes Center in Boston, MA. 
The overall trial design schematic is displayed in Figure 2. 
Figure 2. 
Trial Design Schematic 
3.2 
Indication 
ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid formulation which 
is being studied to improve glycemic control in adults (and children) with T1DM as part of a 
bihormonal BP. 
3.3 
Number of Patients 
Up to 20 adult patients with T1DM can be enrolled. The upper bound is based on the 
expectation that some patients will be excluded after the Screening Visit and the possibility 
that some patients may have to be discontinued before completion (due to, for instance, 
inter-current illness or patient withdrawal). It is expected that up to 10 patients will complete 
the trial protocol. 
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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
The trial will enroll patients who already manage their T1DM using continuous SC insulin 
infusion pump therapy. This requirement is imposed because multiple daily injection therapy 
involves the use of medium-acting or long-acting basal insulin that would require an extended 
washout period. 
 
4.1 
Inclusion Criteria  
1. Male and female patients with T1DM for at least 1 year, as defined by the American 
Diabetes Association 
2. Age ≥18 years  
3. Diabetes managed using an insulin pump for ≥6 months 
4. Prescription medication regimen stable for >1 month (except for medications that will 
not affect the safety of the trial and are not expected to affect any outcome of the trial, 
in the judgment of the Investigator) 
5. Informed consent obtained before any trial-related activities (trial-related activities are 
any procedure that would not have been performed during normal management of the 
patient) 
6. Patients in good health according to age (medical history, physical examination, vital 
signs, 12-lead electrocardiograms [ECGs], laboratory assessments), as judged by the 
Investigator 
 
4.2 
Exclusion Criteria  
1. Unable to provide informed consent (e.g., impaired cognition or judgment) 
2. Unable to safely comply with trial procedures and reporting requirements 
(e.g., impairment of vision or dexterity that prevents safe operation of the BP, impaired 
memory, unable to speak and read English) 
3. Participation in another clinical trial of an investigational agent or device concurrently 
or within 1 month (or 5 half-lives) prior to the Screening Visit 
4. Previous exposure to ZP4207 
5. Females of childbearing potential who are pregnant (positive urine human chorionic 
gonadotropin [HCG]), breast feeding, plan to become pregnant in the immediate future, 
or sexually active without using highly effective contraception methods (highly effective 
methods are considered those with a failure rate less than 1% undesired pregnancies 
per year including surgical sterilization, hormonal intrauterine devices [coil], oral 
hormonal contraceptives, sexual abstinence, or a surgically sterilized partner) or 
postmenopausal 
women 
amenorrheic 
for 
less 
than 
1 year 
with 
serum 
follicle-stimulating hormone (FSH) level ≤40 IU/L and not using highly effective 
contraceptive methods during the trial and until 1 month after last dosing in the trial 
6. Male who is sexually active and not surgically sterilized who or whose partner(s) is not 
using highly effective contraceptive methods (highly effective contraceptive measures 
include surgical sterilization, hormonal intrauterine devices [coil], oral hormonal 
contraceptives, each in combination with spermicide-coated condoms), or who is not 
willing to refrain from sexual intercourse from the first dosing until 1 month after last 
dosing in the trial 
7. Current alcohol abuse (intake averaging >3 drinks daily in last 30 days) or use within 
the last 6 months of controlled substances without a prescription (other than marijuana)  
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8.
New onset clinically significant illness within 4 weeks prior to screening, as judged by
the Investigator
9.
Unwilling or unable to refrain on the treatment visits from:
a.
Acetaminophen in any form
b.
Use of drugs that may dull the sensorium, reduce sensitivity to symptoms of
hypoglycemia, or hinder decision making during the period of participation in
the trial (use of beta blockers will be allowed as long as the dose is stable and
the patient does not meet the criteria for hypoglycemia unawareness while
taking that stable dose, but use of benzodiazepines or narcotics, even if by
prescription, may be excluded according to the judgment of the Investigator)
10. History of liver disease that is expected to interfere with the anti-hypoglycemia action
of glucagon (e.g., liver failure or cirrhosis). Other liver disease (i.e., active hepatitis,
steatosis, active biliary disease, any tumor of the liver, hemochromatosis, glycogen
storage disease) may exclude the patient if it causes significant compromise to liver
function or may do so in an unpredictable fashion.
11. Aspartate 
aminotransferase >2 
× 
upper limit of 
normal (ULN), alanine
aminotransferase >2 × ULN, or bilirubin >1.5 × ULN on screening laboratories
12. Renal failure on dialysis or estimated glomerular filtration rate <30 mL/min/1.73 m2 on
screening laboratories
13. Hemoglobin <12 gm/dL for men and <11 gm/dL for women
14. Personal history of cystic fibrosis, pancreatitis, pancreatic tumor, or any other
pancreatic disease besides T1DM
15. Any known history of coronary artery disease including, but not limited to, history of
myocardial infarction, stress test showing ischemia, history of angina, or history of
intervention such as coronary artery bypass grafting, percutaneous coronary
intervention, or enzymatic lysis of a presumed coronary occlusion)
16. Congestive heart failure with New York Heart Association Functional Classification III
or IV
17. History of transient ischemic attack or stroke in the last 12 months
18. Seizure disorder, history of any non-hypoglycemic seizure within the last 2 years, or
ongoing treatment with anticonvulsants
19. History of hypoglycemic seizures (grand-mal) or coma in the last 12 months
20. History of pheochromocytoma: fractionated metanephrines will be tested in patients
with history increasing the risk for a catecholamine secreting tumor:
a.
Episodic or treatment refractory (requiring 4 or more medications to achieve
normotension) hypertension
b.
Paroxysms of tachycardia, pallor, or headache
c.
Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or
von Hippel-Lindau disease
21. History of adrenal disease or tumor
22. Hypertension with systolic blood pressure ≥160 mm Hg or diastolic blood pressure
≥100 mm Hg despite treatment
23. Untreated or inadequately treated mental illness (indicators would include symptoms
such as psychosis, hallucinations, mania, and any psychiatric hospitalization in the last
year), or treatment with anti-psychotic medications that are known to affect glucose
regulation
24. Electrically powered implants (e.g., cochlear implants, neurostimulators) that might be
susceptible to radio frequency interference
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5 
ASSIGNMENT TO TREATMENT GROUPS 
This trial is an open-label, randomized cross-over trial. Patients who have completed the 
Screening Visit and meet all of the inclusion and none of exclusion criteria will be enrolled into 
the trial. All patients will participate in two 1-day treatment arms in random order (iLet using 
ZP4207 and iLet using Lilly glucagon) according to a pre-generated randomization scheme. 
Up to 2 patients may participate in the trial per day. The order of the iLet visits will be 
randomized in blocks of 2 patients. 
6 
TRIAL TREATMENT 
6.1 
Investigational Medicinal Products 
Insulin: The trial involves SC administration of insulin lispro (Humalog, Lilly), which is 
commercially available by prescription and is indicated for patients with T1DM, but not for use 
in a BP. 
Glucagon: The trial also involves SC administration of Lilly glucagon in one iLet arm. Lilly 
glucagon is commercially available by prescription and is indicated for patients with T1DM in 
severe hypoglycemia, but not for use in a BP. 
ZP4207: The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, 
in the other iLet arm. ZP4207 will be made available by Zealand Pharma A/S, Denmark as 
liquid formulation in prefilled syringes of 0.6 mL. 
6.2 
Storage and Drug Accountability of IMPs 
All IMPs will be stored and handled in accordance with the Sponsor’s instructions and/or the 
product labelling at the Investigator’s site, e.g., refrigerated (+2ºC to +8ºC) and should not be 
exposed to excessive heat, direct sunlight and never be frozen. 
All used, partly used, and unused vials or prefilled syringes must be kept by the Investigator 
and stored between +2ºC and +8ºC (unused) or at room temperature (partly used and used). 
Used and unused pre-filled syringes must be stored separately.  
The Investigator must ensure the availability of proper storage conditions and record and 
evaluate the temperature. Temperature of the refrigerator used for drug storage is monitored 
continuously, an alarm system is established. The Investigator must inform the monitor 
immediately if any IMP has been stored outside specified conditions (e.g., outside temperature 
storage). Investigational Medicinal Product that has been stored improperly must not be 
dispensed to any patient before it has been re-evaluated and approved for further use. The 
Investigator must take appropriate action to ensure correct storage. 
For the IMP, the Investigator must keep an accurate record of all IMPs received and the 
products used for each patient in a Drug Accountability Record. Storage locations, batch 
numbers, and expiry dates are also documented in this form. 
The drug accountability must be performed in a timely manner by the monitor. 
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6.3 
Dispensing and Return of IMPs 
No IMPs may be dispensed to any person not enrolled in the trial. 
Upon completion of the trial, the Sponsor will be responsible for destruction or storage of IMPs 
(used, partially used, or unused). These duties can be delegated to a contract research 
organization (CRO) and must be documented in the trial files. 
6.4 
Doses 
The iLet can administer isolated insulin-glucagon doses once every 5 minutes. A single 
automated bolus of insulin will not exceed 3 units per 5-minute dose (30 µl of U-100 insulin) 
in both systems, and a single meal-priming dose, in response to a meal announcement made 
by the user, will not exceed 12 units (120 µl of U-100 insulin). A single bolus of glucagon will 
not exceed 80 µg (80 µl of 1 mg/mL Lilly glucagon or 1 mg/mL ZP4207). In prior studies, typical 
doses of glucagon were in the range of 0.005-0.04 mg per dose. The iLet is capable of 
administering as little as ~0.1 µl (0.011 units of U-100 insulin or 0.1 µg of 1 mg/mL ZP4207). 
It is expected that the mean total daily doses of glucagon/ZP4207 will be <1.0 mg daily as in 
previous studies. The mean daily glucagon dose in a previous 11-day outpatient trial was 
0.5 mg/day (range 0.2-0.9 mg/day). Currently, single doses of up to 2 mg ZP4207 have been 
administered in clinical trials. The recommended dose of marketed glucagon for adult patients 
suffering from severe hypoglycemia is 1 mg as a single injection. Mean glucagon levels in 
previous inpatient studies have been above the normal fasting range for glucagon only 1% of 
the time. Therefore, the glucagon exposure of patients is expected to be modest. 
6.5 
iLet Bionic Pancreas  
Infusion set: A novel, dual cannula infusion set has been designed specifically for use with 
the iLet. Patients will wear dual channel tubing that will be attached to 2 infusion sets with 
1 steel cannula each, one for insulin infusion and the other for glucagon infusion. The tubing 
and infusion sets will have undergone sterilization prior to being delivered in a sealed pouch. 
The steel cannulae will be inserted in the abdominal SC tissue. 
Continuous glucose monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to 
the controller. The sensor is powered by the battery within the transmitter that clips to the 
sensor and the whole assembly is held to the skin with an adhesive patch and communicates 
wirelessly with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM 
signal), it will be replaced promptly.  
Bionic Pancreas Control Unit: The iLet is being built according to Class III medical device 
standards, adheres to a comprehensive and robust quality system, and is fully compliant with 
International Organization for Standardization (ISO) 13485 standards and document control 
practices. The iLet is a fully-integrated dual-hormone BP system that integrates the CGM 
technology (currently the Dexcom G4 Share system) as well as 2 independent motor-drivetrain 
pumping assemblies, which independently actuate the delivery of insulin and glucagon from 
pre-filled cartridges that are separately loaded into the iLet housing. Each drivetrain assembly 
utilizes a lead screw, which is driven by a precision micromotor, a gear case assembly, and a 
motor controller unit, in a manner similar to what is commonly found in most insulin infusion 
pumps on the market today. The iLet has dosing accuracy that is comparable to 
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FDA-approved insulin pumps currently on the market. The iLet has a built-in Bluetooth Low 
Energy radio that also allows automatic communication with the paired CGM, as well as the 
Nova StatStrip® Xpress BG meter (Nova Biomedical). The iLet does not contain a cellular nor 
a WiFi radio, and does not accept input data from another mobile device (e.g., smartphone), 
other than the paired CGM and BG meter(s). 
The mathematical control algorithms (which are the same as those used in the iPhone-based 
BP), the CGM glucose engine (Dexcom), and the native user interface software, are all 
interconnected through controller framework software and reside as embedded systems on 
printed circuit boards contained within the device housing. The touchscreen-enabled, 
menu-driven user interface and onboard processor provide a comprehensive and standalone 
platform, which allows the iLet to operate independently of smartphones or other devices and 
without the need for internet support during routine operation. The graphical user interface of 
the iLet has the same user options and capabilities of the iPhone BP, including having its 
home screen password protected and its settings options only accessible to trial staff via a 
separate password. 
6.6 
Other Trial Devices 
YSI 2300 STAT Plus™ (Yellow Springs Instruments): The YSI 2300 STAT Plus is an 
FDA-approved glucose analyzer. Blood glucose measurements using the YSI 2300 STAT 
Plus will be obtained off of the IV line during both treatment visits.   
Nova Biomedical StatStrip Xpress Glucose Meter: The Nova StatStrip Xpress glucose 
meter is an FDA-approved glucose meter that is commercially available. Blood glucose 
measurements for CGM calibration will be obtained with the Nova StatStrip Xpress during both 
treatment visits if the YSI 2300 STAT Plus fails and via fingerstick with the Nova StatStrip 
Xpress during any periods when IV blood samples are not available for any reason or the IV 
fails. 
Exercise Bike: The trial will utilize a stationary exercise bike (ergometer) for the in-clinic 
exercise at the treatment visits. This bike will be stored at the Diabetes Research Center when 
not in use. 
6.7 
Concomitant Medications 
6.7.1 
Permitted Medications and/or Procedures 
Patients may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference with 
CGM sensing. All concomitant medications, including over-the-counter medications, should 
be recorded. 
Use of beta blockers will be allowed as long as the dose is stable and the patient does not 
meet the criteria for hypoglycemia unawareness while taking that stable dose. 
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911. 
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6.7.2 
Excluded Medications and/or Procedures  
During the trial, patients will not use any recreational drugs or drugs of abuse. The need to 
take prescription drugs that dull the sensorium, reduce sensitivity to symptoms of 
hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion from the 
trial or discontinuation of participation, a decision that will be made by the Investigator. 
 
Use of benzodiazepines or narcotics, even if by prescription, may be excluded according to 
the judgment of the Investigator. Use of oral anti-diabetic medications (e.g., thiazolidinediones, 
biguanides, sulfonylureas, glitinides, DPP-4 inhibitors, SGLT-2 inhibitors) will also be 
excluded. 
7 
TRIAL PROCEDURES  
7.1 
Informed Consent  
After potential patients have had time to review the consent document, and prior to any 
trial-related activities, they will meet with a trial MD or designee who will explain the trial, 
answer any questions, and administer informed consent. In the event that a volunteer is a 
patient of one of the trial MDs, another staff MD or designee will answer questions and 
administer consent. The patients will be fully informed of their responsibilities and their rights 
while participating in the trial as well as of the possible risks and potential benefits of 
participation in the trial. They will have the opportunity to discuss all questions and ample time 
to consider participation. 
 
Trial-related activities are any procedures that would not have been performed during normal 
management of the patient. Patients who wish to participate in the trial will be asked to 
personally date and sign an informed consent form (ICF). Likewise, the Investigator must also 
personally date and sign the ICF. All patients will be provided with a copy of their own signed 
and dated ICF. 
 
Trial staff will answer any questions that the patients may have during their participation. They 
will share any new information in a timely manner that may be relevant to the patient's 
willingness to continue participating in the trial. The patients may choose to discontinue their 
participation at any time.  
 
7.2 
Screening Visit (Visit 1) 
All patients will have a Screening Visit to confirm eligibility. The patient will be interviewed and 
the electronic Case Report Form (eCRF) will be completed by trial staff to establish whether 
the patient is eligible. 
 
Once all of the results have been returned, a trial MD will review the eCRF to determine patient 
eligibility. If a patient is not eligible to continue in the trial, the results of abnormal tests will be 
reported to the patient and to a health care provider of their choosing. 
7.2.1 
Data Collected at Screening 
• 
Age, sex, race, and ethnicity 
• 
Date of last menstrual period in female patients  
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Confidential & Proprietary 
Final Version 1.0, 10 November 2017 
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Clinical Trial Protocol 
ZP4207-16051 
Version number: 2.0 
Amendment 1.0 
Date: 28 June 2016 
Zealand Pharma A/S 
Confidential 
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•
Medical, surgical, and social history, allergies, and review of systems relevant to
inclusion and exclusion criteria, including:
o
Date of diabetes diagnosis
o
Duration of insulin pump use and type of insulin used in pump
o
Type/model of insulin pump
o
Insulin regimen (basal rate, sensitivity factor, and carbohydrate ratio)
o
Average total daily dose of insulin in the last 30 days as available (from pump
history)
o
Usage of CGM, if any (type of CGM, days per month worn, usage of data,
whether insulin is dosed based on CGM alone, alarm settings)
•
Concomitant illness (any illness present at screening)
•
Concomitant medications (prescription and non-prescription) and date of last change
in medication regimen
•
Height, weight, physical examination, and vital signs including body temperature and
blood pressure
•
12-lead ECG
•
Hemoglobin A1c
•
Chemistry and hematology samples (see Appendix B)
•
Urine HCG pregnancy test for women of childbearing potential
•
FSH level for postmenopausal women amenorrheic for less than 1 year
•
Fractionated plasma metanephrines (if indicated by history)
7.3 
Training Visit (Visit 2) 
A Training Visit will take place before the first treatment visit. Patients will be trained in the 
insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. Trial staff 
will verify that the patients have understood the material and are competent to participate 
safely in the trial. Concomitant medications will also be reviewed. 
7.4 
Treatment Visits (Visit 3 and Visit 4) 
•
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than
30 days after screening (Visit 1).
•
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum
of 3 weeks between Visit 3 and Visit 4.
•
Up to 2 patients may participate per day.
•
Each patient will participate in 2 treatment visits: one with the iLet using ZP4207 and
one with the iLet using Lilly glucagon in a randomized order.
•
The night before the treatment visit, patients will place a Dexcom G4 CGM sensor in
the abdominal skin and calibrate the sensor when prompted using the provided Nova
StatStrip Xpress meter. Patients will be instructed to call if they encounter any difficulty
with their CGM.
•
Patients will be responsible for their own medications other than insulin during the trial.
Any medical advice needed by the patients during their participation that is not directly
related to BG control should be obtained from them in their usual manner. Patients
may take any over-the-counter medications that they wish during the trial, with the
exception of any medication containing acetaminophen as that may cause interference
with CGM sensing. If patients experience urgent or emergent medical concerns
outside the scope of diabetes care and their primary care physicians, they will be taken
Zealand Pharma A/S 
Clinical Trial Report ZP4207-16051 
Confidential & Proprietary 
Final Version 1.0, 10 November 2017 
452 
 


Clinical Trial Protocol 
ZP4207-16051 
Version number: 2.0 
Amendment 1.0 
Date: 28 June 2016 
Zealand Pharma A/S 
Confidential 
Page 31 of 59 
to the MGH walk-in clinic or emergency room, or if necessary call 911. 
•
During the trial, patients will not use any recreational drugs or drugs of abuse. The
need to take prescription drugs that dull the sensorium, reduce sensitivity to symptoms
of hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion
from the trial or discontinuation of participation, a decision that will be made by the
Investigator.
•
Patients will not tamper with the BP, including changing any settings.
•
Patients may not remove the BP during the trial unless the BP failed or they are
withdrawing from the trial.
•
The exact time of each procedure and assessment will be documented.
7.4.1 
Visit Procedures  
•
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the
BP having fasted since 12:00 AM the night before (treatment with simple carbohydrate
of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled
within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the
visit window.
•
Upon arrival to the visit, the patient’s weight and vital signs including body temperature
and blood pressure will be documented.
•
Patient reports of symptoms, any other complaints, and AEs will be reviewed.
•
Concomitant medications will be recorded.
•
Chemistry and hematology samples will be collected at visit start (see Appendix B).
•
ADA samples will be collected before the start of dosing (Visit 3 only).
•
A 12-lead ECG will be performed.
•
A urine HCG pregnancy test will be performed in female patients of childbearing
potential. If the test is positive, the patient will be informed of the result and the visit
will be ended.
•
Patients will complete a baseline survey about their attitudes and experience with their
usual diabetes care.
•
An intravenous (IV) catheter will be placed for blood sampling.
•
Trial staff will assist the patient to calibrate their CGM, review the trial procedures again
and assist with the setup of the BP system, including inserting and priming infusion
sets.
•
The control algorithm will be initialized only with the patient’s weight. Diagnostics will
be performed to ensure that the CGM device is appropriately calibrated and that all of
the components of the BP systems are in working order.
•
The basal rate of the patient’s own insulin infusion pump will be changed to be 2-fold
higher than weighted mean of the basal rate during the trial period. This is intended to
increase the usage of glucagon during the treatment visit.
•
The patients will continue to wear their own infusion pump infusing at the temporary
2-fold basal rate throughout the visit until the start of the structured exercise period, in
addition to the BP.
•
The staff will start the BP as close as possible to a minute divisible by 5 minutes
(i.e., on a 5-minute mark). The starting time will be considered Hour 0.
•
Additional calibrations will be performed at any of the BG checks throughout the day if
the CGM value does not meet the ISO standard (<15 mg/dL difference for BG values
<75 mg/dL; <20% absolute difference for BG values >75 mg/dL) at the time of the BG
Zealand Pharma A/S 
Clinical Trial Report ZP4207-16051 
Confidential & Proprietary 
Final Version 1.0, 10 November 2017 
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Clinical Trial Protocol 
ZP4207-16051 
Version number: 2.0 
Amendment 1.0 
Date: 28 June 2016 
Zealand Pharma A/S 
Confidential 
Page 32 of 59 
measurement AND it is a good time to calibrate (the CGM trend arrow is flat and there 
has been no carbohydrate intake in the last 30 minutes or glucagon boluses in the last 
15 minutes). 
•
Blood samples will be taken from the IV at least hourly and processed for plasma
ZP4207/glucagon. If BG is <150 mg/dL, more frequent samples for plasma
ZP4207/glucagon may be drawn at the discretion of the Investigator. The actual time
of sampling will be recorded in the eCRF.
•
Plasma glucose samples will be taken from the IV at least hourly in parallel with
ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT Plus.
If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes.
If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then
sampling will be every 10 minutes. The actual time of sampling will be recorded in the
eCRF.
•
Patients will be asked to rate any nausea and/or infusion site pain on 10 cm visual
analog scales (VAS) at the beginning of the visit once the infusion sites have been
placed but no drug has yet been administered, then approximately at the top of every
hour during the visit, and at the end of the visit. Trial staff will also evaluate their infusion
sites to document any erythema or edema at the same times. If moderate or severe
pain is reported or swelling or redness occurs at the infusion site, the infusion site will
be replaced in a different location. If moderate or severe pain, swelling, or redness
continues at the old site for more than 30 minutes after the infusion site is removed, or
if moderate or severe pain, swelling, or redness occurs at the new site, all infusion
sites will be removed and the patient will be discontinued from the study.
•
From the start of closed loop control until approximately Hour 3, the patients will
continue to fast.
•
Between approximately Hour 3 and Hour 4, patients will be provided with a lunch meal
of their choice in the Diabetes Research Center from a menu of choices from nearby
restaurants. They will be asked to choose a meal that is a “typical meal” for them. The
content of their meal will not be restricted in any way, with the exception that the
number of carbohydrates should be in the “typical” range for them at lunch, and that
they must eat the same meal at the same time during both visits.
•
At approximately 15 minutes before the meal, patients will administer a bolus for the
meal with their own insulin pump based on the carbohydrate count for the meal.
•
After lunch is completed, the patients will not be allowed any carbohydrate intake
(non-caloric drinks will be permitted) until the trial is completed (except as necessary
to treat hypoglycemia), to allow the BP to control the post-prandial BG without further
interruption.
•
Between approximately Hour 6 and Hour 7, the patients will start a period of structured
exercise.
•
At the start of the exercise period, patients will restore their normal basal insulin profile
so that they will not have elevated insulin levels at the end of the study period when
they are to transition back to their usual care.
•
Patients will exercise on a stationary bike with a heart rate from 120-140 beats per
minute for a total of 4,000 heart beats (approximately 30 minutes). Patients will rate
their exercise intensity using the Borg scale every 5 minutes, with the target intensity
level between 12 and 14. Heart rate will be measured every 5 minutes.
Zealand Pharma A/S 
Clinical Trial Report ZP4207-16051 
Confidential & Proprietary 
Final Version 1.0, 10 November 2017 
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Clinical Trial Protocol 
ZP4207-16051 
Version number: 2.0 
Amendment 1.0 
Date: 28 June 2016 
Zealand Pharma A/S 
Confidential 
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•
BG measurements will be obtained off of the IV line every 10 minutes. If BG is
<80 mg/dL, BG measurements will be obtained off of the IV line every 5 minutes.
o
Carbohydrates will be given for any BG <50 mg/dL according to the following
protocol: Dextrose (g) = BSA (m2)/[1.7 m2 (women) or 1.9 m2 (men)] *15 g.
o
Repeat treatments will be given at 15-minute intervals as long as BG remains
<50 mg/dL.
•
If there is an interruption in the Dexcom CGM output, trial staff will assist the patient in
recovering CGM data streaming. If this requires replacement of the CGM sensor, BGs
will be checked every 10 minutes (every 5 minutes if BG is <80 mg/dL) using blood
from the IV until the CGM is able to be calibrated again. These BGs will be entered
into the BP, which will treat them as CGM values and dose insulin and/or glucagon
appropriately.
•
If there is a complete failure of the BP operation, patients will take over their own BG
control using their personal insulin pump until the BP can be brought back online. If BP
control cannot be promptly resumed (e.g., within 30 minutes), the patient may be asked
to repeat that trial day once.
•
Patients may choose to withdraw from the trial at any time. If they withdraw from the
trial, they should alert a provider immediately.
•
Just prior to the end of the study visit, vital signs including body temperature and blood
pressure will be obtained and a 12-lead ECG will be performed.
•
After approximately Hour 8, but not earlier than at least 60 minutes after end of
exercise, the BP will be stopped and the patient will continue with their personal insulin
pump.
•
The maximum amount of blood loss per study visit will be approximately 230 mL. The
total blood loss for the entire study will be up to 460 mL.
•
Patients will answer questionnaires (see Appendix C).
•
Chemistry and hematology samples will be collected at visit end (see Appendix B).
•
The BP and glucose meters will be collected and downloaded.
•
A trial MD will review the last several hours of insulin and glucagon dosing and assist
the patient in resuming their usual diabetes care. They will be instructed to call trial
staff with any questions, issues, or concerns.
7.4.2 
Data Collected During the Treatment Visits 
•
CGM glucose every 5 minutes from the Dexcom G4 Platinum CGM
•
All BG measurements taken
•
Insulin total dose by the BP and the patient’s own insulin pump
•
Glucagon total dose
•
Timing and content of the meal eaten and carbohydrate amount
•
Timing of meal announcement and size of meal announced
•
Timing and glucose values at calibrations
•
Timing and amount of carbohydrates taken for hypoglycemia
•
Data from a questionnaire about attitudes and expectations regarding the BP before
and after each treatment arm (see Appendix C)
•
Time patients were not under BP control for any reason
•
List of technical faults associated with the BP including cause and resolution
•
ZP4207/glucagon sampling will be collected at least hourly. If BG is <150 mg/dL, more
frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the
Investigator.
Zealand Pharma A/S 
Clinical Trial Report ZP4207-16051 
Confidential & Proprietary 
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Clinical Trial Protocol 
ZP4207-16051 
Version number: 2.0 
Amendment 1.0 
Date: 28 June 2016 
Zealand Pharma A/S 
Confidential 
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•
Plasma glucose sampling will be collected at least hourly in parallel with
ZP4207/glucagon exposure sampling. If BG is <150 mg/dL, then sampling will be every
30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is
<80 mg/dL, then sampling will be every 10 minutes.
•
Nausea and infusion site pain on a VAS at visit start (after insertion and before any
drug administration), hourly, and at visit end
•
Infusion site reaction according to the Draize scale at visit start (after insertion and
before any drug administration), hourly, and at visit end
•
Patient reports of symptoms, any other complaints, and AEs
•
Vital signs including body temperature and blood pressure (at visit start and visit end)
and weight
•
Concomitant medications
•
Chemistry and hematology samples (see Appendix B) at visit start and visit end
•
ADA (Visit 3 only)
•
12-lead ECG at visit start and visit end
•
Urine HCG pregnancy test for women of childbearing potential
7.4.3 
Response to Hypoglycemia 
•
Patients are encouraged to check their BG for any symptoms of hypoglycemia.
•
Patients will be permitted to take 15 grams of carbohydrates for any BG value
<60 mg/dL. Trial staff will ensure proper functioning of the BP, infusion set, and insulin
pump, and will encourage the patient to wait for the BP to treat the low blood sugar for
as long as they feel comfortable.
•
Patients will be required to take 15 grams of carbohydrates for any BG value
<50 mg/dL. After treatment of hypoglycemia, a follow-up measurement will be taken
15 minutes later. Repeated measurements will be taken every 15 minutes until the
BG is >60 mg/dL. Treatment will be repeated if subsequent BG values are still
<50 mg/dL. All carbohydrate treatments for hypoglycemia will be documented by trial
staff (amount and time).
•
Trial staff will check the infusion site, BP, and insulin pump for normal operation any
time hypoglycemia occurs. If there is any suspicion of infusion set malfunction, the site
should be replaced. Trial staff will check the BP for any malfunction and correct any
problems that are found.
•
If no correctable fault is found, but there is doubt regarding the correct function of the
BP system, an entirely new backup BP system may be started.
•
If a patient experiences a seizure or unconsciousness associated with hypoglycemia,
his or her participation in the trial will be discontinued.
7.4.4 
Response to Hyperglycemia 
•
Trial staff will check the infusion site, BP, and insulin pump for normal operation any
time BG is >300 mg/dL. If there is any suspicion of infusion set malfunction, the site
should be replaced. Trial staff will check the BP for any malfunction and correct any
problems that are found. If the BG remains >300 mg/dL for 2 hours despite
troubleshooting, blood ketones will be measured. If the blood ketone result is
>1.5 mmol/L, the visit will be stopped and rescheduled. The patient will be provided
with insulin and a syringe to give an injection based on their correction factor.
•
If a patient experiences diabetic ketoacidosis, his or her participation in the trial will be
discontinued.
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Clinical Trial Protocol 
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Amendment 1.0 
Date: 28 June 2016 
Zealand Pharma A/S 
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•
If no correctable fault is found, but there is doubt regarding the correct function of the
BP system, the treatment visit may be stopped and the visit rescheduled.
7.4.5 
Response to Nausea/Vomiting 
If significant nausea (e.g., that prevents the patient from eating normally) or any vomiting 
occurs, trial staff will notify the Investigator. Trial staff will assist the patient in troubleshooting, 
such as checking BG and the calibration of the CGM (excessive glucagon dosing may occur 
if the CGM is reading lower than the true BG). If a patient experiences persistent nausea and 
vomiting thought to be related to glucagon dosing, his or her participation in the trial will be 
discontinued. 
7.4.6 
Response to Other Medical Needs  
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911.  
7.4.7 
Monitoring of Bionic Pancreas Performance 
Bionic pancreas inventors and developers 
, 
, and/or an 
engineer trained by them will be readily available by phone for consultation for the trial staff at 
all times during the course of the trial.  
7.4.8 
Supervision by Trial Staff  
A trial MD will be on call at all times during the course of the trial. An RN or MD will be with 
the trial patients in the Diabetes Research Center at all times. 
7.5 
Phone Call (Visit 5) 
A phone call will be conducted 7 days ±3 days following the last day of dosing (Visit 4) to 
review AEs and concomitant medications. 
7.6 
Follow-up Visit (Visit 6) 
Patients will return for a Follow-up Visit 25 days ±4 days following the last day of dosing 
(Visit 4), for chemistry, hematology, and ADA sampling, and a review of AEs and concomitant 
medications.  
8 
ENDPOINTS  
8.1 
Primary Endpoint 
The primary endpoint is the safety and tolerability of ZP4207 and the iLet as assessed by: 
•
Number and type of AEs
•
Clinical laboratory measurements
•
Vital signs
•
12-lead ECG
•
Local tolerability and infusion site reactions as measured with the Draize scale
•
Immunogenicity as measured by ADA
•
Pain as measured on a 10 cm VAS
•
Nausea as measured on a 10 cm VAS
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Clinical Trial Protocol 
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Date: 28 June 2016 
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8.2 
Secondary Endpoints 
The secondary endpoints for the iLet and ZP4207 include measurements of BP function as 
well as glycemic and non-glycemic measurements. 
8.2.1 
Bionic Pancreas Function  
This endpoint data will be generated from the BP data during each treatment visit: 
•
Average percent insulin dose amounts calculated by the BP control algorithm that are
successfully delivered by the pump
•
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully delivered by the pump
•
Average percent dose amounts successfully issued to the pump by the BP control
algorithm that are successfully delivered by the pump (calculated doses are not issued
unless the pump is accessible and its delivery channel is available)
o
Average percent insulin dose amounts successfully issued to the pump by the
BP control algorithm that are successfully delivered by the pump
o
Average percent glucagon/ZP4207 dose amounts successfully issued to the
pump by the BP control algorithm that are successfully delivered by the pump
•
Average percent dose amounts calculated by the BP algorithm that are successfully
issued to the pump by the BP (calculated doses are not issued unless the pump is
accessible and its delivery channel is available)
o
Average percent insulin dose amounts calculated by the BP control algorithm
that are successfully issued by the BP
o
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully issued by the BP
•
Average percent of 5-minute steps during which the BP is functioning nominally in all
respects based on real-time CGM data (new CGM glucose reading captured, dose
calculated, and dose issued to pumps)
•
Average percent of 5-minute steps during which the BP is functioning nominally with
or without a new CGM glucose reading captured (dose calculated and dose issued to
pumps). If a CGM signal is not available, the dose calculated may be based on weight
or historical basal rates.
•
CGM reliability index, calculated as percent of possible values actually recorded by
CGM
•
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter
download
•
List of technical faults associated with the BP including cause and resolution
8.2.2 
Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit. 
•
Fraction of time spent within each of the following glucose ranges:
o
<50 mg/dL
o
<60 mg/dL
o
<70 mg/dL
o
70-120 mg/dL
o
70-140 mg/dL
o
70-180 mg/dL
o
>180 mg/dL
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Clinical Trial Report ZP4207-16051 
Confidential & Proprietary 
Final Version 1.0, 10 November 2017 
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Clinical Trial Protocol 
ZP4207-16051 
 
 
Version number: 2.0 
Amendment 1.0 
Date: 28 June 2016 
 
Zealand Pharma A/S 
Confidential 
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o >250 mg/dL 
o >300 mg/dL 
• 
Number of severe hypoglycemic events (patients unable to self-treat, requiring the 
assistance of another person) 
• 
Number of episodes of symptomatic hypoglycemia 
• 
Number of carbohydrate interventions for hypoglycemia 
• 
Total grams of carbohydrates taken for hypoglycemia 
• 
Mean CGM glucose 
8.2.3 
Non-glycemic  
• 
Glucagon/ZP4207 total delivery per kg of body mass 
• 
Insulin total delivery per kg of body mass 
• 
Number of unscheduled infusion set replacements 
• 
Number of unscheduled CGM sensor changes 
9 
LABORATORY ASSESSMENTS 
Descriptions of sample handling and sample processing, storage, and shipment at the site will 
be included in the laboratory manual. 
 
The responsible laboratories are listed in the address list. 
 
9.1 
Safety Laboratory Assessments 
Chemistry and hematology samples will be collected at specified time points. See Appendix A 
for the schedule of procedures and Appendix B for a list of clinical laboratory analytes. 
 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) 
At Visit 3 and Visit 4, plasma glucose samples will be taken from the IV at least hourly in 
parallel with ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT 
Plus. If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for 
glucose measurements. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is 
<100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will 
be every 10 minutes. The actual time of sampling will be recorded in the eCRF. 
 
9.3 
Exposure Assessments (ZP4207 and Glucagon) 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the 
discretion of the Investigator. The actual time of sampling will be recorded in the eCRF. 
 
Bioanalytical Reports will be prepared. 
 
9.4 
Anti-drug Antibody Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken at Visit 3 and the Follow-up Visit 6. 
 
A Bioanalytical Report will be prepared. 
Zealand Pharma A/S 
Clinical Trial Report ZP4207-16051 
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Clinical Trial Protocol 
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10 
SAFETY REPORTING 
10.1 
Adverse Events 
An AE is any untoward medical occurrence in a trial patient administered an IMP and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be 
any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not considered related to 
the IMP. Patients should be instructed to report any AE they experience to the Investigator. 
Note: This includes events from the first trial-related activity from Visit 3. 
AEs for ZP4207 include: 
•
A clinically significant worsening of a concomitant illness
•
A clinical laboratory abnormality which is clinically significant, i.e., any abnormality that
suggests a disease and/or organ toxicity and is of a severity that requires active
management. Active management includes active treatment or further investigations,
for example, change of medicine dose or more frequent follow-up due to the
abnormality.
•
Hypoglycemic episodes  
•
Injection site reactions
The following should not be recorded as AEs, if recorded prior to randomization (on the 
Screening Form or the eCRF): 
•
Pre-planned procedure, unless the condition for which the procedure was planned has
worsened from the first trial-related activity from Visit 3. 
•
Pre-existing conditions found as a result of screening procedures (pre-existing
conditions should be reported as medical history or concomitant illness). 
For known (listed) AEs for Glucagon and Humalog, please refer to SPC for Glucagon and 
Humalog. 
10.1.1 
Follow-up of Adverse Events 
All AEs that are ongoing at the end of the patient’s participation in the trial will be followed-up 
until the event is resolved or reaches a satisfactory outcome as deemed by the Investigator. 
Follow-up actions for all serious adverse events (SAEs) will be performed according to 
appropriate clinical care practices and may depend on the nature of the event. These will be 
determined after internal review and/or Sponsor review. The follow-up information should only 
include new (updated and/or additional) information that reflects the situation at the time of the 
Investigator’s signature. 
Follow-up information on (S)AEs will be updated using the (S)AE Form. If a non-serious event 
becomes serious during the follow-up, the AE Form and SAE Form must be used and reporting 
timelines follow those of an SAE. 
The Investigator must forward follow-up information on SAEs, and if previously non-serious 
AEs become SAEs, to the Sponsor. 
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Clinical Trial Protocol 
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10.1.2 
Precautions 
Normal precautions taken for a human trial will be taken during this trial. Qualified and 
well-trained physicians and medical staff will instruct the patients. During a patient’s 
participation in the trial, the Investigator should ensure that adequate medical care is provided 
to the patient for any AEs, including clinically significant laboratory values related to the trial. 
The Investigator should inform the patient when medical care is needed for intercurrent 
illnesses of which the Investigator becomes aware.  
For further information on safety precautions for ZP4207, Lilly glucagon, Lilly Humalog, and 
the iLet, please refer to the current version of the Investigator’s Brochure (IB) for ZP4207 
(Zealand Pharma A/S, 2015, or any updates hereof), and the SPC for Glucagon (Eli Lilly, 
2012) and Humalog (Eli Lilly, 2015), respectively. 
10.1.3 
Assessment of Adverse Events by the Investigator 
Intensity of an Adverse Event 
The maximum intensity (severity) of all AEs must be assessed by the Investigator and 
documented. Severity should be graded when the AE outcome is known: 
•
Mild: A type of AE that is usually transient and may require only minimal treatment or
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
•
Moderate: A type of AE that is usually alleviated with additional specific therapeutic
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the patient. 
•
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects
clinical status, or may require intensive therapeutic intervention. 
A “severe” reaction does not necessarily deem the AE as “serious,” and an SAE may not be 
“severe” in nature. 
Causality Relationship to IMP 
Insulin (insulin lispro, Lilly Humalog), glucagon (glucagon for injection, Eli Lilly), and ZP4207 
are all regarded as IMP. 
The causality of each AE should be assessed by the Investigator according to the following 
classification: 
•
Related: Good reason and sufficient documentation to assume a causal relationship.
•
Not related: No relationship to trial product can be established.
Outcome of an Adverse Event 
The outcome of all AEs must be assessed by the Investigator and documented by his/her 
staff. The following definitions should be used: 
•
Recovered/resolved: The patient has fully recovered, or by medical or surgical
treatment the condition has returned to the level observed at the first trial-related 
activity from Visit 3. 
•
Recovering/resolving: The condition is improving and the patient is expected to recover
from the event. This term is only applicable if the patient has completed the trial.
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• 
Recovered/resolved with sequelae: The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment, or procedure. If a sequela meets 
an SAE criterion, the AE must be reported as an SAE. 
• 
Not recovered/not resolved: The condition of the patient has not improved and the 
symptoms are unchanged, or the outcome is not known. 
• 
Fatal: This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he/she died should 
be assessed as “recovered/resolved,” “recovering/resolving,” “recovered/resolved with 
sequelae,” or “not recovered/not resolved.” An AE with a fatal outcome must be 
reported as an SAE. 
• 
Unknown: This term is only applicable if the patient is lost to follow-up. 
 
10.2 
Serious Adverse Events   
An SAE is any untoward medical occurrence that at any dose:  
• 
Results in death  
• 
Is life-threatening  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Medically important 
 
Medical judgement must be exercised in deciding whether an AE is believed to be “medically 
important.” Medically important events may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above. 
 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is an AE fulfilling one of the criteria of seriousness and being assessed as related 
to an IMP, the nature or severity of which is not consistent with the applicable reference 
document (e.g., ZP4207 IB or package leaflet/SPC for an approved product). 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety, any life-threatening problem or 
death caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the application; or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. 
 
10.3 
Adverse Event Reporting – Procedures for Investigators  
The Principal Investigator and co-investigators will review any AEs and report any SAEs to 
the Sponsor as soon as possible and within 24 hours of obtaining knowledge of the event. The 
Principal Investigator and co-investigators will promptly report AEs to the Partner’s Institutional 
Review Board (IRB) and to the BU IRB (unless oversight is ceded by the BU IRB to the 
Partners IRB), in accordance with local requirements.  
 
Ed Damiano is the Sponsor of the Investigational Device Exception for the BP and Zealand 
Pharma A/S is the Sponsor of the IND for ZP4207.  
 
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 The following must be collected:  
•
Initial information of the pregnancy
•
Information on the outcome of the pregnancy, including the health status of the
newborn infant(s) at the age of 1 month
•
All AEs in connection with the pregnancy and pregnancy outcome must be reported
on the pregnancy forms. It must be clear in the description if the event occurs in the
patient/patient’s partner, the fetus, or the newborn infant.
•
All SAEs in connection with the pregnancy and pregnancy outcome must be reported
on the pregnancy forms following the same timelines as required for other SAEs. It
must be clear in the description if the event occurs in the patient/patient’s partner, the
fetus, or the newborn infant.
The SAEs that must be reported include abnormal outcome – such as congenital anomalies, 
fetal death, and termination of pregnancy (spontaneous or elective abortion), including any 
anomalies of the fetus observed at gross examination or during autopsy – as well as other 
pregnancy complications (ectopic pregnancy) fulfilling the criteria of an SAE. 
10.5 
Hypoglycemia 
Hypoglycemia will be regarded as an AE and will be recorded and documented on an AE 
Form. For the purposes of AE reporting, the following definitions of hypoglycemia will be used: 
•
Symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia
are accompanied by a BG concentration ≤70 mg/dL 
•
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of
hypoglycemia but with a BG concentration ≤50 mg/dL 
•
Severe hypoglycemia: an event requiring assistance of another person to actively
administer carbohydrates, glucagon, or take other corrective actions 
10.6 
Safety Monitoring 
10.6.1 
Data and Safety Monitoring Board 
An external DSMB will oversee the conduct of the trial, as set forth in the DSMB Charter. 
Additionally, the DSMB will be informed in the event of any serious and unexpected AEs. The 
DSMB will be informed if there are any changes to the trial protocol that could significantly 
impact the safety or scientific validity of the trial. A final DSMB meeting will convene after the 
completion of the trial. 
The participation of individual patients will be discontinued if they experience: 
•
Seizure or unconsciousness associated with hypoglycemia and associated with
participation in the trial 
•
Persistent nausea and vomiting thought to be related to glucagon dosing associated
with participation in the trial 
•
Hospitalization associated with participation in the trial
•
Pregnancy
•
Diabetic ketoacidosis
If more than 1 patient must be withdrawn from the trial for these reasons, the trial will stop and 
a vote of the DSMB will be required to restart it. All AEs that are serious and unexpected but 
related will be reported to the DSMB within 5 working days. 
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Note that patients may discontinue participation at any time. Patients may be removed from 
the trial for other reasons, for instance, failure to comply with trial procedures or intercurrent 
illness that is unrelated to the BP but that precludes safe participation. Discontinuation of 
participation for these reasons will not contribute to a decision to discontinue the trial.  
10.6.2 
Zealand Pharma Safety Committee 
The internal Zealand Pharma Safety Committee is constituted to perform ongoing safety 
surveillance of clinical trials within ZP4207, including this trial. 
If safety signals are observed either based on reported SAEs, periodic review of laboratory 
parameters, planned review of all AEs reported between the safety committee meetings, or 
on notification of significant findings, the Safety Committee will take appropriate measures to 
safeguard the patients. 
11 
STATISTICS 
11.1 
Analysis Populations 
The following analysis sets are defined in accordance with the ICH-E9 guidance: 
The Full Analysis Set is based on the intention-to-treat principle and includes all randomized 
patients. In exceptional cases, patients from the Full Analysis Set may be excluded (will be 
decided in the database review [DBR] meeting). In such cases, the exclusion will be justified 
and documented. Patients will contribute to the evaluation “as randomized.” 
The Per-Protocol Set includes all patients of the Full Analysis Set who completed the trial 
without any major protocol violations. Patients in the Per-Protocol Set will contribute to the 
evaluation “as treated.” This analysis will only be used if it is different than the Full Analysis 
Set. 
The Safety Analysis Set includes all patients receiving at least 1 dose of the IMP. Patients in 
the Safety Analysis Set will contribute to the evaluation “as treated.”  
Analyses of efficacy endpoints will be based on the Full Analysis Set (and the Per-Protocol 
Set if necessary). This decision will be made in the DBR meeting. The analysis of the safety 
endpoints will be based on the Safety Analysis Set.  
Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. At this time, it will be 
determined if patients and/or data should be excluded from the analysis. Furthermore, outliers 
will be identified by data review according to ICH-E9. 
Obviously erroneous data points may be excluded from the analyses or re-analyzed 
(e.g., serum concentrations). The decision to re-analyze or exclude data points from the 
statistical analysis is the joint responsibility of the Sponsor, the Principal Investigator, and the 
Trial Statistician. 
The patients or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to database release. The documentation 
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will be stored together with the remaining trial documentation. The patients and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report. 
11.2 
Statistical Methods  
Medpace will be responsible for the statistical analysis. The statistical planning and conduct 
of analyses of the data from this trial will follow the principles defined in relevant ICH guidelines 
and Medpace’s biostatistical standard operating procedures (SOPs). A general description of 
the statistical methods to be used is given in this section, specific details will be provided in 
the Statistical Analysis Plan (SAP), which will be prepared before database lock. All statistical 
analyses will be performed using SAS® (SAS Institute Inc., Cary, North Carolina, USA), 
version 9.4 or later.  
11.2.1 
Analysis of Safety 
The following variables will be evaluated according to treatment for safety purposes: 
Adverse Events 
All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). Individual AEs will be presented in a listing including relationship to trial 
product/device, severity, and treatment period at onset. If more than 20 treatment-emergent 
AEs (AEs with onset after [first] dosing at Visit 3 until the Follow-up Visit 6) are registered, a 
summary table including number of AEs, number of patients with at least 1 AE, and percentage 
of exposed patients with at least 1 AE will be made by system organ class and treatment 
period at onset. 
Local Tolerability 
Local tolerability at the injection site will be summarized using descriptive statistics as 
appropriate. 
Laboratory Safety Assessments 
Laboratory assessments will be summarized. A listing of abnormal values will be provided. 
Physical Examination 
A frequency table will show the number and percentage of physical examination results. 
Vital Signs 
Vital signs will be summarized using descriptive statistics. 
12-lead ECG 
The Investigator’s evaluations of 12-lead ECGs will be summarized and abnormal individual 
evaluations will be listed together with the Investigator’s comments. Changes in 12-lead ECG 
between measurements will be recorded as AEs if the Investigator judges them to be clinically 
significant.  
11.2.2 
Analysis of Efficacy 
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
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The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis, any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. Further details will be included in the 
SAP. 
 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow.  
11.2.3 
Interim Analysis 
No interim analysis is planned. 
11.2.4 
Sample Size Determination 
No formal sample size calculations were made. It is expected that between 10 and 12 patients 
will be randomized in the trial. The sample size is based on a clinical rather than statistical 
rationale. The sample size is considered adequate to address the primary trial objective of 
exploring the safety of ZP4207 when used in the iLet and with reference to Lilly glucagon used 
in the iLet. 
12 
DATA MANAGEMENT AND RECORD KEEPING 
Data Management is the responsibility of Medpace. The complete Data Management process 
will be described in detail and agreed on in the Data Management Plan for this trial. 
 
12.1 
Data Handling 
Case Report Forms 
Electronic Case Report Forms will be used in this trial. The Data Management Department of 
Medpace will provide the eCRFs. All further information regarding the eCRFs and the data 
flow will be described and agreed on in the Data Management Plan. 
 
Device-Related Data 
During the trial, CGM data, calibration data, insulin dosing data, and glucagon dosing data will 
be automatically stored in the BP device (from which it will be downloaded at intervals), 
combined in a single database that will be compared against the primary data files for integrity, 
and ultimately transferred to Medpace.  
 
12.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
 
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12.3 
Data Entry 
Data must be recorded using the electronic data capture (EDC) system as the trial is in 
progress. The patient questionnaires will be transcribed into the EDC system by site 
personnel. All site personnel must log into the system using their secure user name and 
password in order to enter, review, or correct trial data. These procedures must comply with 
Title 21 of the Code of Federal Regulations (21 CFR Part 11) and other appropriate 
international regulations. All passwords will be strictly confidential. 
12.4 
Medical Information Coding 
Adverse events and medical history will be coded using the latest version of MedDRA. Prior 
and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. 
12.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, 
will be referred to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
12.6 
Record Keeping 
Medpace will be responsible for hosting the TMF. Records of patients, source documents, 
monitoring visit logs, eCRFs, inventory of trial product, regulatory documents, and other 
Sponsor correspondence pertaining to the trial must be kept in the appropriate trial files at the 
site. Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
evaluation and reconstruction of the clinical trial. Source data are contained in source 
documents (original records or certified copies). These records will be retained in a secure file 
for the period as set forth in the Clinical Trial Agreement. Prior to transfer or destruction of 
these records, the Sponsor must be notified in writing and be given the opportunity to further 
store such records. 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL 
13.1 
Ethical Conduct of the Trial 
The trial will be conducted according to Medpace, MGH, and/or the Sponsor’s written 
instructions (SOPs, working instructions, or process descriptions). Content and definitions of 
the written instructions are based on the Declaration of Helsinki and the ICH GCP.  
13.2 
Institutional Review Board  
Written favorable opinion must be obtained from the responsible IRB prior to commencement 
of the trial. Clinical trial submission and reporting requirements before, during, and after 
completion of the trial will be performed in accordance with national law and local regulations. 
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All amendments that affect patient safety or the trial integrity (substantial amendments) must 
not be implemented before favorable opinion has been obtained, unless necessary to 
eliminate hazards to the patients. Non-substantial amendments do not require favorable 
opinion by the IRB, but the respective IRB will be notified according to local requirements.  
 
The Sponsor and Investigator must approve any amendment in writing before its 
implementation. 
 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
IRB. The records should be filed in the Sponsor’s Trial Master File (TMF). 
 
13.3 
Informed Consent  
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirement(s) and adhere to the ICH GCP guideline and the 
requirements in the Declaration of Helsinki. 
 
Prior to any trial-related activity, the Investigator must give the patient oral and written 
information in a form that the patient can read and understand about all aspects of the trial 
that are relevant to the patient’s decision to participate. The patient will be given ample time 
to decide whether or not to participate in the trial. 
 
The patient must be informed that his/her personal trial-related data will be used in accordance 
with the local data protection law. The level of disclosure must also be explained to the patient. 
 
The patient must be informed that his/her medical records may be examined by authorized 
monitors or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
 
A voluntary, personally signed and dated ICF must be obtained from the patient prior to any 
trial-related activity. The ICF must also be signed and dated by the physician or designee who 
conducted the informed consent procedure. A signed copy of the ICF and any additional 
patient information must be given to each patient.  
 
The responsibility for taking informed consent must remain with that of a research physician 
or designee. If information becomes available that may be relevant to the patient’s willingness 
to continue participating in the trial, the Investigator must inform the patient in a timely manner, 
and a revised written informed consent must be obtained. 
 
Should a protocol amendment become necessary, the ICF may need to be revised to reflect 
the changes to the protocol. It is the responsibility of the Sponsor to ensure that an amended 
consent form is reviewed and has received favorable opinion from IRB, and the Investigator 
must ensure that the amended consent form is signed by all patients subsequently entered 
into the trial and those currently in the trial, if affected by the amendment. 
 
13.4 
Trial Monitoring Requirements  
The monitoring procedures for this trial are described in detail in the Monitoring Manual. The 
objectives of the monitoring procedures are to ensure that (i) the safety and rights of the trial 
patients are respected, (ii) that accurate, valid, and complete data are collected, and (iii) that 
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the trial is conducted in accordance with the trial protocol, the principles of GCP, and local 
legislation, including drug accountability. 
 
The monitor must be given direct access to the investigational site files and source documents 
(original documents, data, and records). Direct access includes permission to examine, 
analyze, verify, and reproduce any record(s) and report(s) that are important to evaluation of 
the clinical trial. 
 
Key tasks of the monitor include verifying the presence of informed consent, the adherence to 
the inclusion/exclusion criteria, the documentation of SAEs, and the recording of all safety and 
efficacy variables. The monitor will also confirm the completeness of patient records, the 
adherence to the protocol, ICH GCP, and the progress in patient enrollment and perform drug 
accountability.  
 
Because no information that could reveal the identity of patients may ever be removed from 
the trial site, the monitor will visit the site at regular intervals to perform these monitoring tasks. 
Other contact between the Investigator and monitors will be maintained as required through 
telephone calls and e-mail. The Investigator and/or key members of staff involved in the trial 
must be available to assist the monitors during all visits.  
 
Site Initiation Visit 
During the Site Initiation Visit (SIV) the CRO, Sponsor, and/or monitors will go through 
information on the IMP, the protocol, the eCRFs, and other key aspects of the trial with the 
Investigator and the key members of staff involved in the trial. The topics of the SIV are 
documented in a SIV report made available to the Investigator. Documentation on the SIV 
(e.g., power point presentation) should be filed by both Investigator and Sponsor. 
 
13.5 
Disclosure of Data 
Data generated by this trial must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal 
physician or other appropriate medical personnel responsible for their welfare. 
 
Patient medical information obtained during the trial is confidential and disclosure to third 
parties other than those noted above is prohibited. 
 
13.6 
Retention of Records  
Massachusetts General Hospital will maintain the patient’s medical file according to local 
regulations. MGH will archive the documentation pertaining to the trial in an archive after 
completion or discontinuation of the trial if not otherwise notified. MGH should not destroy any 
documents without prior permission from the Sponsor. 
 
The documentation includes all the raw data generated during the clinical trial, the 
investigational site files, and a copy of the clinical trial report. The documents will be retained 
for a period of at least 15 years at archives by MGH, or its sub-contractor. After this period, 
the Sponsor will be contacted and their advice sought on the return or further retention of the 
trial records. 
 
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The Sponsor will maintain the documentation pertaining to the trial in accordance with national 
regulations. 
13.7 
Publication Policy  
The Principal Investigator of the trial will review and sign the clinical trial report. A summary of 
the final clinical trial report will be submitted to the IRB and Competent Authority. 
According to the Declaration of Helsinki Investigators and Sponsors “have ethical obligations 
with regard to the publication and dissemination of the results of research.” The trial design 
and results may be published as one or more original research manuscripts/abstracts and 
presented at a scientific meeting. The Investigator and Sponsor reserve the right to review any 
proposed presentation of the results of this trial before they are submitted for publication. 
Authorship on any publication(s) resulting from this clinical trial will be assigned according to 
the recommendations of the International Committee of Medicinal Journal Editors. 
Participating patients will not be identified by name in any published reports about the clinical 
trial. 
The Sponsor is responsible for trial registration at ClinicalTrials.gov (www.clinicaltrials.gov) 
according to the requirements from the FDA. 
13.8 
Legal Aspects 
An implicit or explicit approval must be obtained from the Competent Authority prior to 
commencement of the trial. Clinical trial submission and reporting requirements before, during, 
and after completion of the trial will be performed in accordance with national law and local 
regulations. 
An implicit or explicit approval will also be mandatory before implementation of substantial 
changes. Non-substantial amendments do not require approval from the Competent Authority 
but will be notified according to local requirements. 
The Sponsor and Investigator must approve the amendment in writing before its 
implementation. 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
Competent Authority. The records should be filed in the Sponsor’s TMF. 
Audits and Inspections  
In the event of an audit, representatives of the Sponsor or designee, or national and 
international regulatory authorities may request access to all trial records for inspection and 
copying. Such access must be stated in the ICF signed by the patient. 
13.9 
Sponsor Discontinuation Criteria 
The Sponsor, Investigator, or a pertinent regulatory authority may decide to stop the trial or 
part of the trial at any time but agreement on procedures to be followed must be obtained. 
Conditions that may warrant termination of the clinical trial include, but are not limited to: 
•
Safety or administrative reasons
•
The discovery of an unexpected, relevant, or unacceptable risk to the patients enrolled
in the clinical trial
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•
A decision of the Sponsor to suspend or discontinue investigation of the IMP
If the trial is prematurely terminated or suspended, the Investigator should promptly inform the 
patients and assure appropriate therapy and follow-up. Furthermore, the Sponsor should 
promptly inform the IRB and provide a detailed written explanation. The pertinent regulatory 
authorities should be informed according to national regulations. 
If after the termination of the trial the risk/benefit analysis has changed, the new evaluation 
should be provided to the IRB in case it will have an impact on the planned follow-up of the 
patients who have participated in the trial. Necessary actions needed to protect the patients 
should be described. 
13.10 
Patient Compensation 
Financial compensation will be provided to all patients who complete the Screening Visit. 
Patients will be paid $25 for completing the Screening Visit whether or not they are eligible to 
participate in the trial. Patients will be compensated $25 for completing the Training Visit. 
Patients will be compensated $100 for completing each of the 2 treatment visits, $25 for 
completing the phone call, and $25 for completing the Follow-up Visit. Thus, the total 
compensation for a patient who completes the trial would be $300. Patients who are unable 
to complete the trial or choose to stop participation will receive prorated compensation for 
each visit. In addition to the monetary compensation, the cost of the patients’ lunch meals 
during their participation in the trial, as well as the patients’ parking at each visit, will be covered 
by trial funds.  
14 
TRIAL ADMINISTRATIVE INFORMATION 
14.1 
Protocol Amendments  
Any amendments to the trial protocol will be communicated to the Investigators by Medpace 
or the Sponsor. All protocol amendments will undergo the same review and approval process 
as the original protocol. A protocol amendment may be implemented after it has been 
approved by the IRB, unless immediate implementation of the change is necessary for patient 
safety. In this case, the situation must be documented and reported to the IRB within 5 working 
days. 
14.2 
Address List 
14.2.1 
Sponsor 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Telephone: +45 88 77 36 00 
Facsimile: +45 88 77 38 98 
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APPENDIX A: SCHEDULE OF PROCEDURES 
Trial Visit 
Visit 1 [1]
Screening 
Visit 2
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5]
(2nd Treatment 
Visit) 
Visit 5
Phone Call [6] 
Visit 6
Follow-Up [7] 
Informed consent 
X 
 
 
 
 
 
Assess/confirm elig bility 
X 
X 
 
 
 
 
Demographics 
X
Medical, surgical, and social history; 
allergies  
X 
 
 
 
 
 
Concomitant illness 
X 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Height, weight, physical examination, and 
vital signs including body temperature 
and blood pressure [8] 
X 
 
X [9] 
X [9] 
 
 
12-lead ECG 
X 
 
X [10] 
X [10] 
 
 
Urine HCG pregnancy test and menstrual 
history [11]   
X 
 
X 
X 
 
 
FSH [12] 
X 
 
 
 
 
 
Screening labs – HbA1c, optional 
fractionated metanephrines [13] 
X 
 
 
 
 
 
Safety lab sampling including chemistry 
and hematology 
X 
 
X [10] 
X [10] 
 
X 
Training on devices [14] 
 
X 
 
 
 
 
Monitored BP use 
 
 
X 
X 
 
 
Plasma glucose sampling [15] 
 
 
X 
X 
 
 
ZP4207/glucagon exposure sampling [16] 
 
 
X 
X 
 
 
Nausea and infusion site pain VAS and 
infusion site reaction Draize scale (visit 
start [17], hourly, & visit end) 
 
 
X 
X 
 
 
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Trial Visit 
Visit 1 [1]
Screening 
Visit 2
Training 
Visit 3 [2] [3] 
[4] [5] 
(1st Treatment 
Visit) 
Visit 4 [2] [3] [5]
(2nd Treatment 
Visit) 
Visit 5
Phone Call [6] 
Visit 6
Follow-Up [7] 
Standardized lunch [18] 
X 
X 
In-clinic exercise [19] 
X 
X 
Questionnaires (pre & post BP) 
X 
X 
ADA 
X [20] 
X 
Adverse event review 
X 
X 
X 
X 
1.
Once the patient has been enrolled and eligibility has been established, the order of the iLet visits will be randomized in blocks of 2 patients.
2.
Each patient will participate in 2 treatment visits: one with the iLet using ZP4207 and one with the iLet using Lilly glucagon in a randomized order. Up to 2 patients may participate in the
trial per day.
3.
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal skin and calibrate the sensor when prompted using the provided Nova StatStrip Xpress meter.
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the BP having fasted since 12 00 AM the night before (treatment with simple carbohydrate of up to 30 g
for a low is allowed). If the patient is not fasted, the visit will be rescheduled within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the visit window.
4.
Visit 3 will take place at least 48 hours after screening (Visit 1) and no more than 30 days after screening (Visit 1).
5.
There will be a 24-hour minimum washout between Visit 3 and Visit 4 and a maximum of 3 weeks between Visit 3 and Visit 4.
6.
Visit 5 will take place 7 days ±3 days from Visit 4.
7.
Visit 6 will take place 25 days ±4 days from Visit 4.
8.
Height and physical examination will be measured at Visit 1 only.
9.
Vital signs including body temperature and blood pressure will be obtained at visit start and visit end.
10.
At visit start and visit end.
11.
Urine HCG pregnancy test only for women of childbearing potential. The date of the last menstrual period in female patients will be obtained at Visit 1 only.
12.
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year.
13.
If indicated by history.
14.
Patients will be trained in the insertion and calibration of the Dexcom G4 sensor and trial policies and procedures.
15.
Collected at least hourly. If BG is <150 mg/dL, then sampling will be every 30 minutes. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will
be every 10 minutes.
16.
Collected at least hourly. If BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at the discretion of the Investigator.
17.
Once the infusion sites have been placed but no drug has yet been administered.
18.
Between approximately Hour 3 and Hour 4.
19.
Between approximately Hour 6 and Hour 7.
20.
Before the start of dosing.
ADA = anti-drug antibodies; BG = blood glucose; BP = bionic pancreas; CGM = continuous glucose monitor; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
HbA1c = hemoglobin A1c; HCG = human chorionic gonadotropin; VAS = visual analog scale.
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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Chemistry 
Alanine aminotransferase 
Aspartate aminotransferase 
Alkaline phosphatase 
Total protein 
Albumin 
Total and direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Creatinine 
Estimated glomerular filtration rate 
Blood urea nitrogen 
Uric acid
Bicarbonate 
Sodium 
Potassium 
Calcium 
Chloride 
Phosphorus 
 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell count 
White blood cell count and differential 
Platelets 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
 
Pregnancy Test 
A urine HCG pregnancy test will be performed at screening, Visit 3, and Visit 4 only for 
women of childbearing potential. 
 
Anti-drug Antibody Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken prior to first dosing (Visit 3) and at the Follow-up Visit (Visit 6). 
 
ZP4207/Glucagon Exposure Sampling 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <150 mg/dL, more frequent samples for plasma ZP4207/glucagon may be drawn at 
the discretion of the Investigator. 
 
Screening Visit Only 
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year 
Optional fractionated plasma metanephrines (if indicated by history) 
Hemoglobin A1c 
 
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APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES 
Diabetes Treatment Satisfaction Questionnaire - Status (DTSQs) 
The DTSQs measures patient satisfaction with diabetes treatment. It consists of a 6 item scale 
for assessing treatment satisfaction and two additional items assessing perceived frequency 
of hyperglycemia and hypoglycemia. The DTSQs is meant for adults and older children. 
Dr. Clare Bradley has produced a version that is appropriate for bionic pancreas studies for 
this use, along with a version for younger children. It is administered before the intervention. 
The DTSQs is valid and reliable. Administration time is less than 5 minutes. 
Diabetes Treatment Satisfaction Questionnaire – Change (DTSQc) 
Although the DTSQ is responsive to treatment changes, ceiling effects are often seen with this 
instrument, where maximum or close-to-maximum scores at baseline provide little opportunity 
for registering improvement. The DTSQc contains the same items as the DTSQs version but 
asks patients to consider their satisfaction with their current treatment compared with their 
previous treatment. The DTSQc is meant for adults and older children. Dr. Clare Bradley has 
produced a version that is appropriate for bionic pancreas studies for our use, along with a 
version for younger children. It is administered during and at the end of the intervention. The 
DTSQc is valid and reliable. Administration time is less than 5 minutes. 
T1-Diabetes Distress Scale (T1-DDS) 
The T1-DDS is a 28-item survey that assesses seven sources of diabetes distress for type 1 
adults. It captures feelings of powerlessness; management distress; hypoglycemia distress; 
negative social perceptions by others; eating distress; physician (health care) distress; and 
friend/family distress. Items are scored on a 6-point scale from not a problem to a very serious 
problem. It is administered before, during, and at the end of the intervention. The scale is valid 
and reliable, and has been shown to be sensitive to change over time. Administration time is 
5 minutes. 
Problem Areas in Diabetes Survey (PAID) 
There are three versions of the PAID: Teen (PAID-T), Parent (PAID-P), and Child (PAID-C) 
versions. This measure of diabetes-specific emotional distress in youth with diabetes and their 
parents is 26 items. A total score is generated. It is administered before, during, and at the 
end of the intervention. The PAID-T and PAID-P are valid and reliable. Psychometric analysis 
of the PAID-C is in progress. Administration time is 5 minutes. 
Hypoglycemia Fear Survey (HFS) 
There are three versions of the HFS, Adult (HFS), Youth (HFS-Y) and Parent (HFS-P). The 
HFS measures several dimensions of fear of hypoglycemia among adults with type 1 diabetes. 
It consists of 23 items and produces two sub-scale scores; a Behavior sub-scale that 
measures behaviors involved in avoidance and/or over-treatment of hypoglycemia and a 
Worry sub-scale that measures anxiety and fear surrounding hypoglycemia. The HFS-Y 
consists of 25 items and the HFS-P consists of 26 items; both produce sub-scale scores 
similar to the Adult HFS. It is administered before, during, and at the end of the intervention. 
All versions of the HFS are valid and reliable. Administration time is 5-10 minutes. 
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Impact of Daily Diabetes Demands (IDDD) 
There are four versions of the IDDD; Adult (IDDD-A), Youth (IDDD-Y), Parent (IDDD-P), and 
Significant Other (IDDD-SO). This instrument measures the burden related to the demands of 
the daily diabetes regimen and is 22 items. A total score is generated. It is administered before, 
during, and at the end of the intervention. Psychometric analysis of the IDDD-Y is in progress 
using the data from the second Bionic Pancreas Camp Study in pre-adolescent children, and 
of the IDDD-A is in progress using data from the Bionic Pancreas Multicenter Study in adults. 
Administration time is 5 minutes. 
Bionic Pancreas User Opinion Survey (BPUOS) 
There are four versions of the BPUOS; Adult (BPUOS-A), Youth (BPUOS-Y), Parent 
(BPUOS-P), and Significant Other (BPUOS-SO). This measure assessing both the benefits 
from, and difficulties with, use of the bionic pancreas, and consists of 38 items. A total score 
is generated. It is administered during and at the end of the intervention. Psychometric 
analysis of the BPUOS-Y is in progress using the data from the second Bionic Pancreas Camp 
Study in pre-adolescent children, and of the BPUOS -A is in progress using data from the 
Bionic Pancreas Multicenter Study in adults. Administration time is 10 minutes. 
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CLINICAL TRIAL PROTOCOL 
The iLet Feasibility Trial Testing the iLet, a Fully Integrated Bihormonal Bionic 
Pancreas with ZP4207 
Investigational Product: ZP4207 
Protocol Number: ZP4207-16051 
Phase: 2  
Principal Investigator: 
Steven J. Russell, MD, PhD1 
Co-Investigator: 
, MD1 
1Diabetes Research Center, Massachusetts General Hospital, Boston, Massachusetts 
Sponsor: 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Tel: +45 88 77 36 00 
Fax: +45 88 77 38 98 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Zealand Pharma A/S except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical trial for Zealand Pharma A/S. 
You are allowed to disclose the contents of this document only to your Institutional Review 
Board (IRB) and trial personnel directly involved with conducting this protocol. Persons to 
whom the information is disclosed must be informed that the information is confidential and 
proprietary to Zealand Pharma A/S and that it may not be further disclosed to third parties. 
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INVESTIGATOR AGREEMENT 
By signing below I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary 
details for carrying out the trial as described. I will conduct this trial in accordance with the 
design and specific provision of this protocol and will make a reasonable effort to complete 
the trial within the time designated. I will provide copies of this protocol and access to all 
information furnished by Zealand Pharma A/S to trial personnel under my supervision. I will 
discuss this material with them to ensure they are fully informed about the trial product and 
trial procedures. I will let them know that this information is confidential and proprietary to 
Zealand Pharma A/S and that it may not be further disclosed to third parties. I understand that 
the trial may be terminated or enrollment suspended at any time by Zealand Pharma A/S, with 
or without cause, or by me if it becomes necessary to protect the best interests of the trial 
patients. 
I agree to conduct this trial in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Ethic Committee Regulations and ICH Guidelines for Good Clinical 
Practices. 
______________________________________________ 
____________________ 
Investigator’s Signature 
Date 
______________________________________________ 
Investigator’s Printed Name 
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SYNOPSIS 
TITLE: The iLet Feasibility Trial Testing the iLet, a Fully Integrated Bihormonal Bionic 
Pancreas with ZP4207 
PROTOCOL NUMBER: ZP4207-16051 
INVESTIGATIONAL PRODUCT: ZP4207 
PHASE: 2 
INDICATION: ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid 
formulation which is being studied to improve glycemic control in adults (and children) with 
type 1 diabetes mellitus (T1DM) as part of a bihormonal bionic pancreas (BP). 
OBJECTIVES: 
Primary: The primary objective is to conduct a trial testing the safety and tolerability of the 
iLet when used with ZP4207 in 10 adult (≥18 years of age) patients with T1DM. 
Secondary: The secondary objectives are to measure glycemic regulation, including 
hypoglycemia exposure (percent of time spent with continuous glucose monitor [CGM] 
glucose <60 mg/dL), evaluate BP device reliability, and to document the satisfaction of 
patients with the iLet with the goal of optimizing the functionality and user interface of the iLet. 
POPULATION: Up to 20 adult (≥18 years of age) patients who already manage their T1DM 
using continuous subcutaneous (SC) insulin infusion pump therapy can be enrolled. 
TRIAL DESIGN: This trial is a single-center, open-label, randomized cross-over trial. The trial 
will enroll adult patients with T1DM and will assess the safety and efficacy of the iLet using 
the glucagon analog ZP4207 versus the iLet using Lilly glucagon. The iLet will also administer 
insulin (insulin lispro, Lilly Humalog) using the same blood glucose (BG) control algorithm for 
both treatment arms. The trial will be conducted at a single center, the Massachusetts General 
Hospital Diabetes Center in Boston, MA. 
TRIAL TREATMENT: The trial involves SC administration of insulin lispro (Humalog, Lilly), 
which is commercially available by prescription and is indicated for patients with T1DM, but 
not for use in a BP. 
The trial also involves SC administration of Lilly glucagon in one iLet arm. Lilly glucagon is 
commercially available by prescription and is indicated for patients with T1DM in severe 
hypoglycemia, but not for use in a BP.  
The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, in the 
other iLet arm. ZP4207 will be made available by Zealand Pharma A/S, Denmark as liquid 
formulation in prefilled syringes of 0.6 mL. 
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PRIMARY ENDPOINT: 
The primary endpoint is the safety and tolerability of ZP4207 and the iLet as assessed by: 
• 
Number and type of adverse events (AEs) 
• 
Clinical laboratory measurements 
• 
Vital signs 
• 
12-lead electrocardiogram (ECG) 
• 
Local tolerability and infusion site reactions as measured with the Draize scale 
• 
Immunogenicity as measured by anti-drug antibodies 
• 
Pain as measured on a 10 cm visual analog scale (VAS) 
• 
Nausea as measured on a 10 cm VAS 
 
SECONDARY ENDPOINTS: 
The secondary endpoints for the iLet and ZP4207 include measurements of BP function as 
well as glycemic and non-glycemic measurements. 
 
Bionic Pancreas Function 
This endpoint data will be generated from the BP data during each treatment visit: 
• 
Average percent insulin dose amounts calculated by the BP control algorithm that are 
successfully delivered by the pump 
• 
Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts successfully issued to the pump by the BP control 
algorithm that are successfully delivered by the pump (calculated doses are not issued 
unless the pump is accessible and its delivery channel is available) 
o Average percent insulin dose amounts successfully issued to the pump by the 
BP control algorithm that are successfully delivered by the pump 
o Average percent glucagon/ZP4207 dose amounts successfully issued to the 
pump by the BP control algorithm that are successfully delivered by the pump 
• 
Average percent dose amounts calculated by the BP algorithm that are successfully 
issued to the pump by the BP (calculated doses are not issued unless the pump is 
accessible and its delivery channel is available) 
o Average percent insulin dose amounts calculated by the BP control algorithm 
that are successfully issued by the BP 
o Average percent glucagon/ZP4207 dose amounts calculated by the BP control 
algorithm that are successfully issued by the BP 
• 
Average percent of 5-minute steps during which the BP is functioning nominally in all 
respects based on real-time CGM data (new CGM glucose reading captured, dose 
calculated, and dose issued to pumps)  
• 
Average percent of 5-minute steps during which the BP is functioning nominally with 
or without a new CGM glucose reading captured (dose calculated and dose issued to 
pumps). If a CGM signal is not available, the dose calculated may be based on weight 
or historical basal rates. 
• 
CGM reliability index, calculated as percent of possible values actually recorded by 
CGM 
• 
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter 
download 
• 
List of technical faults associated with the BP including cause and resolution 
 
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Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit. 
•
Fraction of time spent within each of the following glucose ranges:
o
<50 mg/dL
o
<60 mg/dL
o
<70 mg/dL
o
70-120 mg/dL
o
70-140 mg/dL
o
70-180 mg/dL
o
>180 mg/dL
o
>250 mg/dL
o
>300 mg/dL
•
Number of severe hypoglycemic events (patients unable to self-treat, requiring the
assistance of another person)
•
Number of episodes of symptomatic hypoglycemia
•
Number of carbohydrate interventions for hypoglycemia
•
Total grams of carbohydrates taken for hypoglycemia
•
Mean CGM glucose
Non-glycemic 
•
Glucagon/ZP4207 total delivery per kg of body mass
•
Insulin total delivery per kg of body mass
•
Number of unscheduled infusion set replacements
•
Number of unscheduled CGM sensor changes
EVALUATION OF TRIAL DATA: The following variables will be evaluated according to 
treatment for safety purposes: AEs, local tolerability, laboratory safety assessments, physical 
examination, vital signs, and 12-lead ECGs.  
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow. 
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SPONSOR: 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Tel: +45 88 77 36 00 
Fax: +45 88 77 38 98 
 
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TABLE OF CONTENTS 
SIGNATURE PAGE ............................................................................................................. 2 
INVESTIGATOR AGREEMENT .......................................................................................... 3 
SYNOPSIS ........................................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................... 8 
LIST OF FIGURES ............................................................................................................ 11 
LIST OF ABBREVIATIONS .............................................................................................. 12 
1 
INTRODUCTION AND BACKGROUND INFORMATION ...................................... 14 
1.1 
Background and Rationale ..................................................................................... 14 
1.2 
Bihormonal Bionic Pancreas System ..................................................................... 15 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System ........................ 16 
1.4 
ZP4207 ................................................................................................................... 18 
1.5 
Risk/Benefit ............................................................................................................ 19 
2 
TRIAL OBJECTIVES .............................................................................................. 21 
2.1 
Primary Objective ................................................................................................... 21 
2.2 
Secondary Objectives ............................................................................................. 21 
3 
TRIAL DESCRIPTION ............................................................................................ 22 
3.1 
Summary of Trial Design ........................................................................................ 22 
3.2 
Indication ................................................................................................................ 22 
3.3 
Number of Patients ................................................................................................. 22 
4 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................ 22 
4.1 
Inclusion Criteria ..................................................................................................... 23 
4.2 
Exclusion Criteria .................................................................................................... 23 
4.3 
Target Population ................................................................................................... 25 
4.4 
Withdrawal Criteria ................................................................................................. 25 
5 
ASSIGNMENT TO TREATMENT GROUPS........................................................... 25 
6 
TRIAL TREATMENT .............................................................................................. 26 
6.1 
Investigational Medicinal Products ......................................................................... 26 
6.2 
Storage and Drug Accountability of IMPs ............................................................... 26 
6.3 
Dispensing and Return of IMPs .............................................................................. 26 
6.4 
Doses ..................................................................................................................... 27 
6.5 
iLet Bionic Pancreas ............................................................................................... 27 
6.6 
Other Trial Devices ................................................................................................. 28 
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6.7 
Concomitant Medications ....................................................................................... 28 
6.7.1 
Permitted Medications and/or Procedures ...................................................... 28 
6.7.2 
Excluded Medications and/or Procedures ....................................................... 28 
7 
TRIAL PROCEDURES ........................................................................................... 29 
7.1 
Informed Consent ................................................................................................... 29 
7.2 
Screening Visit (Visit 1, up to 30 days prior to Visit 2) ............................................ 29 
7.2.1 
Data Collected at Screening ............................................................................ 29 
7.3 
Training Visit (Visit 2) (Day 1) ................................................................................. 30 
7.4 
Treatment Visits (Visit 3 [Day 8 ±3] and Visit 4 [Day 15 ±3]) .................................. 30 
7.4.1 
Visit Procedures .............................................................................................. 31 
7.4.2 
Data Collected During the Treatment Visits .................................................... 33 
7.4.3 
Response to Hypoglycemia ............................................................................. 34 
7.4.4 
Response to Hyperglycemia ........................................................................... 34 
7.4.5 
Response to Nausea/Vomiting ........................................................................ 34 
7.4.6 
Response to Other Medical Needs ................................................................. 34 
7.4.7 
Monitoring of Bionic Pancreas Performance ................................................... 35 
7.4.8 
Supervision by Trial Staff ................................................................................ 35 
7.5 
Phone Call (Visit 5) (Day 22 ±3) ............................................................................. 35 
7.6 
Follow-up Visit (Visit 6) (Day 40 ±3) ....................................................................... 35 
8 
ENDPOINTS ........................................................................................................... 35 
8.1 
Primary Endpoint .................................................................................................... 35 
8.2 
Secondary Endpoints ............................................................................................. 35 
8.2.1 
Bionic Pancreas Function ................................................................................ 35 
8.2.2 
Glycemic .......................................................................................................... 36 
8.2.3 
Non-glycemic ................................................................................................... 36 
9 
LABORATORY ASSESSMENTS ........................................................................... 37 
9.1 
Safety Laboratory Assessments ............................................................................. 37 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) .............................................. 37 
9.3 
Exposure Assessments (ZP4207 and Glucagon) ................................................... 37 
9.4 
Anti-drug Antibody Assessments ............................................................................ 37 
10 
SAFETY REPORTING ............................................................................................ 37 
10.1 
Adverse Events ...................................................................................................... 37 
10.1.1 
Follow-up of Adverse Events ........................................................................... 38 
10.1.2 
Precautions ..................................................................................................... 38 
10.1.3 
Assessment of Adverse Events by the Investigator ........................................ 39 
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10.2 
Serious Adverse Events ......................................................................................... 40 
10.3 
Adverse Event Reporting – Procedures for Investigators ....................................... 40 
10.4 
Pregnancy Reporting .............................................................................................. 42 
10.5 
Hypoglycemia ......................................................................................................... 43 
10.6 
Safety Monitoring .................................................................................................... 43 
10.6.1 
Data and Safety Monitoring Board .................................................................. 43 
10.6.2 
Zealand Pharma Safety Committee ................................................................ 44 
11 
STATISTICS ........................................................................................................... 44 
11.1 
Analysis Populations .............................................................................................. 44 
11.2 
Statistical Methods ................................................................................................. 45 
11.2.1 
Analysis of Safety ............................................................................................ 45 
11.2.2 
Analysis of Efficacy ......................................................................................... 45 
11.2.3 
Interim Analysis ............................................................................................... 46 
11.2.4 
Sample Size Determination ............................................................................. 46 
12 
DATA MANAGEMENT AND RECORD KEEPING ................................................ 46 
12.1 
Data Handling ......................................................................................................... 46 
12.2 
Computer Systems ................................................................................................. 46 
12.3 
Data Entry ............................................................................................................... 46 
12.4 
Medical Information Coding .................................................................................... 47 
12.5 
Data Validation ....................................................................................................... 47 
12.6 
Record Keeping ...................................................................................................... 47 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL ........................... 47 
13.1 
Ethical Conduct of the Trial .................................................................................... 47 
13.2 
Institutional Review Board ...................................................................................... 47 
13.3 
Informed Consent ................................................................................................... 48 
13.4 
Trial Monitoring Requirements ............................................................................... 48 
13.5 
Disclosure of Data .................................................................................................. 49 
13.6 
Retention of Records .............................................................................................. 49 
13.7 
Publication Policy ................................................................................................... 49 
13.8 
Legal Aspects ......................................................................................................... 50 
13.9 
Sponsor Discontinuation Criteria ............................................................................ 50 
13.10 
Patient Compensation ......................................................................................... 51 
14 
TRIAL ADMINISTRATIVE INFORMATION ............................................................ 51 
14.1 
Protocol Amendments ............................................................................................ 51 
14.2 
Address List ............................................................................................................ 51 
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14.2.1 
Sponsor ........................................................................................................... 51 
14.2.2 
Supplier of Device ........................................................................................... 51 
14.2.3 
Principal Investigator (Site) ............................................................................. 52 
14.2.4 
Contract Research Organization (Including Monitoring) ................................. 52 
14.2.5 
Medical Monitoring .......................................................................................... 52 
14.2.6 
Pharmacovigilance .......................................................................................... 52 
14.2.7 
Central Laboratory (Safety Laboratory and Plasma Glucose) ......................... 52 
14.2.8 
Special Laboratory (ZP4207 Exposure and ADA Analyses) ........................... 53 
14.2.9 
Special Laboratory (Glucagon Exposure) ....................................................... 53 
15 
REFERENCES ........................................................................................................ 54 
APPENDIX A: SCHEDULE OF PROCEDURES ............................................................... 55 
APPENDIX B: CLINICAL LABORATORY ANALYTES ................................................... 57 
APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES ....................................... 58 
LIST OF FIGURES 
Figure 1. 
Outpatient Results Summarizing the Distribution of Mean CGM Glucose 
Levels and Hypoglycemia in the BP and Control Arms ............................. 17 
Figure 2. 
Trial Design Schematic ................................................................................. 22 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
BG 
Blood glucose 
BP 
Bionic pancreas 
BU 
Boston University 
CFR 
Code of Federal Regulations 
CGM 
Continuous glucose monitor 
CRO 
Contract research organization 
DBR 
Database review 
DPP-4 
Dipeptidyl peptidase-4 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FHD 
First Human Dose 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HCG 
Human chorionic gonadotropin 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IV 
Intravenous 
MD 
Doctor of Medicine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH 
Massachusetts General Hospital 
MPC 
Model-predictive control 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
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Abbreviation 
Definition 
RN 
Registered nurse 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SGLT-2 
Sodium-glucose co-transporter-2 
SIV 
Site Initiation Visit 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
Type 1 diabetes mellitus 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
 
 
 
 
 
 
 
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1 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1 
Background and Rationale 
To date, clinical trials conducted by Boston University (BU) and Massachusetts General 
Hospital (MGH) in patients with type 1 diabetes mellitus (T1DM) have demonstrated the 
practicality of a wearable automated bionic pancreas (BP) control system for robust glucose 
regulation using a continuous glucose monitor (CGM) to provide the input to the control 
system. Despite current technical limitations in CGMs and infusion pumps, the trials by 
BU/MGH have shown that a bihormonal BP is capable of achieving safe and effective blood 
glucose (BG) control automatically, with minimal hypoglycemia during 11 continuous days in 
the face of unrestrained meals and exercise and with trivial patient input (optional 
announcement of meals).  
The BP provides automatic BG regulation and reduces hypoglycemic episodes. Additionally, 
the system spares the wearer the relentless tasks of carbohydrate counting, frequent BG 
monitoring, estimating the effects of specific meals and exercise activity on BG levels, and 
manual drug administration, which are inexact, demanding, aggravating, and require 
continuous diligence and vigilance. The degree of glycemic control achieved by the BP is 
predicted to dramatically reduce the deleterious and debilitating complications of T1DM. 
In its last tested embodiment, the BP consisted of a Dexcom G4 CGM, and an iPhone that are 
hardwired together, with the iPhone running the control algorithm and communicating via 
Bluetooth with 2 Tandem t:slim pumps to dose insulin and glucagon. The connections are 
repeatedly lost among these 4 components throughout the day, an issue that has the potential 
to adversely impact BG control, whether due to missed CGM values or missed doses. In 
addition, the troubleshooting required to repair these recurring disconnections can be 
burdensome to the user. Integrating these components into a single device would establish 
seamless connectivity among them, which would eliminate the need for such troubleshooting. 
This would lead to a smoother device operation with fewer interruptions, which would enhance 
its user friendliness, optimize its BG control potential, and further improve the quality of life of 
its users.  
The BU Investigators have recently designed, built, and tested a proprietary first-generation 
of such a fully integrated BP system, referred to as the iLet and the iLet infusion set. The iLet 
is a dual-chamber infusion system that currently incorporates the Dexcom G4 CGM 
technology, a custom user interface with touchscreen display, and all of the mathematical 
dosing algorithms that were tested in and validated using the iPhone-based BP in outpatient 
studies over the past 3 years. The iLet infusion set provides 2 independent subcutaneous (SC) 
fluid pathways from the iLet to the patient (1 for insulin and the other for glucagon). One tube 
connects to the prefilled insulin cartridge and the other tube connects to the fillable (single-use) 
glucagon cartridge. 
In order to provide automatic BG regulation, the iLet has the ability to deliver both insulin and 
glucagon. However, currently available glucagon formulations have limited stability at room 
temperature, necessitating frequent changes to the glucagon infusion set. Therefore, the 
current trial is designed to test the glucagon analog ZP4207 in the iLet, as this peptide analog 
of human glucagon is provided in a liquid formulation stable at room temperature. 
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The current trial is a first feasibility trial designed to use the first-generation iLet and iLet 
infusion set to compare ZP4207 with marketed glucagon (Lilly). The trial is intended to 
demonstrate the safety and tolerability of ZP4207 in the iLet and the feasibility of achieving 
comparable autonomous glycemic control. It is not intended to comprehensively demonstrate 
the definitive efficacy of the iLet in extended, continuous daily use, but rather to demonstrate 
its functionality and accuracy in a practical, albeit very controlled, clinical setting. The trial is 
expected to provide practical information that will benefit the design of a next-generation iLet 
and iLet infusion set and help pave the way for a more comprehensive outpatient home-use 
Phase 2 trial and ultimately a pivotal trial where comprehensive safety and efficacy through 
continuous full daily use of the iLet with ZP4207 will be documented. 
 
The data derived from this trial will permit evaluation of the robustness of the iLet as well as 
the safety and efficacy of ZP4207 when used in conjunction with the iLet. The data obtained 
will be used to further improve the iLet and will allow BU/MGH to expand to larger outpatient 
trials using the iLet with ZP4207.  
 
1.2 
Bihormonal Bionic Pancreas System  
The BP is an autonomous, self-learning system that requires only the patient's weight for 
initialization, and then autonomously adapts, modestly or dramatically, as needed, to cope 
with the wide range of insulin requirements of adults, adolescents, and pre-adolescents with 
T1DM. The BP obviates the need for the patient to know, or even appreciate, their insulin 
requirements, and renders obsolete any need for patients or caregivers to know 
carbohydrate-to-insulin ratios, basal rates, or insulin correction factors. 
 
The core technology is a suite of control algorithms that orchestrate the automated dosing of 
insulin and glucagon to regulate BG levels. An insulin controller orchestrates all SC insulin 
dosing. At its centerpiece is a model-predictive control (MPC) algorithm, which bases insulin 
doses on the glucose data and insulin absorption kinetics, compensating for the slow 
absorption rate of SC insulin analogs (peak time in blood of 30-90 min, clearance in 4-8 hr). 
This enables the algorithm to refrain from stacking and overdosing insulin. Furthermore, the 
MPC algorithm automatically adjusts its insulin-dosing aggressiveness continuously and in 
real-time to different insulin needs between individuals and variable needs within the same 
individual. Running in parallel with the MPC algorithm is an algorithm that automatically 
modulates basal insulin delivery over multiple time scales, and another algorithm that 
automatically adapts insulin doses in response to optional meal announcements. Unlike 
current insulin pumps and the insulin-only control algorithms, the adaptive basal insulin 
algorithm obviates the need for the user to set, or even know, his or her “basal-rate profile.” 
Instead, it is capable of automatically adapting to, and compensating for, changes in an 
individual's basal insulin need, such as might occur over a period of hours, days, or weeks 
(e.g., circadian hormonal fluctuations, intercurrent illness, physical activity, or emotional state) 
or as might occur over a period of months or years due to developmental changes 
(e.g., hormonal changes that occur during puberty or menopause). The adaptive meal dose 
controller obviates the need for the user to set, or even know, his or her 
“carbohydrate-to-insulin ratios,” as it makes automatic adjustments based on dosing history 
for similar meal announcements made on previous days, and customizes the dose for each 
individual and for time of day.  
 
The BP also includes a proportional-derivative algorithm governing SC micro-doses of 
glucagon to help prevent impending hypoglycemia. Glucagon dosing is based on the glucose 
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level and rate of descent. It may occur preemptively even if glucose is above range, and it 
includes a feedback term to account for the pending effects of recent glucagon doses.  
Taken together, these mathematical algorithms provide a universal framework for a glycemic 
control strategy that requires no quantitative input from, or participation by, the user (besides 
entering body weight to initialize the system), but which automatically adapts insulin and 
glucagon dosing to meet the individual needs of each user. Another challenge met is enabling 
the technology to remain completely autonomous in managing insulin and glucagon delivery 
even when the CGM is offline. Specifically, when the CGM is offline, the BP invokes the 
high-resolution “basal rate profile” that it had recently learned and stored when the CGM was 
online. On the basis of what the system learned and stored about meal announcements when 
the CGM was online, it is able to respond to meal announcements in the same manner when 
the CGM is offline. Finally, it automatically responds to user-entered BG values when the CGM 
is offline by issuing a correction dose of insulin or glucagon based on what it learned about 
the user's insulin and glucagon needs when the CGM was online. Thus, the BP never relies 
on, or burdens the user with, the determination of subjective dosing decisions, which inevitably 
vary in quality and reliability among different users. The BP provides a turnkey solution for 
people with T1DM that comprehensively manages glycemia across a broad range of individual 
needs and across a large spectrum of circumstances and challenges to glycemic control. 
A significant challenge for the use of glucagon in a bihormonal BP is the lack of a commercially 
available glucagon formation that is stable and well-suited to infusion over several days in a 
pump reservoir. However, BU/MGH have proceeded with studies using a relatively unstable 
marketed formulation that must be reconstituted from a lyophilized powder on a daily basis. 
This allowed BU/MGH to proceed with studies of the bihormonal system while awaiting the 
production of stable glucagon formulations or stable glucagon analogs. 
1.3 
Preliminary Studies with the Bihormonal Bionic Pancreas System 
The BP hardware platform has evolved over the years from a laptop-driven system, which was 
used in all inpatient studies to the first truly mobile wearable iPhone-driven platform, which 
has been used in a number of outpatient studies. Using the iPhone-based BP system, 
>110 outpatient experiments of 5-11 days in duration in each subject have been conducted 
(>800 patient days or >2 patient years of data) across subjects ranging in age between 6 and 
76 years old and in body mass between 21 and 128 kg. The robust adaptation capabilities of 
the BP is evident in the fact that the average total daily dose of insulin among these subjects 
varied by over 13-fold (from 11 to 145 units/day). 
In November 2012, Food and Drug Administration (FDA) approval was obtained to conduct 
the first outpatient study testing the BP in adults 21 years or older with T1DM. This study, 
referred to as the Beacon Hill Study, followed a random-order cross-over design in which 
20 adults with T1DM participated in 5 days on the iPhone-based BP and 5 days of usual care 
in which they wore a CGM with blinded display and muted alarms. In the BP arm, subjects 
kept to a 3-square-mile geographic area centered around the Beacon Hill neighborhood in 
Boston. They ate as they chose at local restaurants, and exercised at will with access to 
2 gyms. Analysis was pre-specified to focus on Days 2-5, since glycemic control is more 
representative of BP performance after most of the adaptation by the BP occurs on Day 1 
(Russell, 2014). Results are summarized in Figure 1.  
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In April 2013, FDA approval was obtained to conduct the first outpatient study testing the BP 
in adolescents 12-20 years old with T1DM. This study, referred to as the 2013 Summer Camp 
Study, followed a random-order cross-over design in which 32 adolescents with T1DM 
participated in 5 days on the BP and 5 days of supervised camp care in which they wore a 
CGM with blinded display and muted alarms. Subjects were fully integrated into normal camp 
activities without restrictions on diet or exercise. The study used the same iPhone-based BP 
that was used in the Beacon Hill Study. Results are summarized in Figure 1 (Russell, 2014). 
In April 2014, FDA approval was obtained to conduct the first outpatient study testing the BP 
in pre-adolescents 6-11 years old with T1DM. This study, referred to as the 2014 Summer 
Camp Study, was similar in design to the 2013 Summer Camp Study. Results are summarized 
in Figure 1 (Russell, 2016).  
In April 2014, FDA approval was obtained to conduct the first multi-center study, which was 
also the first home study, to test the BP in adults 18 years or older with T1DM. This study, 
referred to as the Bionic Pancreas Multi-Center Study, followed a random-order cross-over 
design in which 39 adults participated in 11 days on the BP and 11 days of usual care. 
Participants went to work as usual, and lived and slept at home, all without clinical supervision. 
There were no restrictions placed on diet or exercise. The study included 4 medical centers 
(10 subjects per center), which included MGH, the University of Massachusetts Medical 
School, Stanford University, and the University of North Carolina at Chapel Hill. Results are 
summarized in Figure 1.  
All of these studies used marketed glucagon (glucagon for injection, Eli Lilly). Due to its limited 
stability, Lilly glucagon must be reconstituted immediately before use. Animal studies have 
previously shown that despite its limited chemical stability, Lilly glucagon maintains its 
biological activity for up to 7 days in solution. Using this data, an Investigational New Drug 
(IND) exemption was obtained from the FDA for its use in a pump for up to 27 hours. This 
allowed these studies to be performed by asking volunteers to reconstitute a new vial of 
glucagon and fill the glucagon pump at approximately the same time every day. However, 
marketed Lilly glucagon has no path forward for approval for chronic BP use. 
1.4 
ZP4207 
ZP4207 is a peptide analog of human glucagon that is being developed to treat hypoglycemia 
in patients with T1DM and type 2 diabetes mellitus. ZP4207 exhibits improved physical and 
chemical stability in aqueous media and is suitable for liquid formulation. ZP4207 is comprised 
of 29 amino acids and has 7 amino acid substitutions when compared to native glucagon.  
Two clinical Phase 1 trials have been conducted to establish safety and tolerability of ZP4207 
after single and multiple dosing to healthy patients and T1DM patients under insulin-induced 
hypoglycemic conditions. 
The First Human Dose (FHD) trial (ZP4207-14013) was finalized in April 2015. The trial was 
a randomized, double-blinded trial with the objectives to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics (PD) of ZP4207 as compared to an active 
comparator. Part 1 included a single ascending dose in healthy volunteers in cohorts of 8. In 
each cohort, the patients were randomized 3:1 to ZP4207 (n=6) or Novo Nordisk GlucaGen® 
(n=2). Five cohorts with SC administration (0.01, 0.1, 0.3, 1.0, and 2.0 mg ZP4207 compared 
to 1 mg GlucaGen) and 3 cohorts with intramuscular (IM) administration (0.3, 1.0, and 2.0 mg 
ZP4207 compared to 1 mg GlucaGen) were included. Part 2 included 2 sequence groups of 
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10 hypoglycemic T1DM patients. The patients were treated with fixed single IM doses of 
0.7 mg ZP4207 and 1.0 mg GlucaGen in a sequential cross-over design in a randomized 
treatment order.  
The second clinical trial (ZP4207-15007) was a single-center, double-blind, Phase 1b trial 
investigating the safety and tolerability, PK and PD of ZP4207 following repeated 
administration in healthy volunteers compared to placebo. It was finalized in July 2015. Each 
of the 3 cohorts comprised 8 subjects, who received 5 repeated SC doses of ZP4207 or 
placebo in a 3:1 treatment allocation. The first cohort started with the lowest dose of 0.1 mg. 
Cohort 2 and 3 continued with 0.3 and 1.0 mg, respectively. 
The Phase 1 results did not give rise to specific safety concerns, beyond those related to the 
pharmacological effect of ZP4207. All adverse events (AEs) recorded in the trials were of mild 
or moderate severity. The most frequent systemic AE related to treatment with ZP4207 was 
nausea, which is a known side-effect following administration of glucagon. The most frequent 
injection site reaction was transient erythema, occurring in all ZP4207, glucagon, and placebo 
treatment groups, irrespective of dose. No anti-drug antibodies (ADA) incidences were 
observed. 
The observed PD response, in terms of increased plasma glucose, in insulin-induced 
hypoglycemic patients with T1DM following dosing with 0.7 mg ZP4207 administered IM was 
similar to that observed following IM dosing with 1.0 mg glucagon (GlucaGen, Novo Nordisk). 
An increase in plasma glucose of ≥20 mg/dL from hypoglycemic levels was achieved within 
30 minutes for all patients. 
In terms of PK, ZP4207 had a short half-life and high clearance and dose proportionality for 
both maximum plasma concentration and area under the concentration-time curve from 
time 0 to 300 minutes in the dose range 0.1 to 2.0 mg following SC administration. Following 
IM administration, dose proportionality was shown in the investigated dose range of 0.3 to 
2.0 mg. The PK properties of 0.7 mg ZP4207 IM were comparable with those of 1.0 mg 
glucagon (GlucaGen, Novo Nordisk) with IM administration. 
1.5 
Risk/Benefit 
While the potential risks are minimal, the findings of this trial may reveal information that can 
substantially improve medical care for persons with diabetes. Therefore, the overall 
risk/benefit for patients participating in this trial is assessed as acceptable. 
Potential Risks and Discomforts  
Trial patients will be informed by the Investigator of the potential risks of ZP4207 and other 
trial-related procedures before they enter the trial.  
In this trial, patients with T1DM will be included to test the safety and efficacy of the iLet using 
ZP4207 versus the iLet using Lilly glucagon. The cross-over design with inclusion of the same 
T1DM patients into the 2 treatment arms in a randomized order will allow for a direct 
comparison of the safety and efficacy of the 2 treatments, based on intra-patient variability 
only.  
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Patients may experience mild discomfort associated with the insertion of the infusion sets and 
sensor into the SC tissues. The risk of discomfort due to insertion of infusion sets and sensors 
is expected to be slightly greater than in their lives outside the trial because more infusion sets 
will be inserted and a CGM sensor will be inserted. Most patients will use only one infusion 
set and not all will use a CGM sensor in usual care.  
There is a potential risk of hypoglycemia, since recombinant insulin analog will be 
administered. Due to frequent monitoring of glucose and direct supervision by a registered 
nurse (RN) or Doctor of Medicine (MD) at all times, the risk of a hypoglycemic episodes leading 
to significant harm to patients is expected to be substantially lower than their risk during their 
usual therapy.  
There is a risk of hyperglycemia. This risk is expected to be less than the risk during the 
patients’ lives outside of the trial based on data from earlier BP trials and the design of this 
trial.  
Treatment with ZP4207 and marketed glucagon can result in undesired effects or complaints. 
Undesired effects and complaints such as gastrointestinal side effects including nausea, 
vomiting, and diarrhea are known side effects of glucagon administration at higher dose levels. 
The frequency of nausea associated with the administration of 1 mg of glucagon according to 
the Summary of Product Characteristics (SPC) for Glucagon is described to be between 1/10 
and 1/100. The frequency of vomiting is described to be between 1/100 and 1/1000 (Novo 
Nordisk, 2015). Similar gastrointestinal side effects have also been observed to a limited 
degree in the 2 clinical trials conducted with ZP4207, again at higher dose levels. The 
individual doses of ZP4207 and Lilly glucagon delivered by the BP are expected to be 
significantly lower than doses typically associated with nausea. As with every novel drug 
substance, new and yet unknown side effects may also occur. 
There are limited data available to describe the immunogenic potential of glucagon products 
available on the market, but the data available indicate that marketed glucagon only has a 
small immunogenic potential. A Phase 1 trial performed with recombinant human glucagon 
and animal derived glucagon in 75 healthy patients did not show signs of ADA measured 
13 weeks after trial product administration (Eli Lilly, 2005). In the ZP4207 FHD trial, 
ZP4207-14013, no confirmed anti-ZP4207 or anti-glucagon antibodies were detected in any 
of the samples. In addition, the 5 sequential administrations of ZP4207, as applied in trial 
ZP4207-15007, were not associated with the development of antibodies against ZP4207 in 
the 18 subjects enrolled to receive ZP4207. The optimized formulation of ZP4207, as applied 
in the present trial is not expected to change the immunogenic potential of the Investigational 
Medicinal Product (IMP).  
In relation to diabetes therapy, development of insulin-antibodies is documented more 
substantially and route of administration has been shown to influence immunogenic potential 
of insulins. However, these antibodies against insulin generally do not have an impact on 
insulin action and are thus not clinically relevant. 
In terms of consequence, development of high titer antibodies against ZP4207 could, in theory 
reduce the activity of endogenous glucagon, which again, in theory could influence 
hypoglycemic episodes. However, most patients with T1DM do not secrete glucagon normally 
in response to hypoglycemia, so they would be less likely to be negatively impacted by 
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anti-glucagon antibodies. Limited suppression of glucagon would, however, not be considered 
critical, as low glucose levels can also be corrected by other means, including oral intake of 
glucose and by other endogenous hormones such as oxyntomodulin.  
 
Overall, ZP4207 is judged to be a low-risk molecule, based upon the available clinical data as 
well as the outcome of the risk-based approach to the immunogenicity assessment made. The 
present trial will include sampling for measurement of antibodies against ZP4207 prior to first 
dosing (Visit 3) and at the Follow-up Visit. In line with regulatory guidance documents, these 
samples will be appropriately analyzed and the results will be included in the overall 
assessment of the immunogenic potential of ZP4207 after completion of each trial and as the 
clinical development program advances. 
 
Administration of ZP4207 may be associated with a risk of allergic reactions similar to those 
observed for other therapeutic peptides or proteins. Patients with known or suspected allergies 
to the trial products or related products will be excluded from the trial. Mild or moderate allergic 
reactions may include symptoms of rash, fever, flu-like symptoms, nausea, headache, and 
myalgia. Acute generalized hypersensitivity reactions are usually very rare but may include 
symptoms of flushing, sweating, dizziness, change in blood pressure, and difficulties in 
breathing. The risk of acute hypersensitivity reactions is described to be less than 1/10,000 
for native glucagon. No severe acute hypersensitivity reactions have been observed in the 
2 clinical trials conducted with ZP4207.  
 
Potential Benefits 
 
Based on experiences from previous trials of the BP and the design of this trial, patients 
enrolled in the trial may benefit from a reduction in risk of hypoglycemia and hyperglycemia 
and a better mean glucose compared to their usual diabetes care during their short trial 
participation.  
 
The data derived from this trial will allow evaluation of safety and tolerability of ZP4207 in the 
iLet, and the robustness and effectiveness of the new BP control system. The data obtained 
will be used to further improve the iLet and will allow the expansion to larger outpatient trials 
using the iLet with ZP4207.  
 
This trial is a necessary step in preparing the BP with ZP4207 to become available to people 
with T1DM. Wide availability of the BP with ZP4207 could improve the medical care of adults 
and children with T1DM. 
2 
TRIAL OBJECTIVES  
2.1 
Primary Objective  
The primary objective is to conduct a trial testing the safety and tolerability of the iLet when 
used with ZP4207 in 10 adult (≥18 years of age) patients with T1DM. 
 
2.2 
Secondary Objectives  
The secondary objectives are to measure glycemic regulation, including hypoglycemia 
exposure (percent of time spent with CGM glucose <60 mg/dL), evaluate BP device reliability, 
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and to document the satisfaction of patients with the iLet with the goal of optimizing the 
functionality and user interface of the iLet. 
3 
TRIAL DESCRIPTION 
3.1 
Summary of Trial Design 
This trial is a single-center, open-label, randomized cross-over trial. The trial will enroll adult 
patients with T1DM and will assess the safety and efficacy of the iLet using the glucagon 
analog ZP4207 versus the iLet using Lilly glucagon. The iLet will also administer insulin (insulin 
lispro, Lilly Humalog) using the same BG control algorithm for both treatment arms. The trial 
will be conducted at a single center, the MGH Diabetes Center in Boston, MA. 
The overall trial design schematic is displayed in Figure 2. 
Figure 2. 
Trial Design Schematic 
Screening
Training
ZP4207 in iLet
Lilly glucagon in iLet
ZP4207 in iLet
Lilly glucagon in iLet
Phone Call
Follow-up
Treatment
Visit 1
≤ 30 days
Visit 2
Day 1
Visit 3
Day 8 ± 3
Visit 4
Day 15 ± 3
Visit 5
Day 22 ± 3
Visit 6
Day 40 ± 3
3.2 
Indication 
ZP4207 is an anti-hypoglycemic glucagon analog in a ready-to-use liquid formulation which 
is being studied to improve glycemic control in adults (and children) with T1DM as part of a 
bihormonal BP. 
3.3 
Number of Patients 
Up to 20 adult patients with T1DM can be enrolled. The upper bound is based on the 
expectation that some patients will be excluded after the Screening Visit and the possibility 
that some patients may have to be discontinued before completion (due to, for instance, 
inter-current illness or patient withdrawal). Eligible patients will be randomized until 10 patients 
have completed the trial protocol. It is expected that between 10 and 12 patients will be 
randomized. 
4 
SELECTION AND WITHDRAWAL OF PATIENTS 
The trial will enroll patients who already manage their T1DM using continuous SC insulin 
infusion pump therapy. This requirement is imposed because multiple daily injection therapy 
involves the use of medium-acting or long-acting basal insulin that would require an extended 
washout period. 
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4.1 
Inclusion Criteria 
1.
Male and female patients with T1DM for at least 1 year, as defined by the American
Diabetes Association
2.
Age ≥18 years
3.
Diabetes managed using an insulin pump for ≥6 months
4.
Prescription medication regimen stable for >1 month (except for medications that will
not affect the safety of the trial and are not expected to affect any outcome of the trial,
in the judgment of the Investigator)
5.
Informed consent obtained before any trial-related activities (trial-related activities are
any procedure that would not have been performed during normal management of the
patient)
6.
Patients in good health according to age (medical history, physical examination, vital
signs, 12-lead electrocardiograms [ECGs], laboratory assessments), as judged by the
Investigator
4.2 
Exclusion Criteria  
1.
Unable to provide informed consent (e.g., impaired cognition or judgment)
2.
Unable to safely comply with trial procedures and reporting requirements
(e.g., impairment of vision or dexterity that prevents safe operation of the BP, impaired
memory, unable to speak and read English)
3.
Participation in another clinical trial of an investigational agent or device concurrently
or within 1 month (or 5 half-lives) prior to the Screening Visit
4.
Previous exposure to ZP4207
5.
Females of childbearing potential who are pregnant (positive urine human chorionic
gonadotropin [HCG]), breast feeding, plan to become pregnant in the immediate future,
or sexually active without using highly effective contraception methods (highly effective
methods are considered those with a failure rate less than 1% undesired pregnancies
per year including surgical sterilization, hormonal intrauterine devices [coil], oral
hormonal contraceptives, sexual abstinence, or a surgically sterilized partner) or
postmenopausal 
women amenorrheic for 
less 
than 
1 year with serum
follicle-stimulating hormone (FSH) level ≤40 IU/L and not using highly effective
contraceptive methods during the trial and until 1 month after last dosing in the trial
6.
Male who is sexually active and not surgically sterilized who or whose partner(s) is not
using highly effective contraceptive methods (highly effective contraceptive measures
include surgical sterilization, hormonal intrauterine devices [coil], oral hormonal
contraceptives, each in combination with spermicide-coated condoms), or who is not
willing to refrain from sexual intercourse from the first dosing until 1 month after last
dosing in the trial
7.
Current alcohol abuse (intake averaging >3 drinks daily in last 30 days) or use within
the last 6 months of controlled substances without a prescription (other than marijuana)
8.
New onset clinically significant illness within 4 weeks prior to screening, as judged by
the Investigator
9.
Unwilling or unable to refrain on the treatment visits from:
a.
Acetaminophen in any form
b.
Use of drugs that may dull the sensorium, reduce sensitivity to symptoms of
hypoglycemia, or hinder decision making during the period of participation in
the trial (use of beta blockers will be allowed as long as the dose is stable and
the patient does not meet the criteria for hypoglycemia unawareness while
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taking that stable dose, but use of benzodiazepines or narcotics, even if by 
prescription, may be excluded according to the judgment of the Investigator) 
10. History of liver disease that is expected to interfere with the anti-hypoglycemia action
of glucagon (e.g., liver failure or cirrhosis). Other liver disease (i.e., active hepatitis,
steatosis, active biliary disease, any tumor of the liver, hemochromatosis, glycogen
storage disease) may exclude the patient if it causes significant compromise to liver
function or may do so in an unpredictable fashion.
11. Aspartate 
aminotransferase >2 
× 
upper limit of 
normal (ULN), alanine
aminotransferase >2 × ULN, or bilirubin >1.5 × ULN on screening laboratories
12. Renal failure on dialysis or estimated glomerular filtration rate <30 mL/min/1.73 m2 on
screening laboratories
13. Hemoglobin <12 gm/dL for men and <11 gm/dL for women
14. Personal history of cystic fibrosis, pancreatitis, pancreatic tumor, or any other
pancreatic disease besides T1DM
15. Any known history of coronary artery disease including, but not limited to, history of
myocardial infarction, stress test showing ischemia, history of angina, or history of
intervention such as coronary artery bypass grafting, percutaneous coronary
intervention, or enzymatic lysis of a presumed coronary occlusion)
16. Congestive heart failure with New York Heart Association Functional Classification III
or IV
17. History of transient ischemic attack or stroke in the last 12 months
18. Seizure disorder, history of any non-hypoglycemic seizure within the last 2 years, or
ongoing treatment with anticonvulsants
19. History of hypoglycemic seizures (grand-mal) or coma in the last 12 months
20. History of pheochromocytoma: fractionated metanephrines will be tested in patients
with history increasing the risk for a catecholamine secreting tumor:
a.
Episodic or treatment refractory (requiring 4 or more medications to achieve
normotension) hypertension
b.
Paroxysms of tachycardia, pallor, or headache
c.
Personal or family history of MEN 2A, MEN 2B, neurofibromatosis, or
von Hippel-Lindau disease
21. History of adrenal disease or tumor
22. Hypertension with systolic blood pressure ≥160 mm Hg or diastolic blood pressure
≥100 mm Hg despite treatment
23. Untreated or inadequately treated mental illness (indicators would include symptoms
such as psychosis, hallucinations, mania, and any psychiatric hospitalization in the last
year), or treatment with anti-psychotic medications that are known to affect glucose
regulation
24. Electrically powered implants (e.g., cochlear implants, neurostimulators) that might be
susceptible to radio frequency interference
25. History of adverse reaction to glucagon (including allergy) besides nausea and
vomiting
26. Established history of allergy or severe reaction to adhesive or tape that must be used
in the trial
27. Use of oral anti-diabetic medications (e.g., thiazolidinediones, biguanides,
sulfonylureas, glitinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose
co-transporter-2 [SGLT-2] inhibitors)
28. Inadequate venous access as determined by trial nurse or physician at time of
screening
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6 
TRIAL TREATMENT 
6.1 
Investigational Medicinal Products 
Insulin: The trial involves SC administration of insulin lispro (Humalog, Lilly), which is 
commercially available by prescription and is indicated for patients with T1DM, but not for use 
in a BP. 
Glucagon: The trial also involves SC administration of Lilly glucagon in one iLet arm. Lilly 
glucagon is commercially available by prescription and is indicated for patients with T1DM in 
severe hypoglycemia, but not for use in a BP. 
ZP4207: The trial also involves SC administration of the glucagon analog ZP4207, 1 mg/mL, 
in the other iLet arm. ZP4207 will be made available by Zealand Pharma A/S, Denmark as 
liquid formulation in prefilled syringes of 0.6 mL. 
6.2 
Storage and Drug Accountability of IMPs 
All IMPs will be stored and handled in accordance with the Sponsor’s instructions and/or the 
product labelling at the Investigator’s site, e.g., refrigerated (+2ºC to +8ºC) and should not be 
exposed to excessive heat, direct sunlight and never be frozen. 
All used, partly used, and unused vials or prefilled syringes must be kept by the Investigator 
and stored between +2ºC and +8ºC (unused) or at room temperature (partly used and used). 
Used and unused pre-filled syringes must be stored separately.  
The Investigator must ensure the availability of proper storage conditions and record and 
evaluate the temperature. Temperature of the refrigerator used for drug storage is monitored 
continuously, an alarm system is established. The Investigator must inform the monitor 
immediately if any IMP has been stored outside specified conditions (e.g., outside temperature 
storage). Investigational Medicinal Product that has been stored improperly must not be 
dispensed to any patient before it has been re-evaluated and approved for further use. The 
Investigator must take appropriate action to ensure correct storage. 
For the IMP, the Investigator must keep an accurate record of all IMPs received and the 
products used for each patient in a Drug Accountability Record. Storage locations, batch 
numbers, and expiry dates are also documented in this form. 
The drug accountability must be performed in a timely manner by the monitor. 
6.3 
Dispensing and Return of IMPs 
No IMPs may be dispensed to any person not enrolled in the trial. 
Upon completion of the trial, the Sponsor will be responsible for destruction or storage of IMPs 
(used, partially used, or unused). These duties can be delegated to a contract research 
organization (CRO) and must be documented in the trial files. 
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6.4 
Doses 
The iLet can administer isolated insulin-glucagon doses once every 5 minutes. A single 
automated bolus of insulin will not exceed 3 units per 5-minute dose (30 µl of U-100 insulin) 
in both systems, and a single meal-priming dose, in response to a meal announcement made 
by the user, will not exceed 12 units (120 µl of U-100 insulin). A single bolus of glucagon will 
not exceed 80 µg (80 µl of 1 mg/mL Lilly glucagon or 1 mg/mL ZP4207). In prior studies, typical 
doses of glucagon were in the range of 0.005-0.04 mg per dose. The iLet is capable of 
administering as little as ~0.1 µl (0.011 units of U-100 insulin or 0.1 µg of 1 mg/mL ZP4207). 
It is expected that the mean total daily doses of glucagon/ZP4207 will be <1.0 mg daily as in 
previous studies. The mean daily glucagon dose in a previous 11-day outpatient trial was 
0.5 mg/day (range 0.2-0.9 mg/day). Currently, single doses of up to 2 mg ZP4207 have been 
administered in clinical trials. The recommended dose of marketed glucagon for adult patients 
suffering from severe hypoglycemia is 1 mg as a single injection. Mean glucagon levels in 
previous inpatient studies have been above the normal fasting range for glucagon only 1% of 
the time. Therefore, the glucagon exposure of patients is expected to be modest. 
6.5 
iLet Bionic Pancreas  
Infusion set: A novel, dual cannula infusion set has been designed specifically for use with 
the iLet. Patients will wear dual channel tubing that will be attached to 2 infusion sets with one 
steel cannula each, one for insulin infusion and the other for glucagon infusion. The tubing 
and infusion sets will have undergone sterilization prior to being delivered in a sealed pouch. 
The steel cannulae will be inserted in the abdominal SC tissue. 
Continuous glucose monitors: One transcutaneous glucose sensor for the Dexcom G4 
Platinum (Garcia, 2013) will be inserted in the abdominal SC tissue and will provide input to 
the controller. The sensor is powered by the battery within the transmitter that clips to the 
sensor and the whole assembly is held to the skin with an adhesive patch and communicates 
wirelessly with the BP. If the G4 sensor fails for any reason during the trial (loss of CGM 
signal), it will be replaced promptly.  
Bionic Pancreas Control Unit: The iLet is being built according to Class III medical device 
standards, adheres to a comprehensive and robust quality system, and is fully compliant with 
International Organization for Standardization (ISO) 13485 standards and document control 
practices. The iLet is a fully-integrated dual-hormone BP system that integrates the CGM 
technology (currently the Dexcom G4 Share system) as well as 2 independent motor-drivetrain 
pumping assemblies, which independently actuate the delivery of insulin and glucagon from 
pre-filled cartridges that are separately loaded into the iLet housing. Each drivetrain assembly 
utilizes a lead screw, which is driven by a precision micromotor, a gear case assembly, and a 
motor controller unit, in a manner similar to what is commonly found in most insulin infusion 
pumps on the market today. The iLet has dosing accuracy that is comparable to 
FDA-approved insulin pumps currently on the market. The iLet has a built-in Bluetooth Low 
Energy radio that also allows automatic communication with the paired CGM, as well as the 
Nova StatStrip® Xpress BG meter (Nova Biomedical). The iLet does not contain a cellular nor 
a WiFi radio, and does not accept input data from another mobile device (e.g., smartphone), 
other than the paired CGM and BG meter(s). 
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The mathematical control algorithms (which are the same as those used in the iPhone-based 
BP), the CGM glucose engine (Dexcom), and the native user interface software, are all 
interconnected through controller framework software and reside as embedded systems on 
printed circuit boards contained within the device housing. The touchscreen-enabled, 
menu-driven user interface and onboard processor provide a comprehensive and standalone 
platform, which allows the iLet to operate independently of smartphones or other devices and 
without the need for internet support during routine operation. The graphical user interface of 
the iLet has the same user options and capabilities of the iPhone BP, including having its 
home screen password protected and its settings options only accessible to trial staff via a 
separate password. 
6.6 
Other Trial Devices 
YSI 2300 STAT Plus™ (Yellow Springs Instruments): The YSI 2300 STAT Plus is an 
FDA-approved glucose analyzer. Blood glucose measurements using the YSI 2300 STAT 
Plus will be obtained off of the IV line during both treatment visits.   
Nova Biomedical StatStrip Xpress Glucose Meter: The Nova StatStrip Xpress glucose 
meter is an FDA-approved glucose meter that is commercially available. Blood glucose 
measurements for CGM calibration will be obtained with the Nova StatStrip Xpress during both 
treatment visits if the YSI 2300 STAT Plus fails and via fingerstick with the Nova StatStrip 
Xpress during any periods when IV blood samples are not available for any reason or the IV 
fails. 
Exercise Bike: The trial will utilize a stationary exercise bike (ergometer) for the in-clinic 
exercise at the treatment visits. This bike will be stored at the Diabetes Research Center when 
not in use. 
6.7 
Concomitant Medications 
6.7.1 
Permitted Medications and/or Procedures 
Patients may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference with 
CGM sensing. All concomitant medications, including over-the-counter medications, should 
be recorded. 
Use of beta blockers will be allowed as long as the dose is stable and the patient does not 
meet the criteria for hypoglycemia unawareness while taking that stable dose. 
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911. 
6.7.2 
Excluded Medications and/or Procedures 
During the trial, patients will not use any recreational drugs or drugs of abuse. The need to 
take prescription drugs that dull the sensorium, reduce sensitivity to symptoms of 
hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion from the 
trial or discontinuation of participation, a decision that will be made by the Investigator. 
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Use of benzodiazepines or narcotics, even if by prescription, may be excluded according to 
the judgment of the Investigator. Use of oral anti-diabetic medications (e.g., thiazolidinediones, 
biguanides, sulfonylureas, glitinides, DPP-4 inhibitors, SGLT-2 inhibitors) will also be 
excluded. 
7 
TRIAL PROCEDURES  
7.1 
Informed Consent 
After potential patients have had time to review the consent document, and prior to any 
trial-related activities, they will meet with a trial MD or designee who will explain the trial, 
answer any questions, and administer informed consent. In the event that a volunteer is a 
patient of one of the trial MDs, another staff MD or designee will answer questions and 
administer consent. The patients will be fully informed of their responsibilities and their rights 
while participating in the trial as well as of the possible risks and potential benefits of 
participation in the trial. They will have the opportunity to discuss all questions and ample time 
to consider participation. 
Trial-related activities are any procedures that would not have been performed during normal 
management of the patient. Patients who wish to participate in the trial will be asked to 
personally date and sign an informed consent form (ICF). Likewise, the Investigator must also 
personally date and sign the ICF. All patients will be provided with a copy of their own signed 
and dated ICF. 
Trial staff will answer any questions that the patients may have during their participation. They 
will share any new information in a timely manner that may be relevant to the patient's 
willingness to continue participating in the trial. The patients may choose to discontinue their 
participation at any time.  
7.2 
Screening Visit (Visit 1, up to 30 days prior to Visit 2) 
All patients will have a screening visit to confirm eligibility. The patient will be interviewed and 
the electronic Case Report Form (eCRF) will be completed by trial staff to establish whether 
the patient is eligible. 
Once all of the results have been returned, a trial MD will review the eCRF to determine patient 
eligibility. If a patient is not eligible to continue in the trial, the results of abnormal tests will be 
reported to the patient and to a health care provider of their choosing. 
7.2.1 
Data Collected at Screening 
•
Age, sex, race, and ethnicity
•
Date of last menstrual period in female patients
•
Medical, surgical, and social history, allergies, and review of systems relevant to
inclusion and exclusion criteria, including:
o
Date of diabetes diagnosis
o
Duration of insulin pump use and type of insulin used in pump
o
Type/model of insulin pump
o
Insulin regimen (basal rate, sensitivity factor, and carbohydrate ratio)
o
Average total daily dose of insulin in the last 30 days as available (from pump
history)
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o Usage of CGM, if any (type of CGM, days per month worn, usage of data, 
whether insulin is dosed based on CGM alone, alarm settings) 
• 
Concomitant illness (any illness present at screening) 
• 
Concomitant medications (prescription and non-prescription) and date of last change 
in medication regimen  
• 
Height, weight, physical examination, and vital signs including body temperature and 
blood pressure 
• 
12-lead ECG 
• 
Hemoglobin A1c 
• 
Chemistry and hematology samples (see Appendix B) 
• 
Urine HCG pregnancy test for women of childbearing potential 
• 
FSH level for postmenopausal women amenorrheic for less than 1 year 
• 
Fractionated plasma metanephrines (if indicated by history) 
 
7.3 
Training Visit (Visit 2) (Day 1) 
A training visit will take place before the first treatment visit. Patients will be trained in the 
insertion and calibration of the Dexcom G4 sensor and trial policies and procedures. Trial staff 
will verify that the patients have understood the material and are competent to participate 
safely in the trial. Concomitant medications will also be reviewed. 
 
7.4 
Treatment Visits (Visit 3 [Day 8 ±3] and Visit 4 [Day 15 ±3]) 
• 
Up to 2 patients may participate per day.  
• 
Each patient will participate in 2 treatment visits: one with the iLet using ZP4207 and 
one with the iLet using Lilly glucagon in a randomized order. 
• 
The night before the treatment visit, patients will place a Dexcom G4 CGM sensor in 
the abdominal skin and calibrate the sensor when prompted using the provided Nova 
StatStrip Xpress meter. Patients will be instructed to call if they encounter any difficulty 
with their CGM.  
• 
Patients will be responsible for their own medications other than insulin during the trial. 
Any medical advice needed by the patients during their participation that is not directly 
related to BG control should be obtained from them in their usual manner. Patients 
may take any over-the-counter medications that they wish during the trial, with the 
exception of any medication containing acetaminophen as that may cause interference 
with CGM sensing. If patients experience urgent or emergent medical concerns 
outside the scope of diabetes care and their primary care physicians, they will be taken 
to the MGH walk-in clinic or emergency room, or if necessary call 911. 
• 
During the trial, patients will not use any recreational drugs or drugs of abuse. The 
need to take prescription drugs that dull the sensorium, reduce sensitivity to symptoms 
of hypoglycemia, or hinder appropriate decision-making may be grounds for exclusion 
from the trial or discontinuation of participation, a decision that will be made by the 
Investigator.  
• 
Patients will not tamper with the BP, including changing any settings. 
• 
Patients may not remove the BP during the trial unless the BP failed or they are 
withdrawing from the trial. 
• 
The exact time of each procedure and assessment will be documented. 
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7.4.1 
Visit Procedures  
•
Patients will be asked to arrive at the visit at least 1 hour in advance of the start of the
BP having fasted since 12:00 AM the night before (treatment with simple carbohydrate
of up to 30 g for a low is allowed). If the patient is not fasted, the visit will be rescheduled
within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the
visit window.
•
Upon arrival to the visit, the patient’s weight and vital signs including body temperature
will be documented.
•
Patient reports of symptoms, any other complaints, and AEs will be reviewed.
•
Concomitant medications will be recorded.
•
Chemistry and hematology samples will be collected at visit start (see Appendix B).
•
ADA samples will be collected before the start of dosing (Visit 3 only).
•
A 12-lead ECG will be performed.
•
A urine HCG pregnancy test will be performed in female patients of childbearing
potential. If the test is positive, the patient will be informed of the result and the visit
will be ended.
•
Patients will complete a baseline survey about their attitudes and experience with their
usual diabetes care.
•
An intravenous (IV) catheter will be placed for blood sampling.
•
Trial staff will assist the patient to calibrate their CGM, review the trial procedures again
and assist with the setup of the BP system, including inserting and priming infusion
sets.
•
The control algorithm will be initialized only with the patient’s weight. Diagnostics will
be performed to ensure that the CGM device is appropriately calibrated and that all of
the components of the BP systems are in working order.
•
The basal rate of the patient’s own insulin infusion pump will be changed to be 2-fold
higher than weighted mean of the basal rate during the trial period. This is intended to
increase the usage of glucagon during the treatment visit.
•
The patients will continue to wear their own infusion pump infusing at the temporary
2-fold basal rate throughout the visit until the start of the structured exercise period, in
addition to the BP.
•
The staff will start the BP as close as possible to a minute divisible by 5 minutes (i.e., on
a 5-minute mark). The starting time will be considered Hour 0.
•
Additional calibrations will be performed at any of the BG checks throughout the day if
the CGM value does not meet the ISO standard (<15 mg/dL difference for BG values
<75 mg/dL; <20% absolute difference for BG values >75 mg/dL) at the time of the BG
measurement AND it is a good time to calibrate (the CGM trend arrow is flat and there
has been no carbohydrate intake in the last 30 minutes or glucagon boluses in the last
15 minutes).
•
Blood samples will be taken from the IV at least hourly and processed for plasma
ZP4207/glucagon. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG
is <80 mg/dL, then sampling will be every 10 minutes. The actual time of sampling will
be recorded in the eCRF.
•
Plasma glucose samples will be taken from the IV at least hourly in parallel with
ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT Plus.
If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for
glucose measurements. If BG is <100 mg/dL, then sampling will be every 20 minutes.
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If BG is <80 mg/dL, then sampling will be every 10 minutes. The actual time of sampling 
will be recorded in the eCRF. 
• 
Patients will be asked to rate any nausea and/or infusion site pain on 10 cm visual 
analog scales (VAS) at the beginning of the visit once the infusion sites have been 
placed but no drug has yet been administered, then approximately at the top of every 
hour during the visit, and at the end of the visit. Trial staff will also evaluate their infusion 
sites to document any erythema or edema at the same times. If moderate or severe 
pain is reported or swelling or redness occurs at the infusion site, the infusion site will 
be replaced in a different location. If moderate or severe pain, swelling, or redness 
continues at the old site for more than 30 minutes after the infusion site is removed, or 
if moderate or severe pain, swelling, or redness occurs at the new site, all infusion 
sites will be removed and the patient will be discontinued from the study. 
• 
From the start of closed loop control until approximately Hour 3, the patients will 
continue to fast. 
• 
Between approximately Hour 3 and Hour 4, patients will be provided with a lunch meal 
of their choice in the Diabetes Research Center from a menu of choices from nearby 
restaurants. They will be asked to choose a meal that is a “typical meal” for them. The 
content of their meal will not be restricted in any way, with the exception that the 
number of carbohydrates should be in the “typical” range for them at lunch, and that 
they must eat the same meal at the same time during both visits. 
• 
At approximately 15 minutes before the meal, patients will administer a bolus for the 
meal with their own insulin pump based on the carbohydrate count for the meal. 
• 
After lunch is completed, the patients will not be allowed any carbohydrate intake 
(non-caloric drinks will be permitted) until the trial is completed (except as necessary 
to treat hypoglycemia), to allow the BP to control the post-prandial BG without further 
interruption.  
• 
Between approximately Hour 6 and Hour 7, the patients will start a period of structured 
exercise. 
• 
At the start of the exercise period, patients will restore their normal basal insulin profile 
so that they will not have elevated insulin levels at the end of the study period when 
they are to transition back to their usual care.  
• 
Patients will exercise on a stationary bike with a heart rate from 120-140 beats per 
minute for a total of 4,000 heart beats (approximately 30 minutes). Patients will rate 
their exercise intensity using the Borg scale every 5 minutes, with the target intensity 
level between 12 and 14. Heart rate will be measured every 5 minutes. 
• 
BG measurements will be obtained off of the IV line every 10 minutes. If BG is 
<80 mg/dL, BG measurements will be obtained off of the IV line every 5 minutes.  
o 
Carbohydrates will be given for any BG <50 mg/dL according to the following 
protocol: Dextrose (g) = BSA (m2)/[1.7 m2 (women) or 1.9 m2 (men)] *15 g. 
o 
Repeat treatments will be given at 15-minute intervals as long as BG remains 
<50 mg/dL.  
• 
If there is an interruption in the Dexcom CGM output, trial staff will assist the patient in 
recovering CGM data streaming. If this requires replacement of the CGM sensor, BGs 
will be checked every 10 minutes (every 5 minutes if BG is <80 mg/dL) using blood 
from the IV until the CGM is able to be calibrated again. These BGs will be entered 
into the BP, which will treat them as CGM values and dose insulin and/or glucagon 
appropriately. 
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•
If there is a complete failure of the BP operation, patients will take over their own BG
control using their personal insulin pump until the BP can be brought back online. If BP
control cannot be promptly resumed (e.g., within 30 minutes), the patient may be asked
to repeat that trial day once.
•
Patients may choose to withdraw from the trial at any time. If they withdraw from the
trial, they should alert a provider immediately.
•
Just prior to the end of the study visit, vital signs including body temperature will be
obtained and a 12-lead ECG will be performed.
•
After approximately Hour 8, but not earlier than at least 60 minutes after end of
exercise, the BP will be stopped and the patient will continue with their personal insulin
pump.
•
Patients will answer questionnaires (see Appendix C).
•
Chemistry and hematology samples will be collected at visit end (see Appendix B).
•
The BP and glucose meters will be collected and downloaded.
•
A trial MD will review the last several hours of insulin and glucagon dosing and assist
the patient in resuming their usual diabetes care. They will be instructed to call trial
staff with any questions, issues, or concerns.
7.4.2 
Data Collected During the Treatment Visits 
•
CGM glucose every 5 minutes from the Dexcom G4 Platinum CGM
•
All BG measurements taken
•
Insulin total dose by the BP and the patient’s own insulin pump
•
Glucagon total dose
•
Timing and content of the meal eaten and carbohydrate amount
•
Timing of meal announcement and size of meal announced
•
Timing and glucose values at calibrations
•
Timing and amount of carbohydrates taken for hypoglycemia
•
Data from a questionnaire about attitudes and expectations regarding the BP before
the trial and after each treatment arm (see Appendix C)
•
Time patients were not under BP control for any reason
•
List of technical faults associated with the BP including cause and resolution
•
ZP4207/glucagon sampling collected at least hourly. If BG is <100 mg/dL, then
sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will be every
10 minutes.
•
Plasma glucose sampling will be collected at least hourly in parallel with
ZP4207/glucagon exposure sampling. If BG is <100 mg/dL, then sampling will be every
20 minutes. If BG is <80 mg/dL, then sampling will be every 10 minutes.
•
Nausea and infusion site pain on a VAS at visit start (after insertion and before any
drug administration), hourly, and at visit end
•
Infusion site reaction according to the Draize scale at visit start (after insertion and
before any drug administration), hourly, and at visit end
•
Patient reports of symptoms, any other complaints, and AEs
•
Vital signs including body temperature (at visit start and visit end) and weight
•
Concomitant medications
•
Chemistry and hematology samples (see Appendix B) at visit start and visit end
•
ADA (Visit 3 only)
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• 
12-lead ECG at visit start and visit end 
• 
Urine HCG pregnancy test for women of childbearing potential 
7.4.3 
Response to Hypoglycemia  
• 
Patients are encouraged to check their BG for any symptoms of hypoglycemia.  
• 
Patients will be permitted to take 15 grams of carbohydrates for any BG value 
<60 mg/dL. Trial staff will ensure proper functioning of the BP, infusion set, and insulin 
pump, and will encourage the patient to wait for the BP to treat the low blood sugar for 
as long as they feel comfortable. 
• 
Patients will be required to take 15 grams of carbohydrates for any BG value 
<50 mg/dL. After treatment of hypoglycemia, a follow-up measurement will be taken 
15 minutes later. Repeated measurements will be taken every 15 minutes until the 
BG is >60 mg/dL. Treatment will be repeated if subsequent BG values are still 
<50 mg/dL. All carbohydrate treatments for hypoglycemia will be documented by trial 
staff (amount and time).  
• 
Trial staff will check the infusion site, BP, and insulin pump for normal operation any 
time hypoglycemia occurs. If there is any suspicion of infusion set malfunction, the site 
should be replaced. Trial staff will check the BP for any malfunction and correct any 
problems that are found.  
• 
If no correctable fault is found, but there is doubt regarding the correct function of the 
BP system, an entirely new backup BP system may be started. 
• 
If a patient experiences a seizure or unconsciousness associated with hypoglycemia, 
his or her participation in the trial will be discontinued.  
7.4.4 
Response to Hyperglycemia  
• 
Trial staff will check the infusion site, BP, and insulin pump for normal operation any 
time BG is >300 mg/dL. If there is any suspicion of infusion set malfunction, the site 
should be replaced. Trial staff will check the BP for any malfunction and correct any 
problems that are found.  
• 
If no correctable fault is found, but there is doubt regarding the correct function of the 
BP system, the treatment visit may be stopped and the visit rescheduled. 
7.4.5 
Response to Nausea/Vomiting 
If significant nausea (e.g., that prevents the patient from eating normally) or any vomiting 
occurs, trial staff will notify the Investigator. Trial staff will assist the patient in troubleshooting, 
such as checking BG and the calibration of the CGM (excessive glucagon dosing may occur 
if the CGM is reading lower than the true BG). If a patient experiences persistent nausea and 
vomiting thought to be related to glucagon dosing, his or her participation in the trial will be 
discontinued. 
7.4.6 
Response to Other Medical Needs  
If patients experience urgent or emergent medical concerns outside the scope of diabetes 
care and their primary care physicians, they will be taken to the MGH walk-in clinic or 
emergency room, or if necessary call 911.  
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o
Average percent insulin dose amounts successfully issued to the pump by the
BP control algorithm that are successfully delivered by the pump
o
Average percent glucagon/ZP4207 dose amounts successfully issued to the
pump by the BP control algorithm that are successfully delivered by the pump
•
Average percent dose amounts calculated by the BP algorithm that are successfully
issued to the pump by the BP (calculated doses are not issued unless the pump is
accessible and its delivery channel is available)
o
Average percent insulin dose amounts calculated by the BP control algorithm
that are successfully issued by the BP
o
Average percent glucagon/ZP4207 dose amounts calculated by the BP control
algorithm that are successfully issued by the BP
•
Average percent of 5-minute steps during which the BP is functioning nominally in all
respects based on real-time CGM data (new CGM glucose reading captured, dose
calculated, and dose issued to pumps)
•
Average percent of 5-minute steps during which the BP is functioning nominally with
or without a new CGM glucose reading captured (dose calculated and dose issued to
pumps). If a CGM signal is not available, the dose calculated may be based on weight
or historical basal rates.
•
CGM reliability index, calculated as percent of possible values actually recorded by
CGM
•
CGM Mean Absolute Relative Difference versus time-stamped BG values from meter
download
•
List of technical faults associated with the BP including cause and resolution
8.2.2 
Glycemic 
All of following metrics will be generated from the Dexcom G4 Platinum CGM data during each 
treatment visit. 
•
Fraction of time spent within each of the following glucose ranges:
o
<50 mg/dL
o
<60 mg/dL
o
<70 mg/dL
o
70-120 mg/dL
o
70-140 mg/dL
o
70-180 mg/dL
o
>180 mg/dL
o
>250 mg/dL
o
>300 mg/dL
•
Number of severe hypoglycemic events (patients unable to self-treat, requiring the
assistance of another person)
•
Number of episodes of symptomatic hypoglycemia
•
Number of carbohydrate interventions for hypoglycemia
•
Total grams of carbohydrates taken for hypoglycemia
•
Mean CGM glucose
8.2.3 
Non-glycemic 
•
Glucagon/ZP4207 total delivery per kg of body mass
•
Insulin total delivery per kg of body mass
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• 
Number of unscheduled infusion set replacements 
• 
Number of unscheduled CGM sensor changes 
9 
LABORATORY ASSESSMENTS 
Descriptions of sample handling and sample processing, storage, and shipment at the site will 
be included in the laboratory manual. 
 
The responsible laboratories are listed in the address list. 
 
9.1 
Safety Laboratory Assessments 
Chemistry and hematology samples will be collected at specified time points. See Appendix A 
for the schedule of procedures and Appendix B for a list of clinical laboratory analytes. 
 
9.2 
Pharmacodynamic Assessments (Plasma Glucose) 
At Visit 3 and Visit 4, plasma glucose samples will be taken from the IV at least hourly in 
parallel with ZP4207/glucagon exposure sampling and measured using the YSI 2300 STAT 
Plus. If the YSI 2300 STAT Plus and/or IV fails, the Nova StatStrip Xpress will be used for 
glucose measurements. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is 
<80 mg/dL, then sampling will be every 10 minutes. The actual time of sampling will be 
recorded in the eCRF. 
 
9.3 
Exposure Assessments (ZP4207 and Glucagon) 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling 
will be every 10 minutes. The actual time of sampling will be recorded in the eCRF. 
 
Bioanalytical Reports will be prepared. 
 
9.4 
Anti-drug Antibody Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken at specified time points; see Appendix A. 
 
A Bioanalytical Report will be prepared. 
10 
SAFETY REPORTING 
10.1 
Adverse Events  
An AE is any untoward medical occurrence in a trial patient administered an IMP and which 
does not necessarily have a causal relationship with the treatment. An AE can therefore be 
any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an IMP, whether or not considered related to 
the IMP. Patients should be instructed to report any AE they experience to the Investigator. 
 
Note: This includes events from the first trial-related activity from Visit 3.  
 
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AEs for ZP4207 include: 
• 
A clinically significant worsening of a concomitant illness 
• 
A clinical laboratory abnormality which is clinically significant, i.e., any abnormality that 
suggests a disease and/or organ toxicity and is of a severity that requires active 
management. Active management includes active treatment or further investigations, 
for example, change of medicine dose or more frequent follow-up due to the 
abnormality. 
• 
Hypoglycemic episodes  
• 
Injection site reactions 
 
The following should not be recorded as AEs, if recorded prior to randomization (on the 
Screening Form or the eCRF): 
• 
Pre-planned procedure, unless the condition for which the procedure was planned has 
worsened from the first trial-related activity from Visit 3. 
• 
Pre-existing conditions found as a result of screening procedures (pre-existing 
conditions should be reported as medical history or concomitant illness). 
 
For known (listed) AEs for Glucagon and Humalog, please refer to SPC for Glucagon and 
Humalog. 
10.1.1 
Follow-up of Adverse Events 
All AEs that are ongoing at the end of the patient’s participation in the trial will be followed-up 
until the event is resolved or reaches a satisfactory outcome as deemed by the Investigator. 
Follow-up actions for all serious adverse events (SAEs) will be performed according to 
appropriate clinical care practices and may depend on the nature of the event. These will be 
determined after internal review and/or Sponsor review. The follow-up information should only 
include new (updated and/or additional) information that reflects the situation at the time of the 
Investigator’s signature. 
 
Follow-up information on (S)AEs will be updated using the (S)AE Form. If a non-serious event 
becomes serious during the follow-up, the AE Form and SAE Form must be used and reporting 
timelines follow those of an SAE. 
 
The Investigator must forward follow-up information on SAEs, and if previously non-serious 
AEs become SAEs, to the Sponsor. 
10.1.2 
Precautions 
Normal precautions taken for a human trial will be taken during this trial. Qualified and 
well-trained physicians and medical staff will instruct the patients. During a patient’s 
participation in the trial, the Investigator should ensure that adequate medical care is provided 
to the patient for any AEs, including clinically significant laboratory values related to the trial. 
The Investigator should inform the patient when medical care is needed for intercurrent 
illnesses of which the Investigator becomes aware.  
 
For further information on safety precautions for ZP4207, Lilly glucagon, Lilly Humalog, and 
the iLet, please refer to the current version of the Investigator’s Brochure (IB) for ZP4207 
(Zealand Pharma A/S, 2015, or any updates hereof), and the SPC for Glucagon (Eli Lilly, 
2012) and Humalog (Eli Lilly, 2015), respectively. 
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10.1.3 
Assessment of Adverse Events by the Investigator 
Intensity of an Adverse Event 
The maximum intensity (severity) of all AEs must be assessed by the Investigator and 
documented. Severity should be graded when the AE outcome is known: 
•
Mild: A type of AE that is usually transient and may require only minimal treatment or
therapeutic intervention. The event does not generally interfere with usual activities of
daily living.
•
Moderate: A type of AE that is usually alleviated with additional specific therapeutic
intervention. The event interferes with usual activities of daily living, causing discomfort
but poses no significant or permanent risk of harm to the patient.
•
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects
clinical status, or may require intensive therapeutic intervention.
A “severe” reaction does not necessarily deem the AE as “serious,” and an SAE may not be 
“severe” in nature. 
Causality Relationship to IMP 
Insulin (insulin lispro, Lilly Humalog), glucagon (glucagon for injection, Eli Lilly), and ZP4207 
are all regarded as IMP. 
The causality of each AE should be assessed by the Investigator according to the following 
classification: 
•
Related: Good reason and sufficient documentation to assume a causal relationship.
•
Not related: No relationship to trial product can be established.
Outcome of an Adverse Event 
The outcome of all AEs must be assessed by the Investigator and documented by his/her 
staff. The following definitions should be used: 
•
Recovered/resolved: The patient has fully recovered, or by medical or surgical
treatment the condition has returned to the level observed at the first trial-related
activity from Visit 3.
•
Recovering/resolving: The condition is improving and the patient is expected to recover
from the event. This term is only applicable if the patient has completed the trial.
•
Recovered/resolved with sequelae: The patient has recovered from the condition, but
with lasting effect due to a disease, injury, treatment, or procedure. If a sequela meets
an SAE criterion, the AE must be reported as an SAE.
•
Not recovered/not resolved: The condition of the patient has not improved and the
symptoms are unchanged, or the outcome is not known.
•
Fatal: This term is only applicable if the patient died from a condition related to the
reported AE. Outcomes of other reported AEs in a patient before he/she died should
be assessed as “recovered/resolved,” “recovering/resolving,” “recovered/resolved with
sequelae,” or “not recovered/not resolved.” An AE with a fatal outcome must be
reported as an SAE.
•
Unknown: This term is only applicable if the patient is lost to follow-up.
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10.2 
Serious Adverse Events   
An SAE is any untoward medical occurrence that at any dose: 
•
Results in death
•
Is life-threatening
•
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability or incapacity
•
Is a congenital anomaly or birth defect
•
Medically important
Medical judgement must be exercised in deciding whether an AE is believed to be “medically 
important.” Medically important events may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above. 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is an AE fulfilling one of the criteria of seriousness and being assessed as related 
to an IMP, the nature or severity of which is not consistent with the applicable reference 
document (e.g., ZP4207 IB or package leaflet/SPC for an approved product). 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety, any life-threatening problem or 
death caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the application; or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. 
10.3 
Adverse Event Reporting – Procedures for Investigators 
The Principal Investigator and co-investigators will review any AEs and report any SAEs to 
the Sponsor as soon as possible and within 24 hours of obtaining knowledge of the event. The 
Principal Investigator and co-investigators will promptly report AEs to the Partner’s Institutional 
Review Board (IRB) and to the BU IRB (unless oversight is ceded by the BU IRB to the 
Partners IRB), in accordance with local requirements.  
Ed Damiano is the Sponsor of the Investigational Device Exception for the BP and Zealand 
Pharma A/S is the Sponsor of the IND for ZP4207.  
Reports of AEs will be submitted to the FDA in compliance with the terms of the Code of 
Federal Regulations. 
All events meeting the definition of an AE must be collected and reported from the first 
trial-related activity from Visit 3 until the end of the post-treatment follow-up period. At each 
contact with the site (visit or telephone, excluding safety visits, where the patient is not seeing 
the Investigator or staff [e.g., visits to the laboratory], the patient must be asked about AEs. 
All AEs, either observed by the Investigator or reported by the patient, must be recorded by 
the Investigator and evaluated. 
The Investigator should record the diagnosis, if possible. If no diagnosis can be made, the 
Investigator should record each sign and symptom as individual AEs. 
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•
All SAEs in connection with the pregnancy and pregnancy outcome must be reported
on the pregnancy forms following the same timelines as required for other SAEs. It
must be clear in the description if the event occurs in the patient/patient’s partner, the
fetus, or the newborn infant.
The SAEs that must be reported include abnormal outcome – such as congenital anomalies, 
fetal death, and termination of pregnancy (spontaneous or elective abortion), including any 
anomalies of the fetus observed at gross examination or during autopsy – as well as other 
pregnancy complications (ectopic pregnancy) fulfilling the criteria of an SAE. 
10.5 
Hypoglycemia 
Hypoglycemia will be regarded as an AE and will be recorded and documented on an AE 
Form. For the purposes of AE reporting, the following definitions of hypoglycemia will be used: 
•
Symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia
are accompanied by a BG concentration ≤70 mg/dL 
•
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of
hypoglycemia but with a BG concentration ≤50 mg/dL 
•
Severe hypoglycemia: an event requiring assistance of another person to actively
administer carbohydrates, glucagon, or take other corrective actions 
10.6 
Safety Monitoring 
10.6.1 
Data and Safety Monitoring Board 
An external DSMB will oversee the conduct of the trial, as set forth in the DSMB Charter. 
Additionally, the DSMB will be informed in the event of any serious and unexpected AEs. The 
DSMB will be informed if there are any changes to the trial protocol that could significantly 
impact the safety or scientific validity of the trial. A final DSMB meeting will convene after the 
completion of the trial. 
The participation of individual patients will be discontinued if they experience: 
•
Seizure or unconsciousness associated with hypoglycemia and associated with
participation in the trial 
•
Persistent nausea and vomiting thought to be related to glucagon dosing associated
with participation in the trial 
•
Hospitalization associated with participation in the trial
•
Pregnancy
If more than 1 patient must be withdrawn from the trial for these reasons, the trial will stop and 
a vote of the DSMB will be required to restart it. All AEs that are serious and unexpected but 
related will be reported to the DSMB within 5 working days. 
Note that patients may discontinue participation at any time. Patients may be removed from 
the trial for other reasons, for instance, failure to comply with trial procedures or intercurrent 
illness that is unrelated to the BP but that precludes safe participation. Discontinuation of 
participation for these reasons will not contribute to a decision to discontinue the trial.  
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10.6.2 
Zealand Pharma Safety Committee 
The internal Zealand Pharma Safety Committee is constituted to perform ongoing safety 
surveillance of clinical trials within ZP4207, including this trial. 
 
If safety signals are observed either based on reported SAEs, periodic review of laboratory 
parameters, planned review of all AEs reported between the safety committee meetings, or 
on notification of significant findings, the Safety Committee will take appropriate measures to 
safeguard the patients. 
11 
STATISTICS  
11.1 
Analysis Populations  
The following analysis sets are defined in accordance with the ICH-E9 guidance: 
 
The Full Analysis Set is based on the intention-to-treat principle and includes all randomized 
patients. In exceptional cases, patients from the Full Analysis Set may be excluded (will be 
decided in the database review [DBR] meeting). In such cases, the exclusion will be justified 
and documented. Patients will contribute to the evaluation “as randomized.” 
 
The Per-Protocol Set includes all patients of the Full Analysis Set who completed the trial 
without any major protocol violations. Patients in the Per-Protocol Set will contribute to the 
evaluation “as treated.” This analysis will only be used if it is different than the Full Analysis 
Set. 
 
The Safety Analysis Set includes all patients receiving at least 1 dose of the IMP. Patients in 
the Safety Analysis Set will contribute to the evaluation “as treated.”  
 
Analyses of efficacy endpoints will be based on the Full Analysis Set (and the Per-Protocol 
Set if necessary). This decision will be made in the DBR meeting. The analysis of the safety 
endpoints will be based on the Safety Analysis Set.  
 
Before data are released for statistical analysis, a blinded review of all data will take place to 
identify protocol deviations that may potentially affect the results. At this time, it will be 
determined if patients and/or data should be excluded from the analysis. Furthermore, outliers 
will be identified by data review according to ICH-E9. 
 
Obviously erroneous data points may be excluded from the analyses or re-analyzed 
(e.g., serum concentrations). The decision to re-analyze or exclude data points from the 
statistical analysis is the joint responsibility of the Sponsor, the Principal Investigator, and the 
Trial Statistician. 
  
The patients or observations to be excluded and the reason for their exclusion will be 
documented and signed by those responsible prior to database release. The documentation 
will be stored together with the remaining trial documentation. The patients and observations 
excluded from analysis sets, and the reason for this, will be described in the clinical trial report. 
 
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11.2 
Statistical Methods  
Medpace will be responsible for the statistical analysis. The statistical planning and conduct 
of analyses of the data from this trial will follow the principles defined in relevant ICH guidelines 
and Medpace’s biostatistical standard operating procedures (SOPs). A general description of 
the statistical methods to be used is given in this section, specific details will be provided in 
the Statistical Analysis Plan (SAP), which will be prepared before database lock. All statistical 
analyses will be performed using SAS® (SAS Institute Inc., Cary, North Carolina, USA), 
version 9.4 or later.  
11.2.1 
Analysis of Safety 
The following variables will be evaluated according to treatment for safety purposes: 
Adverse Events 
All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). Individual AEs will be presented in a listing including relationship to trial 
product/device, severity, and treatment period at onset. If more than 20 treatment-emergent 
AEs (AEs with onset after [first] dosing at Visit 3 until the follow-up Visit 6) are registered, a 
summary table including number of AEs, number of patients with at least 1 AE, and percentage 
of exposed patients with at least 1 AE will be made by system organ class and treatment 
period at onset. 
Local Tolerability 
Local tolerability at the injection site will be summarized using descriptive statistics as 
appropriate. 
Laboratory Safety Assessments 
Laboratory assessments will be summarized. A listing of abnormal values will be provided. 
Physical Examination 
A frequency table will show the number and percentage of physical examination results. 
Vital Signs 
Vital signs will be summarized using descriptive statistics. 
12-lead ECG 
The Investigator’s evaluations of 12-lead ECGs will be summarized and abnormal individual 
evaluations will be listed together with the Investigator’s comments. Changes in 12-lead ECG 
between measurements will be recorded as AEs if the Investigator judges them to be clinically 
significant.  
11.2.2 
Analysis of Efficacy 
The analysis of BP function endpoints and glycemic endpoints will be on an intention-to-treat 
basis. In cases where a treatment arm was not completed (and that arm was not repeated 
according to protocol criteria), available data from that arm will be used in the data analysis.  
The Shapiro-Wilk test will be used to determine the normality of the residuals for each 
comparison. Summary tables that display descriptive statistics, including percentages, means 
or medians, and standard deviation and/or ranges, as appropriate, will be provided. 
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A paired t-test or the Wilcoxon signed rank test for comparison of means with normally or 
non-normally distributed residuals, respectively, will be used. In a secondary analysis, any 
period effect and any interaction between treatment and period will be looked for, although no 
such interaction is predicted for the efficacy outcome. Further details will be included in the 
SAP. 
The number of patients and proportions of severe hypoglycemic events, symptomatic 
hypoglycemia, and carbohydrate interventions due to hypoglycemia with the event counts will 
be summarized descriptively, and the proportions will be analyzed by a Fisher’s exact test if 
data allow.  
11.2.3 
Interim Analysis 
No interim analysis is planned. 
11.2.4 
Sample Size Determination 
No formal sample size calculations were made. It is expected that between 10 and 12 patients 
will be randomized in the trial. The sample size is based on a clinical rather than statistical 
rationale. The sample size is considered adequate to address the primary trial objective of 
exploring the safety of ZP4207 when used in the iLet and with reference to Lilly glucagon used 
in the iLet. 
12 
DATA MANAGEMENT AND RECORD KEEPING 
Data Management is the responsibility of Medpace. The complete Data Management process 
will be described in detail and agreed on in the Data Management Plan for this trial. 
12.1 
Data Handling 
Case Report Forms 
Electronic Case Report Forms will be used in this trial. The Data Management Department of 
Medpace will provide the eCRFs. All further information regarding the eCRFs and the data 
flow will be described and agreed on in the Data Management Plan. 
Device-Related Data 
During the trial, CGM data, calibration data, insulin dosing data, and glucagon dosing data will 
be automatically stored in the BP device (from which it will be downloaded at intervals), 
combined in a single database that will be compared against the primary data files for integrity, 
and ultimately transferred to Medpace.  
12.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
12.3 
Data Entry 
Data must be recorded using the electronic data capture (EDC) system as the trial is in 
progress. The patient questionnaires will be transcribed into the EDC system by site 
personnel. All site personnel must log into the system using their secure user name and 
password in order to enter, review, or correct trial data. These procedures must comply with 
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Title 21 of the Code of Federal Regulations (21 CFR Part 11) and other appropriate 
international regulations. All passwords will be strictly confidential. 
 
12.4 
Medical Information Coding  
Adverse events and medical history will be coded using the latest version of MedDRA. Prior 
and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. 
 
12.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, 
will be referred to the investigative site for resolution through data queries. 
 
The eCRFs must be reviewed and electronically signed by the Investigator. 
 
12.6 
Record Keeping 
Medpace will be responsible for hosting the TMF. Records of patients, source documents, 
monitoring visit logs, eCRFs, inventory of trial product, regulatory documents, and other 
Sponsor correspondence pertaining to the trial must be kept in the appropriate trial files at the 
site. Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
evaluation and reconstruction of the clinical trial. Source data are contained in source 
documents (original records or certified copies). These records will be retained in a secure file 
for the period as set forth in the Clinical Trial Agreement. Prior to transfer or destruction of 
these records, the Sponsor must be notified in writing and be given the opportunity to further 
store such records. 
13 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
13.1 
Ethical Conduct of the Trial 
The trial will be conducted according to Medpace, MGH, and/or the Sponsor’s written 
instructions (SOPs, working instructions, or process descriptions). Content and definitions of 
the written instructions are based on the Declaration of Helsinki and the ICH GCP.  
 
13.2 
Institutional Review Board  
Written favorable opinion must be obtained from the responsible IRB prior to commencement 
of the trial. Clinical trial submission and reporting requirements before, during, and after 
completion of the trial will be performed in accordance with national law and local regulations.  
 
All amendments that affect patient safety or the trial integrity (substantial amendments) must 
not be implemented before favorable opinion has been obtained, unless necessary to 
eliminate hazards to the patients. Non-substantial amendments do not require favorable 
opinion by the IRB, but the respective IRB will be notified according to local requirements.  
 
The Sponsor and Investigator must approve any amendment in writing before its 
implementation. 
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The Sponsor must maintain an accurate and complete record of all submissions made to the 
IRB. The records should be filed in the Sponsor’s Trial Master File (TMF). 
13.3 
Informed Consent 
In obtaining and documenting informed consent, the Investigator must comply with the 
applicable regulatory requirement(s) and adhere to the ICH GCP guideline and the 
requirements in the Declaration of Helsinki. 
Prior to any trial-related activity, the Investigator must give the patient oral and written 
information in a form that the patient can read and understand about all aspects of the trial 
that are relevant to the patient’s decision to participate. The patient will be given ample time 
to decide whether or not to participate in the trial. 
The patient must be informed that his/her personal trial-related data will be used in accordance 
with the local data protection law. The level of disclosure must also be explained to the patient. 
The patient must be informed that his/her medical records may be examined by authorized 
monitors or Clinical Quality Assurance auditors appointed by the Sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
A voluntary, personally signed and dated ICF must be obtained from the patient prior to any 
trial-related activity. The ICF must also be signed and dated by the physician or designee who 
conducted the informed consent procedure. A signed copy of the ICF and any additional 
patient information must be given to each patient.  
The responsibility for taking informed consent must remain with that of a research physician 
or designee. If information becomes available that may be relevant to the patient’s willingness 
to continue participating in the trial, the Investigator must inform the patient in a timely manner, 
and a revised written informed consent must be obtained. 
Should a protocol amendment become necessary, the ICF may need to be revised to reflect 
the changes to the protocol. It is the responsibility of the Sponsor to ensure that an amended 
consent form is reviewed and has received favorable opinion from IRB, and the Investigator 
must ensure that the amended consent form is signed by all patients subsequently entered 
into the trial and those currently in the trial, if affected by the amendment. 
13.4 
Trial Monitoring Requirements 
The monitoring procedures for this trial are described in detail in the Monitoring Manual. The 
objectives of the monitoring procedures are to ensure that (i) the safety and rights of the trial 
patients are respected, (ii) that accurate, valid, and complete data are collected, and (iii) that 
the trial is conducted in accordance with the trial protocol, the principles of GCP, and local 
legislation, including drug accountability. 
The monitor must be given direct access to the investigational site files and source documents 
(original documents, data, and records). Direct access includes permission to examine, 
analyze, verify, and reproduce any record(s) and report(s) that are important to evaluation of 
the clinical trial. 
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Key tasks of the monitor include verifying the presence of informed consent, the adherence to 
the inclusion/exclusion criteria, the documentation of SAEs, and the recording of all safety and 
efficacy variables. The monitor will also confirm the completeness of patient records, the 
adherence to the protocol, ICH GCP, and the progress in patient enrollment and perform drug 
accountability.  
 
Because no information that could reveal the identity of patients may ever be removed from 
the trial site, the monitor will visit the site at regular intervals to perform these monitoring tasks. 
Other contact between the Investigator and monitors will be maintained as required through 
telephone calls and e-mail. The Investigator and/or key members of staff involved in the trial 
must be available to assist the monitors during all visits.  
 
Site Initiation Visit 
During the Site Initiation Visit (SIV) the CRO, Sponsor, and/or monitors will go through 
information on the IMP, the protocol, the eCRFs, and other key aspects of the trial with the 
Investigator and the key members of staff involved in the trial. The topics of the SIV are 
documented in a SIV report made available to the Investigator. Documentation on the SIV 
(e.g., power point presentation) should be filed by both Investigator and Sponsor. 
 
13.5 
Disclosure of Data 
Data generated by this trial must be available for inspection by the FDA, the Sponsor or their 
designee, applicable foreign health authorities, and the IRB as appropriate. Patients or their 
legal representatives may request their medical information be given to their personal 
physician or other appropriate medical personnel responsible for their welfare. 
 
Patient medical information obtained during the trial is confidential and disclosure to third 
parties other than those noted above is prohibited. 
 
13.6 
Retention of Records  
Massachusetts General Hospital will maintain the patient’s medical file according to local 
regulations. MGH will archive the documentation pertaining to the trial in an archive after 
completion or discontinuation of the trial if not otherwise notified. MGH should not destroy any 
documents without prior permission from the Sponsor. 
 
The documentation includes all the raw data generated during the clinical trial, the 
investigational site files, and a copy of the clinical trial report. The documents will be retained 
for a period of at least 15 years at archives by MGH, or its sub-contractor. After this period, 
the Sponsor will be contacted and their advice sought on the return or further retention of the 
trial records. 
 
The Sponsor will maintain the documentation pertaining to the trial in accordance with national 
regulations. 
 
13.7 
Publication Policy  
The Principal Investigator of the trial will review and sign the clinical trial report. A summary of 
the final clinical trial report will be submitted to the IRB and Competent Authority. 
  
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According to the Declaration of Helsinki Investigators and Sponsors “have ethical obligations 
with regard to the publication and dissemination of the results of research.” The trial design 
and results may be published as one or more original research manuscripts/abstracts and 
presented at a scientific meeting. The Investigator and Sponsor reserve the right to review any 
proposed presentation of the results of this trial before they are submitted for publication. 
Authorship on any publication(s) resulting from this clinical trial will be assigned according to 
the recommendations of the International Committee of Medicinal Journal Editors. 
Participating patients will not be identified by name in any published reports about the clinical 
trial. 
The Sponsor is responsible for trial registration at ClinicalTrials.gov (www.clinicaltrials.gov) 
according to the requirements from the FDA. 
13.8 
Legal Aspects 
An implicit or explicit approval must be obtained from the Competent Authority prior to 
commencement of the trial. Clinical trial submission and reporting requirements before, during, 
and after completion of the trial will be performed in accordance with national law and local 
regulations. 
An implicit or explicit approval will also be mandatory before implementation of substantial 
changes. Non-substantial amendments do not require approval from the Competent Authority 
but will be notified according to local requirements. 
The Sponsor and Investigator must approve the amendment in writing before its 
implementation. 
The Sponsor must maintain an accurate and complete record of all submissions made to the 
Competent Authority. The records should be filed in the Sponsor’s TMF. 
Audits and Inspections  
In the event of an audit, representatives of the Sponsor or designee, or national and 
international regulatory authorities may request access to all trial records for inspection and 
copying. Such access must be stated in the ICF signed by the patient. 
13.9 
Sponsor Discontinuation Criteria 
The Sponsor, Investigator, or a pertinent regulatory authority may decide to stop the trial or 
part of the trial at any time but agreement on procedures to be followed must be obtained. 
Conditions that may warrant termination of the clinical trial include, but are not limited to: 
•
Safety or administrative reasons
•
The discovery of an unexpected, relevant, or unacceptable risk to the patients enrolled
in the clinical trial
•
A decision of the Sponsor to suspend or discontinue investigation of the IMP
If the trial is prematurely terminated or suspended, the Investigator should promptly inform the 
patients and assure appropriate therapy and follow-up. Furthermore, the Sponsor should 
promptly inform the IRB and provide a detailed written explanation. The pertinent regulatory 
authorities should be informed according to national regulations. 
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If after the termination of the trial the risk/benefit analysis has changed, the new evaluation 
should be provided to the IRB in case it will have an impact on the planned follow-up of the 
patients who have participated in the trial. Necessary actions needed to protect the patients 
should be described. 
 
13.10 
Patient Compensation 
Financial compensation will be provided to all patients who complete the Screening Visit. 
Patients will be paid $25 for completing the Screening Visit whether or not they are eligible to 
participate in the trial. Patients will be compensated $25 for completing the Training Visit. 
Patients will be compensated $100 for completing each of the 2 treatment visits, $25 for 
completing the phone call, and $25 for completing the Follow-Up Visit. Thus, the total 
compensation for a patient who completes the trial would be $300. Patients who are unable 
to complete the trial or choose to stop participation will receive prorated compensation for 
each visit. In addition to the monetary compensation, the cost of the patients’ lunch meals 
during their participation in the trial, as well as the patients’ parking at each visit, will be covered 
by trial funds.  
14 
TRIAL ADMINISTRATIVE INFORMATION 
14.1 
Protocol Amendments  
Any amendments to the trial protocol will be communicated to the Investigators by Medpace 
or the Sponsor. All protocol amendments will undergo the same review and approval process 
as the original protocol. A protocol amendment may be implemented after it has been 
approved by the IRB, unless immediate implementation of the change is necessary for patient 
safety. In this case, the situation must be documented and reported to the IRB within 5 working 
days. 
 
14.2 
Address List 
14.2.1 
Sponsor 
Zealand Pharma A/S 
Smedeland 36 
DK-2600 Glostrup (Copenhagen) 
Denmark 
Telephone: +45 88 77 36 00 
Facsimile: +45 88 77 38 98 
14.2.2 
Supplier of Device 
, PhD 
Beta Bionics, Inc. 
Business Innovation Center, Photonics Center 
8 Saint Mary’s Street, Suite 936 
Boston, Massachusetts 02215-2421 
United States 
Tel: 
 
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APPENDIX A: SCHEDULE OF PROCEDURES 
Trial Visit 
Visit 1 [1]
Screening 
Visit 2
Training 
Visit 3 [2] [3] 
Treatment 
Visit 4 [2] [3]
Treatment 
Visit 5
Phone Call 
Visit 6
Follow-Up 
Trial Day 
Up to 30 days
prior to Visit 2 
Day 1
Day 8 
(±3 days) 
Day 15
(±3 days) 
Day 22
(±3 days) 
Day 40
(±3 days) 
Informed consent 
X 
Assess/confirm elig bility 
X 
X 
Demographics 
X 
Medical, surgical, and social history; 
allergies  
X 
Concomitant illness 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Height, weight, physical examination, and 
vital signs including body temperature 
and blood pressure [4] 
X 
X [5] 
X [5] 
12-lead ECG 
X 
X [6] 
X [6] 
Urine HCG pregnancy test and menstrual 
history [7]   
X 
X 
X 
FSH [8] 
X 
Screening labs – HbA1c, optional 
fractionated metanephrines [9] 
X 
Safety lab sampling including chemistry 
and hematology 
X 
X [6] 
X [6] 
X 
Training on devices [10] 
X 
Monitored BP use 
X 
X 
Plasma glucose sampling [11] 
X 
X 
ZP4207/glucagon exposure sampling [12] 
X 
X 
Nausea and infusion site pain VAS and 
infusion site reaction Draize scale (visit 
start [11], hourly, & visit end) 
X 
X 
Standardized lunch [13] 
X 
X 
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Trial Visit 
Visit 1 [1]
Screening 
Visit 2
Training 
Visit 3 [2] [3] 
Treatment 
Visit 4 [2] [3]
Treatment 
Visit 5
Phone Call 
Visit 6
Follow-Up 
Trial Day 
Up to 30 days
prior to Visit 2 
Day 1
Day 8 
(±3 days) 
Day 15
(±3 days) 
Day 22
(±3 days) 
Day 40
(±3 days) 
In-clinic exercise [14] 
X 
X 
Questionnaires (pre & post BP) 
X 
X 
ADA 
X [15] 
X 
Adverse event review 
X 
X 
X 
X 
1.
Once the patient has been enrolled and eligibility has been established, the order of the iLet visits will be randomized in blocks of 2 patients.
2.
Each patient will participate in 2 treatment visits: one with the iLet using ZP4207 and one with the iLet using Lilly glucagon in a randomized order. Up to 2 patients can participate in the
trial per day.
3.
The night before the visit, patients will place a Dexcom G4 CGM sensor in the abdominal skin and calibrate the sensor when prompted using the provided Nova StatStrip Xpress meter.
Patients will arrive at the visit at least 1 hour in advance of the start of the BP having fasted since 12 00 AM the night before (treatment with simple carbohydrate of up to 30 g for a low is
allowed). If the patient is not fasted, the visit will be rescheduled within the visit window. If BG is >250 mg/dL, the visit will be rescheduled within the visit window.
4.
Height, blood pressure, and physical examination will be measured at Visit 1 only.
5.
Vital signs including body temperature will be obtained at visit start and visit end.
6.
At visit start and visit end.
7.
Urine HCG pregnancy test only for women of childbearing potential. The date of the last menstrual period in female patients will be obtained at Visit 1 only.
8.
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year.
9.
If indicated by history.
10.
Patients will be trained in the insertion and calibration of the Dexcom G4 sensor and trial policies and procedures.
11.
Collected at least hourly. If BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then sampling will be every 10 minutes.
12.
Once the infusion sites have been placed but no drug has yet been administered.
13.
Between approximately Hour 3 and Hour 4.
14.
Between approximately Hour 6 and Hour 7.
15.
Before the start of dosing.
ADA = anti-drug antibodies; BG = blood glucose; BP = bionic pancreas; CGM = continuous glucose monitor; ECG = electrocardiogram; FSH = follicle-stimulating hormone; 
HbA1c = hemoglobin A1c; HCG = human chorionic gonadotropin; VAS = visual analog scale.
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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Chemistry 
Alanine aminotransferase 
Aspartate aminotransferase 
Alkaline phosphatase 
Total protein 
Albumin 
Total and direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Creatinine 
Estimated glomerular filtration rate 
Blood urea nitrogen 
Uric acid
Bicarbonate 
Sodium 
Potassium 
Calcium 
Chloride 
Phosphorus 
Hematology 
Hemoglobin 
Hematocrit 
Red blood cell count 
White blood cell count and differential 
Platelets 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Pregnancy Test 
A urine HCG pregnancy test will be performed at screening, Visit 3, and Visit 4 only for 
women of childbearing potential. 
Anti-drug Antibody Assessments 
Blood samples (including back-up samples) for serum anti-ZP4207 and anti-glucagon 
antibodies will be taken prior to first dosing (Visit 3) and at the Follow-up Visit (Visit 6). 
ZP4207/Glucagon Exposure Sampling 
At Visit 3 and Visit 4, ZP4207/glucagon exposure sampling will be collected at least hourly. If 
BG is <100 mg/dL, then sampling will be every 20 minutes. If BG is <80 mg/dL, then 
sampling will be every 10 minutes. 
Screening Visit Only 
Test for FSH level only for postmenopausal women amenorrheic for less than 1 year 
Optional fractionated plasma metanephrines (if indicated by history) 
Hemoglobin A1c 
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APPENDIX C: BRIEF DESCRIPTION OF QUESTIONNAIRES  
Diabetes Treatment Satisfaction Questionnaire - Status (DTSQs)  
The DTSQs measures patient satisfaction with diabetes treatment. It consists of a 6 item scale 
for assessing treatment satisfaction and two additional items assessing perceived frequency 
of hyperglycemia and hypoglycemia. The DTSQs is meant for adults and older children. 
Dr. Clare Bradley has produced a version that is appropriate for bionic pancreas studies for 
this use, along with a version for younger children. It is administered before the intervention. 
The DTSQs is valid and reliable. Administration time is less than 5 minutes. 
 
Diabetes Treatment Satisfaction Questionnaire – Change (DTSQc) 
Although the DTSQ is responsive to treatment changes, ceiling effects are often seen with this 
instrument, where maximum or close-to-maximum scores at baseline provide little opportunity 
for registering improvement. The DTSQc contains the same items as the DTSQs version but 
asks patients to consider their satisfaction with their current treatment compared with their 
previous treatment. The DTSQc is meant for adults and older children. Dr. Clare Bradley has 
produced a version that is appropriate for bionic pancreas studies for our use, along with a 
version for younger children. It is administered during and at the end of the intervention. The 
DTSQc is valid and reliable. Administration time is less than 5 minutes. 
 
T1-Diabetes Distress Scale (T1-DDS) 
The T1-DDS is a 28-item survey that assesses seven sources of diabetes distress for type 1 
adults. It captures feelings of powerlessness; management distress; hypoglycemia distress; 
negative social perceptions by others; eating distress; physician (health care) distress; and 
friend/family distress. Items are scored on a 6-point scale from not a problem to a very serious 
problem. It is administered before, during, and at the end of the intervention. The scale is valid 
and reliable, and has been shown to be sensitive to change over time. Administration time is 
5 minutes. 
 
Problem Areas in Diabetes Survey (PAID) 
There are three versions of the PAID: Teen (PAID-T), Parent (PAID-P), and Child (PAID-C) 
versions. This measure of diabetes-specific emotional distress in youth with diabetes and their 
parents is 26 items. A total score is generated. It is administered before, during, and at the 
end of the intervention. The PAID-T and PAID-P are valid and reliable. Psychometric analysis 
of the PAID-C is in progress. Administration time is 5 minutes. 
 
Hypoglycemia Fear Survey (HFS) 
There are three versions of the HFS, Adult (HFS), Youth (HFS-Y) and Parent (HFS-P). The 
HFS measures several dimensions of fear of hypoglycemia among adults with type 1 diabetes. 
It consists of 23 items and produces two sub-scale scores; a Behavior sub-scale that 
measures behaviors involved in avoidance and/or over-treatment of hypoglycemia and a 
Worry sub-scale that measures anxiety and fear surrounding hypoglycemia. The HFS-Y 
consists of 25 items and the HFS-P consists of 26 items; both produce sub-scale scores 
similar to the Adult HFS. It is administered before, during, and at the end of the intervention. 
All versions of the HFS are valid and reliable. Administration time is 5-10 minutes. 
 
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Impact of Daily Diabetes Demands (IDDD) 
There are four versions of the IDDD; Adult (IDDD-A), Youth (IDDD-Y), Parent (IDDD-P), and 
Significant Other (IDDD-SO). This instrument measures the burden related to the demands of 
the daily diabetes regimen and is 22 items. A total score is generated. It is administered before, 
during, and at the end of the intervention. Psychometric analysis of the IDDD-Y is in progress 
using the data from the second Bionic Pancreas Camp Study in pre-adolescent children, and 
of the IDDD-A is in progress using data from the Bionic Pancreas Multicenter Study in adults. 
Administration time is 5 minutes. 
Bionic Pancreas User Opinion Survey (BPUOS) 
There are four versions of the BPUOS; Adult (BPUOS-A), Youth (BPUOS-Y), Parent 
(BPUOS-P), and Significant Other (BPUOS-SO). This measure assessing both the benefits 
from, and difficulties with, use of the bionic pancreas, and consists of 38 items. A total score 
is generated. It is administered during and at the end of the intervention. Psychometric 
analysis of the BPUOS-Y is in progress using the data from the second Bionic Pancreas Camp 
Study in pre-adolescent children, and of the BPUOS -A is in progress using data from the 
Bionic Pancreas Multicenter Study in adults. Administration time is 10 minutes. 
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