Clinical trial NCT04028960
Conditions: Type1diabetes
Sponsor: HealthPartners Institute
Start date: 2019-10-23; Completion date: 2020-04-08
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine how Humulin-R regular insulin affects the body's ability to feel low blood sugar (hypoglycemia) when delivered intranasally compared to placebo in subjects with Type 1 Diabetes (T1D) with hypoglycemia awareness. The study will use continuous glucose monitoring (CGM) to collect this information. The study drug or placebo will be administered using an intranasal device.

Detailed description:
Hypoglycemia occurs with high frequency among patients with T1D. With repeated episodes of hypoglycemia, the counter-regulatory pathways to restore normal glucose are blunted, and patients can become unaware of the hypoglycemia. It is estimated that 40% of patients with T1D have hypoglycemia unawareness.

The study has the following objectives:

1. Primary:

   a. To assess non-inferiority of dangerous hypoglycemia with administration of intranasal insulin in T1D participants with intact awareness of hypoglycemia.
2. Secondary:

   1. To describe changes in overall glycemic control with administration of intranasal insulin in T1D participants with intact awareness of hypoglycemia
   2. To describe changes in hypoglycemia awareness with administration of intranasal insulin in T1D participants with intact awareness of hypoglycemia
   3. To describe changes in safety endpoints with administration of intranasal insulin in T1D participants with intact awareness of hypoglycemia.
3. Exploratory:

   1. To describe changes in memory, attention and executive function with administration of intranasal insulin in T1D participants with intact awareness of hypoglycemia

Arms: arm 1: No active drug arm 2: Insulin
Interventions: intervention 1: Regular insulin (Humulin-R), intranasal route intervention 2: SipNose intranasal device
Intervention descriptions: intervention 1: Humulin-R insulin is approved by the U.S. Food and Drug Administration (FDA) for the treatment of diabetes. intervention 2: The SipNose device is an aerosol nasal delivery platform that uses pressurized delivery through the discharge of compressed air, resulting in an aerosol that delivers the drug in a narrow plume geometry, which targets the olfactory epithelium in the upper nasal cavity. From the olfactory epithelium, therapeutics rapidly reach the central nervous system, traveling extracellularly along the olfactory nerves. The device is not currently commercially available, but numerous studies have demonstrated its ability to intranasally deliver radiolabeled and therapeutic compounds to the brain.

Protocol documents:
Prot_SAP_000.pdf: 
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Intranasal Insulin: A Novel Therapy for Hypoglycemia Unawareness in Type 1 Diabetes 
 
 
 
Clinical Study Protocol 
Amendment 03 
US IND Number: 144462 
Serial Number: 0000 
Sponsors 
 
International Diabetes Center 
3800 Park Nicollet Blvd 
Minneapolis, MN 55416 
 
Funding Support 
JDRF 
Grant Number: 2-SRA-2018-601-M-B 
 
 
 
 
 
 
This study will be conducted in compliance with the protocol, IND regulations and other applicable regulatory 
requirements. 
 
 
 
 
 
 
Confidential Information 
No use or disclosure of this document outside HealthPartners Center for Memory and Aging or International Diabetes 
Center is permitted without prior written authorization from HealthPartners Center for Memory and Aging and 
International Diabetes Center. 
 
 


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PROTOCOL SIGNATURE PAGE 
 
 
 
 
 
 
 
I have read this protocol and agree to adhere to the requirements. I will provide copies of this protocol and pertinent 
information to the study personnel under my supervision and my hospital ethics committee/institutional review 
board (EC/IRB). I will discuss this material with them and ensure they are fully informed regarding the study 
medication and the conduct of the study according to this protocol, applicable law, applicable regulatory 
requirements including 21 CFR parts, 50, 54, 56 and 812, general standards of good clinical practice and hospital 
EC/IRB requirements. 
 
 
 
 
 
 
 
 
 
_______________________________________                              
Principal Investigator 
 
 
 
____________________ 
Date  
 
 


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Table of Contents 
List of Figures .......................................................................................................................................................................... 6 
List of Tables ........................................................................................................................................................................... 7 
Definitions ............................................................................................................................................................................... 8 
Protocol Summary .................................................................................................................................................................. 9 
1 
Introduction .................................................................................................................................................................. 12 
1.1 
Background/Rationale .......................................................................................................................................... 12 
2 
Summary of Device Descriptions .................................................................................................................................. 15 
2.1 
Intranasal SipNose Device Overview .................................................................................................................... 15 
2.1.1 
Intranasal SipNose Device ............................................................................................................................. 15 
2.1.2 
SipNose Utility, Reliability, and Safety .......................................................................................................... 16 
2.2 
Continuous Glucose Monitor (CGM) device ......................................................................................................... 17 
3 
Objectives ...................................................................................................................................................................... 18 
3.1 
Primary Objective .................................................................................................................................................. 18 
3.2 
Secondary Objectives ............................................................................................................................................ 18 
3.3 
Exploratory Objective............................................................................................................................................ 18 
4 
Endpoint(s) .................................................................................................................................................................... 18 
4.1 
Primary Endpoints ................................................................................................................................................. 18 
4.2 
Secondary Endpoints ............................................................................................................................................ 18 
4.3 
Exploratory Endpoints ........................................................................................................................................... 19 
5 
Study Design .................................................................................................................................................................. 19 
5.1 
Drug Administration Training ................................................................................................................................ 19 
5.2 
Drug Administration with SipNose ........................................................................................................................ 20 
5.3 
Device Dose Loading and Administration ............................................................................................................. 21 
5.4 
CGM Device and Training ...................................................................................................................................... 24 
5.5 
Outcome Measures ............................................................................................................................................... 25 
5.6 
Study Duration ...................................................................................................................................................... 25 
6 
Study Population ........................................................................................................................................................... 25 
6.1 
Eligibility Criteria ................................................................................................................................................... 25 
6.1.1 
Inclusion Criteria ........................................................................................................................................... 25 
6.1.2 
Exclusion Criteria ........................................................................................................................................... 25 
7 
Study Assessments and Procedures .............................................................................................................................. 26 
7.1.1 
Visit 1: Screening (Day -14 to -7) ................................................................................................................... 26 
7.1.2 
Visit 2: Randomization/Start of Treatment Period 1 (Day 0) - This will be scheduled as a morning 
appointment to accommodate visit length .................................................................................................................. 26 
7.1.3 
Phone Visit 3: Safety Check (visit 2 +1 day) .................................................................................................. 27 


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7.1.4 
Phone Visit 4: Safety Check (Day 6 +/- 2 days).............................................................................................. 27 
7.1.5 
Visit 5: End of Treatment Period 1 (Day 17 +/- 3 days) ................................................................................. 27 
7.1.6 
Phone Visit 6: Safety Check 1 Week into the 2 Week Washout (Day 24 +/-2 days) ..................................... 27 
7.1.7 
Visit 7:  Crossover/Start of Period Treatment 2 (Day 31 +/- 2 days) ............................................................. 27 
7.1.8 
Phone Visit 8:  Safety Check (visit 7 + 1 day) ................................................................................................. 28 
7.1.9 
Phone Visit 9:  Safety Check (Day 37 +/- 2 days) ........................................................................................... 28 
7.1.10 
Visit 10:  End of Treatment Period 2 (Day 48 +/- 3 days ............................................................................... 28 
7.1.11 
Visit 11:  Safety Visit (Day 55 +/- 2 days) ....................................................................................................... 29 
7.2 
Early Withdrawal ................................................................................................................................................... 29 
7.3 
Safety .................................................................................................................................................................... 29 
7.3.1 
Vital Signs ...................................................................................................................................................... 29 
7.3.2 
ECG ................................................................................................................................................................ 29 
7.3.3 
Laboratory Samples ...................................................................................................................................... 29 
7.4 
Early Withdrawal ................................................................................................................................................... 29 
7.5 
Safety .................................................................................................................................................................... 29 
7.5.1 
Vital Signs ...................................................................................................................................................... 30 
7.5.2 
ECG ................................................................................................................................................................ 30 
7.5.3 
Laboratory Samples ...................................................................................................................................... 30 
7.6 
Neuropsychological Assessment ........................................................................................................................... 30 
7.6.1 
Columbia-Suicide Severity Scale (C-SSRS) ..................................................................................................... 30 
7.6.2 
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) ......................................... 30 
7.6.3 
Trail Making Test (TMT) Parts A & B ............................................................................................................. 30 
8 
Investigational Product(s) ............................................................................................................................................. 30 
8.1 
Description of Investigational Product ................................................................................................................. 30 
8.2 
Handling and Storage ............................................................................................................................................ 30 
8.3 
Treatment Assignment .......................................................................................................................................... 31 
8.4 
Packaging and Labeling ......................................................................................................................................... 31 
8.5 
Occupational Safety: ............................................................................................................................................. 31 
No known significant safety risks exist to site personnel in direct or indirect contact with the study drug. ............... 31 
9 
Concomitant Medications and Non-Drug Therapies .................................................................................................... 31 
9.1 
Permitted Medications ......................................................................................................................................... 31 
9.2 
Prohibited Medications ......................................................................................................................................... 31 
10 
Subject Completion, Compensation and Withdrawal ............................................................................................... 31 
10.1 
Subject Completion ............................................................................................................................................... 31 
10.2 
Subject Compensation .......................................................................................................................................... 31 
10.3 
Subject Withdrawal ............................................................................................................................................... 31 


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11 
Adverse Events (AE) and Serious Adverse Events (SAE) ........................................................................................... 32 
11.1 
Definition of AE ..................................................................................................................................................... 32 
11.2 
Definition of SAE ................................................................................................................................................... 32 
11.3 
Relationship of Adverse Event to Study Treatment .............................................................................................. 32 
11.4 
Intensity of Adverse Event .................................................................................................................................... 33 
11.5 
Timing of Event Detection and Reporting ............................................................................................................. 33 
11.6 
Glycemic Events .................................................................................................................................................... 33 
11.6.1 
Hypoglycemic Events .................................................................................................................................... 33 
11.6.2 
Hyperglycemic/Ketotic Events ...................................................................................................................... 33 
11.7 
Clinical Laboratory Abnormalities & Other Abnormal Assessments as AEs & SAEs ............................................. 34 
11.8 
SipNose Failures and Malfunctions ....................................................................................................................... 34 
11.9 
Pregnancy Reporting ............................................................................................................................................. 34 
12 
Data Analysis and Statistical Considerations ............................................................................................................ 34 
12.1 
Analysis Overview ................................................................................................................................................. 34 
12.2 
Statistical Analysis of Primary Outcomes .............................................................................................................. 34 
12.3 
Statistical Analysis of Secondary and Exploratory Outcomes ............................................................................... 35 
12.4 
Power Calculation ................................................................................................................................................. 35 
13 
Study Conduct Considerations .................................................................................................................................. 35 
13.1 
Regulatory and Ethical Considerations, Including the Informed Consent Process ............................................... 35 
13.2 
Data Safety Monitoring Board .............................................................................................................................. 35 
13.3 
Quality Assurance ................................................................................................................................................. 35 
13.4 
Study Closure ........................................................................................................................................................ 35 
13.5 
Records Retention ................................................................................................................................................. 36 
13.6 
Provision of Study Results and Information to Investigators ............................................................................... 36 
13.7 
Data Management ................................................................................................................................................ 36 
13.8 
Device and Drug Accountability ............................................................................................................................ 36 
14 
References ................................................................................................................................................................ 36 
15 
Appendices ................................................................................................................................................................ 38 
15.1 
Appendix 1: SipNose Investigator Brochure ......................................................................................................... 38 
15.2 
Appendix 2: SipNose Drug-device Compatibility Testing ...................................................................................... 38 
15.3 
Appendix 3: Insulin Full Prescribing Information .................................................................................................. 38 
15.4 
Appendix 4: Questionnaires and Exam Batteries .................................................................................................. 38 
15.5 
Appendix 5: Visit Schedule - Phase 1 .................................................................................................................... 38 
 
 
 


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List of Figures 
Figure 1: Nasal Aerosol Deposition - Traditional (Djupesland and Skretting, 2012) and SipNose (99MTC-DTPA) Devices . 15 
Figure 2: SipNose Device Components- SP1N1C1 ................................................................................................................ 16 
Figure 3: Dexcom G6 CGM System ....................................................................................................................................... 18 
Figure 4: Study Design Flow Diagram ................................................................................................................................... 20 
Figure 5: SipNose Device -Sp1N1C1 ...................................................................................................................................... 20 
Figure 6: Study Drug Administration Materials .................................................................................................................... 21 
Figure 7: Open Device Cover ................................................................................................................................................. 21 
Figure 8: Remove Cap (A) and Cleaning Vial (B) ................................................................................................................... 22 
Figure 9: Filling Syringe ......................................................................................................................................................... 22 
Figure 10: Prepare Device for Administration ...................................................................................................................... 23 
Figure 11: Filling SipNose Device .......................................................................................................................................... 23 
Figure 12: Placement of Device for Nasal Administration .................................................................................................... 23 
Figure 13: Inserting the CGM Sensor .................................................................................................................................... 24 
Figure 14: Possible outcomes of non-inferiority analysis ..................................................................................................... 34 
 
 
 


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List of Tables 
Table 1: Intranasal insulin improves memory function in phase II human clinical trials. ..................................................... 14 
Table 2: SipNose devices in MAF311 compared to SP1N1C1 ............................................................................................... 15 
Table 3: Prohibited Medications ........................................................................................................................................... 31 
 
 
 


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Definitions 
Abbreviation 
Definition 
Adverse event (AE)  
Any undesirable patient experience that may include but is not 
limited to an abnormal sign, symptom, illness, abnormal 
laboratory value, or other medical event. 
Application (app) 
A piece of software downloaded to a person’s smartphone, used 
to record, display and transmit data 
Blood brain barrier (BBB) 
The layer of tissue separating the central nervous system from 
the periphery 
Columbia-Suicide Severity Rating 
Scale (C-SSRS) 
A scale designed to quantify the severity of suicidal ideation and 
behavior. 
Continuous glucose monitor 
(CGM) 
A device worn on the skin which measures interstitial glucose 
and displays by a transmitter to a receiver  
Data Safety Monitoring Board 
(DSMB) 
An independent group assigned to review safety data to monitor 
for incidence of trends that would warrant termination of the 
trial. 
Intranasal (IN) 
A method of drug delivery that is particularly applicable to 
delivering centrally acting medications into the central nervous 
system. 
Investigator Brochure (IB) 
A comprehensive document summarizing the body of 
information about an investigational product 
Michigan Neuropathy Screening 
Instrument (MNSI) 
A standardized physical exam technique using light touch, 
vibratory sensation and ankle reflexes to establish risk for 
peripheral neuropathy 
Repeated Battery for the 
Assessment of 
Neuropsychological Status 
(RBANS) 
A standardized neuropsychological assessment with five scores 
for each of five domains (immediate memory, 
visuospatial/constructional, language, attention, and delayed 
memory). 
Serious adverse events (SAE) 
Any symptom, sign, illness or experience that develops during 
the study and results in a life-threatening situation, 
hospitalization, significant disability, and other events 
determined by the investigator to be significant. 
Trail Making Test (TMT) Parts A & 
B 
A standardized neuropsychological test of visual attention and 
task switching. 
 
 
 


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Protocol Summary 
 
PROTOCOL TITLE 
Intranasal Insulin: A Novel Therapy for Hypoglycemia 
Unawareness in Type 1 Diabetes 
SHORT TITLE  
IN Insulin in Type 1 Diabetes (T1D) Hypoglycemia Unawareness: 
Safety Only Phase 
STUDY PHASE 
Phase II 
STUDY OBJECTIVES AND PURPOSE  
Primary Objective:  
Demonstrate no significant increase in dangerous hypoglycemia with administration of intranasal insulin in T1D 
participants with intact awareness of hypoglycemia  
Secondary Objectives:  
1. Describe changes in overall glycemic control with administration of intranasal insulin in T1D participants 
with intact awareness of hypoglycemia  
2. Describe changes in hypoglycemia awareness with administration of intranasal insulin in T1D participants 
with intact awareness of hypoglycemia  
3. Describe changes in safety endpoints with administration of intranasal insulin in T1D participants with 
intact awareness of hypoglycemia 
Exploratory Objective:  
Describe changes in memory, attention and executive function with administration of intranasal insulin in T1D 
participants with intact awareness of hypoglycemia 
STUDY DESIGN  
Study Type 
Safety 
Control Type 
Placebo Crossover 
Study Indication Type 
Treatment 
Randomization Schema 
Insulin vs Placebo First 
Device 
SipNose intranasal device 
Study Design 
Prospective, randomized, cross-over, placebo controlled 
Planned Duration of Subject Participation 
10 weeks 
Planned Duration of Treatment with IN insulin 
14-20 days  
PRIMARY ENDPOINTS 
Dangerous hypoglycemia defined by percent time below range (<54 mg/dL), from real-time continuous glucose 
monitoring (CGM) 
SECONDARY  ENDPOINTS 
1. Overall metrics and glycemic control from real-time CGM data during each treatment period defined as: 
a. Percent time in range (70-180 mg/dL)  
b. Percent time below range (<70 mg/dL)  


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c. Percent time above range (>180 mg/dL, >250 mg/dL)  
d. Mean glucose  
e. Coefficient of variation (%CV)  
f. Glucose management indicator (GMI)  
g. Percent time of active sensor wear  
2. Hypoglycemia awareness measured three ways using: 
a. 3 hypoglycemia unawareness questionnaires/scores (Gold Score, Clarke survey, HypoA-Q)  
b. Time from CGM reading of, <70 mg/dL, 54-<70 mg/dL and <54 mg/dL to time of participant 
hypoglycemia awareness obtained from participant journals 
c. Glucose value from real-time CGM at onset time of hypoglycemia awareness obtained from 
participant journals 
3. Safety outcomes include: 
a. Adverse events 
b. Neuropathy test changes 
c. Review of patient non-study medications  
d. HbA1c 
e. EKG 
f. Smell test changes 
g. C-SSRS assessment 
EXPLORATORY ENDPOINTS  
1. Memory and attention using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
2. Executive function using Trail Making Parts A and B 
INVESTIGATIONAL PRODUCTS, DOSE AND MODE OF ADMINISTRATION 
Investigational Product 
Humulin-R 20 IU/IN (0.1ml/10 units IN in each nostril) BID  
SUBJECT SELECTION 
Targeted Accrual 
10 subjects are anticipated to complete this study.  We estimate a need to consent up 
to 20 subjects in order to reach this goal. 
INCLUSION CRITERIA 
• 
Adult patients (age ≥18) with type 1 diabetes diagnosis and a duration of diabetes of at least 10 years  
• 
Gold score <4  
• 
HbA1c ≥6.5% within the last 3 months or at screen visit 
• 
Stable insulin regimen (MDI or insulin pump) for at least 3 months, as deemed stable by principal 
investigator  
• 
Depression/anxiety medications stable for at least 3 months 
• 
Ability and willingness to wear CGM continuously during study participation 
• 
Participants must use their own smartphone, and have the ability and willingness to use CGM 
smartphone applications compatible with their smartphone  
• 
Ability and willingness to check SMBG using own supplies, as instructed by study staff  
• 
Ability and willingness to document when having symptoms of hypoglycemia in the CGM smartphone 
app or in a diary  
• 
If using insulin pump, willing to operate insulin pump without threshold suspend feature or hybrid 
closed-loop, if applicable 
• 
Proficient in speaking, reading and understanding English in order to complete surveys and testing of 
cognitive function 
• 
Women of child-bearing age must agree to procure and use contraception throughout the study 


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EXCLUSION CRITERIA 
• 
Pregnancy or planning pregnancy 
• 
eGFR ≤ 30 mL/min/1.73m2, if available from medical record 
• 
Currently participating in a research study or completed any other research study within 6 months of 
screening date  
• 
Current or recent use within 3 months of an insulin delivery system that adjusts insulin in response to 
continuous glucose monitoring (CGM) data (such as an automated insulin delivery system like hybrid 
closed-loop insulin pump therapy) 
• 
Known dementia or mild cognitive impairment diagnosis  
• 
Diabetic ketoacidosis within the last 6 months 
• 
Use of non-insulin medications to treat diabetes 
• 
Those planning to change diet or exercise regimen during the study 
• 
History of trans-sphenoidal surgery or surgery to the upper part of the nasal cavity, chronic sinusitis, 
severe deviated septum, or difficulty with smell and/or taste 
• 
Severe psychiatric illness 
• 
Allergy to adhesives, insulin or any components of insulin product 
• 
Subject cannot adequately demonstrate ability to use and deploy the devices as determined by 
investigator 
• 
Evidence of suicidality using the Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Subject has history of any of the following: moderate to severe pulmonary disease, poorly controlled 
congestive heart failure, significant cardiovascular and/or cerebrovascular events within previous 6 
months, condition known to affect absorption, distribution, metabolism, or excretion of drugs such as 
any hepatic, renal or gastrointestinal disease or any other clinically relevant abnormality or illness that 
inclusion would pose a safety risk to the subject as determined by investigator. 
 
 
 


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1 Introduction 
1.1 Background/Rationale 
Hypoglycemia, or the fear of it, is one of the most significant limits to current management of type 1 diabetes (T1D). 
Consequences of hypoglycemia, both physical and cognitive, can be severe and in some cases fatal.1,2 Unfortunately, 
hypoglycemia occurs with high frequency among patients with T1D. Occurrence estimates put the frequency of mild 
hypoglycemia at 1 to 2 events per patient per week and severe hypoglycemia (requiring assistance from another person) 
at 0.2 to 3.2 events per patient per year.1 Data from the T1D Exchange Clinic Registry (77 clinics in 35 states collecting 
common data on children and adults with T1D), has shown 18.6% of patients with T1D for ≥40 years have had 1 or more 
severe hypoglycemia episodes (resulting in seizure or loss of consciousness) within the last year.3 With repeated 
episodes of hypoglycemia, the counter-regulatory pathways to restore normal glucose are blunted, and patients can 
become unaware of the hypoglycemia. It is estimated that 40% of patients with T1D have hypoglycemia unawareness.4 
Patients with long-standing T1D, intensive therapy at advanced age, and frequent hypoglycemia are at the highest risk 
for hypoglycemia unawareness.5,6 
Guidelines suggest treating older patients with T1D and those with longer duration of disease with less aggressive HbA1c 
targets, with the assumption that this will help reduce the risk of hypoglycemia.7 Despite these more conservative 
glycemic targets, they do not appear to protect patients from severe hypoglycemia.3 Indeed, even those patients with 
T1D who think they can tell when they are hypoglycemic are still at risk for hypoglycemia. Taking patients ≥60 years old 
who have had T1D ≥20 years, and comparing those who have had at least 1 severe hypoglycemia episode in the last year 
to a case-control group with no severe hypoglycemia in the last 3 years, it was shown that those with severe 
hypoglycemia had more glucose variability (P = 0.008) and had continuous glucose monitoring (CGM) levels <60 mg/dL 
for ≥20 min on 46% of days compared with 33% of days in control subjects (P = 0.10). This was despite there being no 
appreciable difference in HbA1c levels.6 It is also of note that the group with perceived “awareness” to hypoglycemia 
had surprisingly high numbers of hypoglycemic episodes. In T1D patients ≥60 years old, time spent in hypoglycemia (<70 
mg/dL) was highest in younger patients, those with shorter diabetes duration, and lower HbA1c levels, and was strongly 
correlated to glycemic variability based on CGM.8 
The use of CGM technology can reduce the frequency of hypoglycemia and allows for more aggressive insulin titration to 
lower HbA1c without increasing hypoglycemia events.9-11 Indeed, higher HbA1c goals may help reduce the amount of 
time in hypoglycemia for patients with longer duration of T1D, however higher HbA1c targets are not enough to prevent 
severe hypoglycemia.8 The use of CGM, however, does not reliably restore hypoglycemia awareness.11 Advancements in 
insulin pump therapy and CGM using hybrid closed-loop artificial pancreas systems holds promise as well for better 
glycemic control without severe hypoglycemia.12 Despite these benefits, only 15-20% of patients with T1D use CGM with 
insulin injections or insulin pump therapy.13 
While some of the factors associated with hypoglycemia unawareness have been identified, as discussed above, the 
actual pathophysiology of hypoglycemia unawareness is multifactorial and not well understood. Possible mechanisms 
include reliance on alternative fuels in the brain (such as lactate), so that with frequent hypoglycemia, the brain adapts 
to use non-glucose fuels like lactate, which then leads to blunting of awareness to hypoglycemia. Alterations of the 
hypothalamic-pituitary axis have also been proposed, as well as decreased neuronal communication.14 Further, cerebral 
blood flow to key areas of the brain responsible for hypoglycemia awareness appears to be decreased in hypoglycemia 
unawareness.15 It has also been noted that recurrent moderate hypoglycemia may precondition the brain to limit the 
extent of severe hypoglycemia.16 Mice with a knockout of the insulin receptor in the brain have a blunted response to 
hypoglycemia.17 Moreover, there is evidence that the brain plays a role in glucose homeostasis via pancreatic islet 
innervation resulting in peripheral insulin and glucagon changes.18 While it is becoming clear that there is a connection 
between the brain and glucose homeostasis, the precise mechanisms in T1D patients remain unknown. 
Evidence is mounting that diabetes is associated with cognitive dysfunction, and the relationship appears to go in both 
directions. Hyperinsulinemia in the fasting state predicts nearly a doubling in risk for Alzheimer’s disease and decline in 
memory, even in patients without known diabetes.19 In patients with type 2 diabetes (T2D), there is higher incidence of 
dementia, and dementia onset occurs at a younger age.20 There is active research attempting to elucidate further the 
connection between insulin and cognition.21 One possible mechanism involves amyloid beta oligomers, a hallmark of 
Alzheimer’s disease pathogenesis. These amyloid deposits have been shown to reduce insulin receptors in hippocampal 


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neurons, and by delivering insulin in vitro to these cells, the insulin receptors were maintained, and the amyloid 
oligomers reduced.22 Insulin has also been reported to enhance amyloid beta clearance from the brain.23 Further, the 
activity of glycogen-synthase kinase-3-beta, the enzyme that phosphorylates tau to create Alzheimer’s neurofibrillary 
tangles, has been reported to be down-regulated in response to insulin. Also insulin receptor signaling increases synaptic 
density, and loss of synapses is key to the neuropathology of Alzheimer’s disease. 
The novel therapy of intranasal insulin, invented and patented by Dr. Frey, one of our investigators (U.S. Patents 
5,624,898; 6,313,093), has been proposed as a therapy for Alzheimer’s disease21,24 and PTSD,25 and is known to improve 
memory, attention and functioning in patients with mild cognitive impairment and Alzheimer’s disease without any 
major adverse side effects24,26,27 (Table 1). Intranasal delivery sends insulin directly from the nose to the brain along the 
olfactory and trigeminal nerves28 and does not alter the blood levels of insulin or glucose.21,26 In normal healthy adults24 
and those with type 2 diabetes29, intranasal insulin improves memory without altering the blood levels of insulin or 
glucose (although to date this has not been evaluated using CGM as we are proposing). FDG-PET imaging has shown that 
patients with Alzheimer’s disease have a marked global decrease in the cerebral metabolic rate of glucose metabolism 
leaving brain cells starved for energy.30 Glucose is the primary energy source for brain cells. Intranasal insulin has been 
found to rapidly target the brain, help maintain glucose uptake and utilization, and increase brain cell energy (ATP).31,32 
Further, it also attenuates the HPA axis elevation of cortisol (which inhibits glucose uptake to the brain) resulting in 
improved attention, memory, and function.25,33 Finally, in rodent models, central insulin signaling directly alters glucose 
sensing in hypothalamic neurons.17 Taking all these mechanisms together, intranasal insulin may play a beneficial role in 
the counter-regulatory response to recurrent hypoglycemia. 
In addition to co-authoring the first clinical trials to demonstrate that improved intranasal insulin improves memory in 
patients with mild cognitive impairment (MCI) and Alzheimer’s,34,35 Dr. Frey’s team is currently conducting two trials 
using intranasal insulin. The first titled, “Investigation of the Safety of Intranasal Glulisine in Down Syndrome” 
(ClinicalTrials.gov, Identifier: NCT02432716), is a single center, randomized, double-blind, placebo-controlled, cross-over 
pilot study designed to assess the safety of intranasally delivered glulisine versus placebo in older patients with Down 
Syndrome who would be expected to have Alzheimer’s brain pathology. The second titled, “Intranasal Glulisine in 
Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer's Disease” (ClinicalTrials.gov Identifier: 
NCT02503501), is a Phase II, single center, randomized, double-blind, placebo-controlled 6-month study of the safety 
and the therapeutic effectiveness of intranasal glulisine in amnestic mild cognitive impairment and probable mild 
Alzheimer’s disease. The team also recently completed and published a safety trial of rapid acting insulin in Alzheimer’s 
patients.36 The study team has expertise in intranasal clinical trial design, investigator-initiated IND submissions to FDA, 
tracking and dispensing investigational products and intranasal devices, training of patients on the use of intranasal 
devices, and creation of secure REDcap databases for participant tracking and data entry. From the clinical trials listed in 
Table 1, 10IU BID of regular insulin have repeatedly shown benefit and safety in healthy adults and patients with either 
MCI or Alzheimer’s disease. 


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Table 1: Intranasal insulin improves memory function in phase II human clinical trials. 
Subjects 
Intranasal insulin 
duration/dose 
Main result 
References 
Healthy Adults 
4 × 40 IU/day, for 8 weeks 
Intranasal intake of insulin enhanced long-term declarative memory and positively affected mood in 
humans without causing systemic side effects like hypoglycemia. 
Benedict et 
al.,2004 
Healthy Adults 
4 × 40 IU/day, for 8 
weeks; regular and rapid-
acting  
Declarative memory was improved in insulin and insulin aspart groups compared to placebo group 
without altering glucose levels.  Insulin aspart treated subjects performed even better that those of 
insulin treated group. 
Benedict et 
al.,2007 
Healthy Adults 
Single dose of regular 
human insulin 160 IU 
Hippocampus-dependent memory and working memory were improved in women where as men did 
not benefit from acute insulin treatment 
Benedict et al., 
2008 
Healthy Adults 
Single dose of regular 
human insulin 160 IU 
Enhanced performance in the prefrontal cortex-dependent working memory task in both 
postmenopausal and young women 
Krug et al., 2010 
Healthy Adults 
4 × 40 IU/day, for 8 weeks 
Declarative memory and mood were improved and HPA axis activity as assessed by circulating ACTH and 
cortisol levels was reduced. 
Hallschmid et al., 
2008 
MCI and mild 
AD patients 
20 or 40 IU of insulin 
acute treatment 
Acute intranasal insulin administration improved verbal memory in AD and MCI subjects without the 
APOE- ε 4 allele 
Reger et al.,2006 
MCI and AD 
patients 
10, 20, 40, or 60 IU for 5 
days 
10, 20, and 40 IU of insulin improved declarative memory only in APOE-ε 4 negative patients.  Memory 
facilitation generally peaked at the 20 IU dose. 
↑ Aβ42 levels for memory-impaired adults from saline to 10 IU regardless of APOE-ε 4 status.  
Intranasal insulin did not affect peripheral glucose or insulin levels. 
Reger et al.,2008a 
MCI and AD 
patients 
20 IU BID for 21 days 
Insulin-treated subjects retained more verbal information and improved attention and functional status.  
Insulin treatment raised fasting plasma Aβ40/Aβ42 ratio. 
Reger et al.,2008b 
MCI and mild to 
moderate AD 
patients 
20 or 40 IU for 4 months 
Treatment with 20 IU of insulin improved delayed memory.  Both dosages preserved caregiver-rated 
functional ability and general cognition.  Unchanged Aβ42 and tau levels after insulin treatment. 
Craft et al.,2012 
AD patients 
with ApoE4 
allele 
Rapid acting insulin 
Rapid acting insulin failed to have an acute impact on cognition in ApoE4 carriers with AD 
Rosenbloom et 
al., 2014 
MCI and mild 
AD patients 
20 or 40 IU of insulin 
detemir for 21 days 
High dose (40 IU) improved visuospatial and verbal working memory. High dose improved memory for 
adults with MCI and AD who were APOE-ε 4 positive patients.  APOE-ε 4 carriers taking high dose also 
improved peripheral insulin resistance.  APOE-ε 4 negative patients taking high dose experiences 
increased peripheral insulin resistance. 
Claxton et 
al.,2015 
Older adults 
with and 
without type 2 
DM 
Single dose of 40 IU 
randomized, crossover 
design 
Intranasal insulin administration appears safe in older adults with type 2 DM, does not affect systemic 
glucose control.  Improvements of visuospatial memory after insulin administration in the DM group and 
in the verbal fluency test in the control group, potentially through improved regional perfusion and 
vasoreactivity mechanisms 
Novak et al., 2014 
 
Modified from Bedse, Gaurav, et al. "Aberrant insulin signaling in Alzheimer's disease: current knowledge." Frontiers in Neuroscience 9 (2015) 


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2 Summary of Device Descriptions 
2.1 Intranasal SipNose Device Overview 
The intranasal SipNose device proposed to be utilized in this protocol is the same device (SP1N1C1) under IND 139885. 
IND 139885 is an investigator initiated clinical trial, titled “A Single Center Feasibility Study of Intranasal Insulin in 
Frontotemporal Dementia [NIFT-D (Nasal Insulin in Frontotemporal dementia)]”. The Principal Investigator is Dr. Michael 
H Rosenbloom. In addition, Table 2 summarizes the SipNose devices in MAF311, when compared to the SP1N1C1 device. 
The next set of sections summarizes the information provided for this protocol, along with updated Instructions for Use 
(Version 4), Investigator’s brochure (Version 3) as attachments. Also letters are provided from SipNose Ltd, and Dr. 
Michael H Rosenbloom regarding IND 139885 providing permission to review the submitted documents to FDA.  
Table 2: SipNose devices in MAF311 compared to SP1N1C1 
 
HealthPartners - Clinical trials with 
Insulin- SP1N1C1 
MAF311 devices 
SP1N2C2-NV1 and SP1N3C4 
Functional unit: same unit in 
all devices 
SP1 
SP1 
Nose Piece, “N” 
N1: Allows medium volume 
administration – up to ~250-300ul 
N2: Allows medium volume 
administration – up to ~200ul 
N3: Allows maximal volume 
administration – up to ~1000ul 
Cover, “C” which serves also as 
the safety lock 
C1: cover is suitable for N1 in length, no 
drug-filling features, 
C2-NV1: Cover includes drug-filling 
features (needle). 
C4: cover is suitable for N3 in length, no 
drug-filling features. 
Assembly, Validation 
Same process in principle, same verification and validation process. 
 
2.1.1 Intranasal SipNose Device 
The delivery of drugs to the CNS remains a development challenge mainly due to the impenetrable nature of the BBB. 
SipNose's innovative approach enables broad, consistent drug delivery (either liquids or powders) to the upper area of 
the nasal cavity, which improves the absorption of the active ingredients when compared to traditional nasal delivery 
devices (see Figure 1: Nasal Aerosol Deposition - Traditional (Djupesland and Skretting, 2012) and SipNose (99MTC-
DTPA) Devices).  Currently available nasal devices such as droppers, sprays, or pumps deliver aerosol mainly to the lower 
and mid turbinate of the nasal cavity and only minor amounts, about 5% to the upper turbinate of the nasal cavity 37. 
SipNose has conducted animal studies using an intranasal device with the same technology that is designed for humans. 
To address the different nasal cavity size and structure, adaptations were used for the device to fit each animal model. 
The SipNose device is an aerosol nasal delivery platform that uses pressurized delivery through the discharge of 
compressed air, resulting in an aerosol that delivers the drug in a narrow plume geometry, which targets the olfactory 
SipNose Nasal Delivery 
Traditional Nasal Pump 
Figure 1: Nasal Aerosol Deposition - Traditional (Djupesland and Skretting, 2012) and SipNose (99MTC-
DTPA) Devices 


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epithelium in the upper nasal cavity. From the olfactory epithelium, therapeutics rapidly reach the central nervous 
system, traveling extracellularly along the olfactory nerves.  The device is not currently commercially available, but 
numerous studies have demonstrated its ability to intranasally deliver radiolabeled and therapeutic compounds to the 
brain.  
SipNose has successfully completed a set of experiments that demonstrate the advantages of its nasal delivery system. A 
set of in vitro tests, in vivo tests, and small clinical studies have been conducted and described below that support the 
following (for further details see Investigator brochure): 
1. Reproducible and non-user dependent nasal delivery (Section 11.4-11.8 in Investigator’s brochure)  
2. Improved drug dispersion and deposition targeting to the upper third of the nasal cavity when compared to 
other nasal delivery devices (Figure 9, Sections 5.1 and 5.3 in Investigator’s brochure) 
3. Significant delivery of aerosolized drug to the upper nasal cavity and olfactory epithelium with minimal lung 
contamination (Sections 5.2, 5.3 in Investigator’s brochure) 
4. Increased CNS concentration of drug when compared to other nasal applications (Sections 5.1 and 11.4, Human 
Study # 3 in Investigator’s brochure) 
5. Safety and tolerability of the SipNose device (MAF 311) 
2.1.2 SipNose Utility, Reliability, and Safety 
The SipNose device was specifically designed to facilitate drug loading and user experience particularly suited for the 
purposes of this trial.  
2.1.2.1 
Utility 
The SipNose device consists of a nose piece, compressed air chamber, activation lock to prevent unwanted activation, 
and activation button (Figure 2: SipNose Device Components- SP1N1C1). The device also consists of a cover that 
prevents the device being activated accidently.   
The drug is kept within its original commercial bottle or primary container until use and stored under the required 
conditions as stated in the original drug label. Prior to administration, the drug is drawn out from the primary container 
using a commercial syringe, and transferred into the Device Nose Piece that serves as a secondary drug container for a 
short period of time (several minutes). The drug contacts only with the device parts that are made of polypropylene 
(PP), medical grade USP Class VI compliant. PP is an acceptable material for short term exposure of drugs, including 
insulin 38. For example, this material has been used in the following products: MONOJECT SoftPack; GLUCOPRO Insulin 
Syringe; BD Insulin Syringes, all commonly utilized syringes in clinical settings.  
The nostrils come in contact only with the nose piece which is made of the same PP mentioned above. The parts that 
come in contact with intact skin (subject's hands) are made of PET-G TritanTM – Estman MX711 (details in sections 3 and 
4 of Investigator’s brochure). 
Nose Piece & Secondary Drug 
Container 
Compressed Air Chamber 
  
Activation Lock 
  Activation Button 
  
Device Cover 
Figure 2: SipNose Device Components- SP1N1C1 


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Drug stability studies have not been conducted for this study as insulin has been shown to be stable at refrigeration and 
room temperature conditions for up to 31 days [39; Section 16.2 –package insert). 
2.1.2.2 
Reliability 
The SipNose device has demonstrated an ability to reliably reproduce the same spray dose volume consistency.  The U.S. 
Food & Drug Administration (FDA) guidance recommends a consistency of ≤1 spray outside 80 – 120% and 0 sprays 
outside 75 – 125% dose volume.  During tests with insulin, SipNose devices expelled an average volume of 105.14ul 
(Range: 99.6-112ul), all individual spray volumes were within the range of 93%-107% of the target volume 100ul, and 
mean spray volume was within 95%-105% of the target volume of 100ul. Therefore, both individual and mean results 
meet the FDA guidelines (See Compatibility Testing document – for details).  
Studies have shown that the SipNose device consistently targets the upper nasal cavity, thus delivering the dispelled 
agent to the region critical for CNS delivery.   When using a human nasal model cast, the SipNose more reliably targeted 
the upper nasal cavity (see section 5.1 in IB) as compared to other commercial devices (LMA MAD NasalTM).   In a 
preclinical rat model, 11C-choline was reliably delivered to the olfactory epithelium and into the brain immediately 
following administration (detected in brain ~3min following administration).  PET-CT scan were measured from ~3 min 
following administration up to 1 hour. An example of the scan at 40-45 minutes after drug administration is shown in the 
IB. (See section 5.2 in IB).   In addition, midazolam brain concentrations using the intranasal SipNose device were 
comparable to that obtained with IV administration in a rat model, although blood levels were lower than the IV 
administration (see section 11 in Investigator’s brochure).  The SipNose device demonstrated higher anterior and 
posterior brain concentrations of insulin following IN delivery as compared to IV administration (see section 11.8 in 
Investigator’s brochure).    
In a human study using SPECT-CT analysis, it was found that the volume of drug deposition effectively targeted the 
upper/middle posterior region of the nasal cavity with negligible lung deposition (see section 5.3 in Investigator’s 
brochure).   Another human study involving patients presenting with epileptic seizures treated with IN midazolam using 
the SipNose device showed that the treatment improved electrographic seizures and was well-tolerated in this 
population (See section 11.4 in Investigator’s brochure).  Finally, delivery of IN midazolam anesthesia with the SipNose 
device resulted in a higher level of sedation in patients undergoing a surgical procedure compared to IN drug delivery 
with a commercial delivery device (see section 11.4 from Investigator’s brochure). 
2.1.2.3 
Safety 
SipNose device is an aerosol nasal delivery platform that uses pressurized delivery through the discharge of compressed 
air. The pressure used in the SipNose is similar to that used in commercial nasal inhalers and is up to 6 bars (1 bar=14.5 
Psi).  Impact force of the SipNose device is in the range of 1.5-6.5 grams, and is comparable to that found in commercialized 
inhalers, dry powder inhalers and other nasal delivery devices in the field 40 The actual impact force that is detected 
following aerosol release via the SipNose device, is found to be 2-5gr, and specifically with 100ul of the drug Insulin is 
2.7±0.3gr. 
Safety experiments performed have shown no evidence of irritation or local tissue damage following treatment 
with the SipNose nasal delivery device in both humans and animals (see section 11 in Investigator’s brochure). 
2.2 Continuous Glucose Monitor (CGM) device 
The commercially available Dexcom G6 CGM system (Figure 3) measures the glucose level in the interstitial fluid under 
the skin. The CGM system includes a sensor which has a small wire that is inserted under the skin, a transmitter that 
attaches to the sensor and a smartphone app that collects and displays the glucose results. The sensor will be placed 
under the skin and can stay in place for up to 10 days. The sensor will measure the glucose level in the interstitial fluid 
every five minutes and transmit that data to the smartphone. The screen will show in real-time the participant’s glucose 
value, most recent glucose trends, and an arrow indicating which way the glucose trend is predicted to go. Alarms can 


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be set to alert the participant to glucoses that are too high or too low, or if glucose trends are changing quickly. The data 
collected by the system can be downloaded and evaluated for several CGM-based metrics.  
 
3 Objectives 
3.1 Primary Objective 
Demonstrate no significant increase in dangerous hypoglycemia with administration of intranasal insulin in T1D 
participants with intact awareness of hypoglycemia. 
3.2 Secondary Objectives 
1. Describe changes in overall glycemic control with administration of intranasal insulin in T1D participants with 
intact awareness of hypoglycemia  
2. Describe changes in hypoglycemia awareness with administration of intranasal insulin in T1D participants with 
intact awareness of hypoglycemia  
3. Describe changes in safety endpoints with administration of intranasal insulin in T1D participants with intact 
awareness of hypoglycemia 
3.3 Exploratory Objective 
Describe changes in memory, attention and executive function with administration of intranasal insulin in T1D 
participants with intact awareness of hypoglycemia. 
4 Endpoint(s) 
4.1 Primary Endpoints 
Dangerous hypoglycemia defined by percent time below range (<54 mg/dL) from real-time continuous glucose 
monitoring (CGM). 
4.2 Secondary Endpoints 
• 
Overall metrics and glycemic control from real-time CGM data during each treatment period defined as:: 
o Percent time in range (70-180 mg/dL) from real-time CGM 
o Percent time below range (<70 mg/dL) from real-time CGM 
o Percent time above range (>180 mg/dL and >250 mg/dL) from real-time CGM 
o Mean glucose from real-time CGM 
o Coefficient of variation (%CV) from real-time CGM 
o Glucose management indicator (GMI) from real-time CGM 
o Percent time of active sensor wear from real-time CGM 
• 
Hypoglycemia awareness measured three ways using: 
Figure 3: Dexcom G6 CGM System 


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o 3 hypoglycemia unawareness questionnaires/scores (Gold Score, Clarke survey, HypoA-Q)  
o Time from CGM reading of, <70 mg/dL, 54-<70 mg/dL and <54 mg/dL to time of participant 
hypoglycemia awareness obtained from participant journals 
o Glucose value from real-time CGM at onset time of hypoglycemia awareness obtained from participant 
journals 
• 
Safety outcomes include: 
o Adverse events 
o Neuropathy test changes 
o Review of patient non-research insulin doses and medications 
o HbA1c 
o EKG 
o Smell test changes 
o C-SSRS assessment 
4.3 Exploratory Endpoints 
• 
Memory and attention using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
• 
Executive function using Trail Making Parts A and B  
5 Study Design 
This study is a single center trial designed to assess the safety of administering intranasal (IN) regular insulin in subjects 
with type 1 diabetes and intact hypoglycemia awareness Figure 4. 
After written informed consent has been obtained, subjects will be screened to assess study eligibility based on study 
inclusion/exclusion criteria. Subjects who are eligible at the end of the screening visit (Visit 1) will be scheduled for a 
baseline visit to take place 1 to 2 weeks later (Visit 2). During the baseline/randomization visit, subjects will be 
administered the hypoglycemia and cognitive questionnaires and tests.  Patients then are randomized 1:1 to either 
treatment with intranasal insulin or placebo. They will wear two 10-day real-time CGMs, and then crossover to the other 
group for another two 10-day period following a 2 week washout period. A final safety/assessment visit will take place 
up to 1 week after visit 10.  
5.1 Drug Administration Training 
All subjects will receive training at start of treatment visits regarding home administration of IN insulin using the SipNose 
device during visits 2 and 7.  Subjects will be required to administer the dose twice daily, one in the morning and the 
other in the evening (at least 8 hours between doses). If the SipNose device is discharged prior to insertion into the 
nose, then a retrial admission would be indicated.  However, if the device is discharged following nasal insertion, then a 
retrial would not be permitted. The steps to ensure that subjects maintain compliance with the study protocol over 4 
weeks include conducting the following: 
• 
In-clinic training sessions: baseline/randomization (Visit 2) and start of treatment period 2 (visit 7) 
• 
Phone call from study coordinator/investigator 1 day and 5 days after baseline visit and after Visit 7. 


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5.2 Drug Administration with SipNose 
Each dosing administration will require the following items:  a) 2 SipNose Devices (2) 2 nose piece covers; b) device 
holder; c) study drug vial (10 ml vial of regular Insulin (Humulin-R or Placebo)); d) Insulin syringe; e) alcohol wipe; f) 
needle clipper and/or sharps container. 
Activation Button 
Nose Piece 
Device Cover 
Device Cover 
Activation Button 
Figure 5: SipNose Device Components -SP1N1C1 
Figure 5: SipNose Device -Sp1N1C1 
Subjects  
Cross Over 
Randomization 1:1 
Hypoglycemia and 
cognitive questionnaires 
Hypoglycemia and 
cognitive questionnaires 
Phase 1 
Intranasal Insulin 
(n=5) 
14-20 days unblinded 
CGM (with alarms) 
Placebo 
(n=5) 
14-20 days unblinded 
CGM (with alarms) 
Screen T1D Pts w/ Hypoglycemic Awareness 
(N=10) 
2 Week Washout 
Safety visit 1 week after treatment period 
Hypoglycemia and 
cognitive questionnaires 
Placebo 
(n=5) 
14-20 days unblinded 
CGM (with alarms) 
Intranasal Insulin 
(n=5) 
14-20 days unblinded 
CGM (with alarms) 
Figure 4: Study Design Flow Diagram 


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During the baseline/randomization visit the subject will administer the study drug in front of study personnel to ensure 
adherence to study protocol for drug administration. To ensure safety and medication compliance, subjects will be 
followed-up with a routine phone call 1 day and 5 days after baseline/randomization visit, 1 day and 5 days after Visit 7 
(start of treatment period 2) and 1 week after final treatment visit.  
Devices will be shipped to the clinical study site. One device with a nose piece cover will be supplied for each dose to be 
administered in the study. Devices are one-time use only. A kit containing all necessary items will be distributed to each 
subject and replaced at each study visit or as necessary. This will include several extra devices in case there are issues 
with any devices. Each device is to be loaded with a 10 unit dose of study drug to be used immediately or up to a 
maximum of 10 minutes prior to IN administration. The Nose Piece and Secondary Drug Container (temporary) are the 
only components of the device that will come into contact with the study drug and subject’s nasal cavity.  
5.3 Device Dose Loading and Administration 
1. Gather and prepare the needed materials.  
2. Open the devices covers and place the devices in the device holder 
 
3. Remove the protective cap from the study drug vial as shown in figure 8 if you have not already done this step.  
4.  Load the drug formulation into the device.  
a. Remove the cap from the top of the vial.   
*Not the actual syringe and study drug. The above pic for illustration only.  
 
Syringe* 
Devices 
Device Holder 
Study  
Drug* 
Alcohol Wipes 
Figure 6: Study Drug Administration Materials 
Figure 7: Open Device Cover 


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b. Wipe the top of the vial with an alcohol wipe. 
c. Immediately before (within 10 minutes) of taking dose, load the 0.1 ml (10 Units) desired study drug 
dose volume from the vial using the Insulin syringe following the instructions provided with the drug 
formulation. 
i. Pull syringe plunger down to 0.1 ml (10 Units) 
ii. Push air into the vial 
iii. Turn the medication vial upside-down and slowly pull the syringe plunger down, withdrawing 
the study drug until 0.3ml (30 Units) line is visible just above the plunger. Tap the syringe to 
move any air bubbles to the top 
iv. Slowly push the plunger up to the 0.1ml (10 Units) line to push any air bubbles back into the vial. 
v. Turn the medication vial upright and gently pull the syringe without moving the plunger. 
 
d. Insert the syringe with the needle carefully into the top of the device (Figure 10). 
e. Slowly depress the syringe plunger, ensuring that no study drug leaks from the device. After the plunger 
is fully depressed, remove the syringe with the needle carefully from the device and leave the device in 
the device holder. 
f. Dispose of the syringe with the needle by using a needle clipper and/or a sharps container.  
g. Repeat these steps, using another syringe for the second device. 
h. The study drug must be administered within 10 minutes after loading it into the device. 
 
5. Instruct the subject to blow their nose into tissue prior to administering the first dose. 
B 
A 
Remove cap from the vial  
 
Figure 8: Remove Cap (A) and Cleaning Vial (B) 
E 
Pull the syringe  
plunger down  
 
Figure 9: Filling Syringe 


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6. Instruct the subject to turn the device upside down and flick the nose piece to allow the drug to concentrate at 
its edge as shown in the figure below (Figure 10). This helps the subject to see if the drug is loaded prior to 
administration.  
7. The research staff will provide guidance to the subject on placement for nasal administration for the first dose.  
a. Place the nose piece of the device comfortably in the nose as shown in the figure below (Figure 12) 
b. After the initial placement, the examiner will make slight adjustments to orient the nose piece in the 
proper direction (parallel to the nasal septum).  
8. Use thumb to press the activation button to administer the drug in the nasal cavity. 
F 
Figure 11: Filling SipNose Device 
Hold the 
Device  
Nose Piece  
Activation 
Button 
 
Device 
Neck Area 
 
Figure 10: Prepare Device for Administration 
Press Activation Button 
to Administer Study Drug 
Nose Piece Placement 
in the Nose 
Figure 12: Placement of Device for Nasal Administration 


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9. Without blowing nose, repeat steps 6-8 for the other nostril using the second prepared device. 
10. Place used devices into the Ziploc bag in the dosing kit to be returned to the study staff for disposal via 
biohazard waste.  Devices that malfunction will be placed into a separate plastic bag and returned to SipNose for 
quality inspection. 
5.4 CGM Device and Training 
CGM device and smartphone app training will occur at the start of both treatment periods, and user guide materials will 
be provided. Participants will first download the Dexcom G6 Mobile app to their smartphone. After entering their 
transmitter’s serial number into the app, there is a 2 hour warm-up for the CGM. Next they will identify a location on 
their abdomen as directed by study staff for insertion of the sensor. After cleaning the skin, participants are instructed 
how to use the applicator to insert the sensor and connect the transmitter to the sensor. After the 2 hour warm up is 
over, the CGM will start transmitting real-time glucose data. Participants will be allowed to use CGM data for their 
diabetes management. Blood glucose monitoring can be performed using the participant’s own glucose meters if CGM 
readings do not match a participant’s symptoms. CGM alert thresholds will be set at default levels of 70 mg/dL for low 
glucose, and 180 mg/dL for high glucose. These alerts can be adjusted during the study as needed. The G6 app also has a 
feature where wearers can mark events such as food or exercise; for the purposes of this study, participants will be 
instructed to use the “other” activity as a marker of symptomatic hypoglycemia (which they can use as an alternative to 
the hard-copy participant journal for documentation of symptomatic hypoglycemia) 
 
The Dexcom G6 system allows for the wearer to share their glucose data with up to 5 followers remotely through the 
Follow app. This “sharing” feature will be downloaded and started with assistance of the study staff. The study staff, 
including the PI, will have 24 hour access to this data for safety purposes, if participants call with any concerns during 
the study. A CLARITY mobile account will be set up for participants (using the CLARITY app which links to the G6 Mobile 
app) and linked to the research site, which can capture device data for analysis.  
Figure 13: Inserting the CGM Sensor 


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5.5  Outcome Measures 
CGM data will be downloaded at the end of each treatment period. We will capture percent time in each glucose range 
of interest as well as mean glucose and other glycemic metrics. Hypoglycemia unawareness questionnaires, cognitive 
tests, and neuropathy tests will be collected at beginning and end of the first treatment period and at the end of the 
second treatment period. AE’s will be assessed throughout the study. The remaining safety outcomes will only be 
measured at screening and post-study completion.  
5.6 Study Duration 
Study participation will last approximately 10 weeks, consisting of a screening visit, 4 study phase visits, 1 follow-up 
safety assessment visit and at least 5 phone call visits. Subjects will receive treatment with IN insulin for a period of 14-
20 days.  Subjects who discontinue treatment will continue to complete follow-up measures as possible. 
6 Study Population 
6.1 Eligibility Criteria 
6.1.1 Inclusion Criteria 
• 
Adult patients (age ≥18) with type 1 diabetes diagnosis and a duration of diabetes of at least 10 years  
• 
Gold score <4  
• 
HbA1c ≥6.5% within the last 3 months or at screen visit 
• 
Stable insulin regimen (MDI or insulin pump) for at least 3 months, as deemed stable by principal investigator  
• 
Depression/anxiety medications stable for at least 3 months 
• 
Ability and willingness to wear CGM continuously during study participation 
• 
Participants must use their own smartphone, and have the ability and willingness to use CGM smartphone 
applications compatible with their smartphone  
• 
Ability and willingness to check SMBG using own supplies, as instructed by study staff  
• 
Ability and willingness to document when having symptoms of hypoglycemia in the CGM smartphone app or 
in a diary  
• 
If using insulin pump, willing to operate insulin pump without threshold suspend feature or hybrid closed-
loop, if applicable 
• 
Proficient in speaking, reading and understanding English in order to complete surveys and testing of cognitive 
function 
• 
Women of child-bearing age must agree to procure and use contraception throughout the study 
6.1.2 
Exclusion Criteria 
A subject will not be included for consideration in this study if any of the following criteria are met: 
• 
Pregnancy or planning pregnancy 
• 
eGFR ≤ 30 mL/min per 1.73 m2, if available from medical record 
• 
Currently participating in a research study or completed any other research study within 6 months of 
screening date 
• 
Current or recent use within 3 months of an insulin delivery system that adjusts insulin in response to 
continuous glucose monitoring (CGM) data (such as an automated insulin delivery system like hybrid closed-
loop insulin pump therapy) 
• 
Known dementia or mild cognitive impairment diagnosis  
• 
Diabetic ketoacidosis within the last 6 months 
• 
Use of non-insulin medications to treat diabetes 
• 
Those planning to change diet or exercise regimen during the study 
• 
History of trans-sphenoidal surgery or surgery to the upper part of the nasal cavity, chronic sinusitis, severe 
deviated septum, or difficulty with smell and/or taste 
• 
Severe psychiatric illness 
• 
Allergy to adhesives, insulin or any components of insulin product 
• 
Subject cannot adequately demonstrate ability to use and deploy the devices as determined by investigator 


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• 
Evidence of suicidality using the Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Subject has history of any of the following: moderate to severe pulmonary disease, poorly controlled 
congestive heart failure, significant cardiovascular and/or cerebrovascular events within previous 6 months, 
condition known to affect absorption, distribution, metabolism, or excretion of drugs such as any hepatic, 
renal or gastrointestinal disease or any other clinically relevant abnormality or illness that inclusion would 
pose a safety risk to the subject as determined by investigator. 
7 Study Assessments and Procedures 
A summary of study events and procedures is outlined in the Study Visit Table (see appendix 5).  Demographic and 
Baseline Assessments 
7.1.1 Visit 1: Screening (Day -14 to -7) 
The following procedures will be performed at this visit: 
• 
Obtain written informed consent from subject prior to any study related procedures 
• 
Obtain Gold score – if <4, can stop here. 
• 
Review inclusion/exclusion criteria 
• 
Review medical history, as it pertains to inclusion/exclusion criteria 
• 
Obtain subject’s demographic information (date of birth, gender, race, education, etc.) 
• 
Obtain details of medications, prescription, over the counter and vitamin/nutraceuticals taken over the course 
of the last 30 days prior to screening 
• 
Collect vital signs (blood pressure & pulse), height, weight and BMI 
• 
Obtain laboratory studies (Na, K, CO2, Creat/GFR, AST/ALT, CBC w/ diff) and HbA1c POC, if not obtained within 
the past 3 months 
• 
Urine pregnancy test in women of child bearing potential 
• 
Perform a standard 12-lead ECG 
• 
Download participant’s blood glucose meter and/or CGM to evaluate recent glucose control 
• 
Provide patients with glucagon self-injection kit, if they do not have a current kit at home 
• 
Provider to see patient at this visit for visit assessment review 
7.1.2 Visit 2: Randomization/Start of Treatment Period 1 (Day 0) - This will be scheduled as a morning 
appointment to accommodate visit length 
The following procedures will be performed at this visit before SipNose administration: 
• 
Assess for AE/SAEs 
• 
Collect vital signs (blood pressure & pulse) 
• 
CGM placed and started before testing (requires 2 hour warm up) 
• 
Document BG values before and after cognitive testing 
• 
C-SSRS questionnaire 
• 
MNSI survey 
• 
Hypo surveys (Clarke, HypoAQ) 
• 
Cognitive tests (RBANS, Trail-making)  
• 
Smell test (12-item UPSIT test versions A & B) 
• 
Ensure patient still meets inclusion/exclusion criteria 
• 
Randomize after completion of cognitive testing and hypo surveys 
• 
SipNose device teaching 
 
Administer first dose of intranasal insulin in clinic after above testing done, observe patient for 4 hours (only if 
randomized to intranasal insulin for treatment period 1).  
The following procedures will be performed after the first dose is administered: 
 


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• 
Teach daily diary (or how to document within the Dexcom G6 app that symptomatic hypoglycemia is 
commencing) 
• 
Teach glucagon and hypoglycemia management 
• 
Teach CGM & apps (Including G6, Clarity, Follow apps); provide user guide materials  
• 
Download participant’s SMBG (if used) and/or CGM, and review for hypoglycemia and overall glucose control 
• 
Provider to see patient at this visit for visit assessment review 
• 
Subject instructed to call if any hypoglycemia occurs before the next day phone call 
• 
Subject instructed to return devices (used and unused) to study staff. 
7.1.3 Phone Visit 3: Safety Check (visit 2 +1 day) 
The following procedures will be performed at this visit: 
• 
Study staff phone call to assess IN insulin compliance and AEs/SAEs 
• 
Reinforce SipNose device training 
• 
Reinforce daily diary training 
• 
Review CGM data in Clarity 
7.1.4 Phone Visit 4: Safety Check (Day 6 +/- 2 days) 
The following procedures will be performed at this visit: 
• 
Study staff phone call to assess IN insulin compliance and AEs/SAEs 
• 
Reinforce SipNose device training 
• 
Reinforce daily diary training 
• 
Review CGM data in Clarity 
7.1.5 Visit 5: End of Treatment Period 1 (Day 17 +/- 3 days) 
The following procedures will be performed at this visit: 
• 
Safety check and assess AEs/SAEs 
• 
Gold score (for data collection purposes only) 
• 
Medication review for any changes since screening 
• 
VS (blood pressure/pulse) 
• 
MNSI survey 
• 
Hypo surveys 
• 
Document BG values before and after cognitive testing 
• 
Cognitive tests (study drug must have been taken prior to testing) 
• 
Review daily diary 
• 
Evaluate CGM for adequate data collected 
• 
Inventory returned devices  
• 
Download SMBG for safety, if used 
• 
Download and review CGM data  
• 
Provider to see patient at this visit for visit assessment review 
• 
In the event the study site is recommending no non-essential in person clinic contacts (such as during the 
COVID-19 pandemic), this visit may be done remotely and study staff will obtain as much of the above 
procedural information as possible. Procedures such as MNSI survey and VS may not be able to be done.  
7.1.6 Phone Visit 6: Safety Check 1 Week into the 2 Week Washout (Day 24 +/-2 days) 
The following procedures will be performed at this visit: 
• 
Study staff phone call to assess for AEs/SEs 
7.1.7 Visit 7:  Crossover/Start of Period Treatment 2 (Day 31 +/- 2 days) 
The following procedures will be performed at this visit: 
• 
Safety check and assess AEs/SAEs 
• 
Medication review for any changes since screening 


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• 
Vital signs (blood pressure/pulse) 
 
Administer first dose of intranasal insulin in clinic after above testing done, observe patient for 4 hours (only if 
randomized to intranasal insulin for treatment period 2).  
The following procedures will be performed after the first dose is administered: 
 
• 
SipNose device teaching 
• 
Teach daily diary (or how to document within the G6 app that symptomatic hypoglycemia is commencing) 
• 
Teach glucagon and hypoglycemia management 
• 
Download SMBG for safety (if used) 
• 
CGM placed 
• 
Teach CGM & apps (Including G6, Clarity, Follow apps); provide user guide materials  
• 
Provider to see patient at this visit for visit assessment review 
• 
Subject instructed to call if any hypoglycemia before phone call occurs the next day 
• 
In the event the study site is recommending no non-essential in person clinic contacts (such as during the 
COVID-19 pandemic), this visit may be done remotely and study staff will obtain as much of the above 
procedural information as possible, IF the participant is beginning the saline phase of the study only (not for 
insulin start). Distribution of supplies may be done remotely as well. If the participant is to begin the intranasal 
insulin part of the study, then the washout will be extended until a time when non-essential clinic visits at the 
site are permitted.   
7.1.8 Phone Visit 8:  Safety Check (visit 7 + 1 day) 
The following procedures will be performed at this visit: 
• 
Study staff phone call to assess IN insulin compliance and AEs/SAEs 
• 
Reinforce SipNose device training 
• 
Reinforce daily diary training 
• 
Review CGM data in Clarity 
7.1.9 Phone Visit 9:  Safety Check (Day 37 +/- 2 days) 
The following procedures will be performed at this visit: 
• 
Study staff phone call to assess IN insulin compliance and AEs/SAEs 
• 
Reinforce SipNose device training 
• 
Reinforce daily diary training 
• 
Review CGM data in Clarity 
7.1.10 Visit 10:  End of Treatment Period 2 (Day 48 +/- 3 days 
The following procedures will be performed at this visit: 
• 
Safety check and assess AEs/SAEs 
• 
Gold score  
• 
Medication review for any changes since screening 
• 
VS (blood pressure/pulse) 
• 
Height/weight/BMI 
• 
MNSI survey 
• 
Hypo surveys (Clarke, HypoAQ) 
• 
Document BG values before and after cognitive testing 
• 
Cognitive tests (study drug must have been taken prior to testing) (RBANS, Trail-making) 
• 
Smell test (12-item UPSIT test versions A & B) 
• 
Review daily diary 
• 
Download SMBG for safety (if used) 
• 
Evaluate CGM for adequate data collected 


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• 
Inventory returned devices 
• 
Review CGM data in Clarity 
• 
Provider to see patient at this visit for visit assessment review 
• 
In the event the study site is recommending no non-essential in person clinic contacts (such as during the 
COVID-19 pandemic), this visit may be done remotely and study staff will obtain as much of the above 
procedural information as possible. MSNI, VS, height/weight/BMI may not be able to be obtained. Supplies may 
need to be returned remotely.  
• 
Study visits 10 and 11 may be combined into 1 visit to conclude the patient’s participation in the study, with as 
many of the data points for both of these visits being obtained at the same visit.  Any assessments that are able 
to be done remotely (such as assessment of AE/SAEs) may be done remotely by phone. 
7.1.11 Visit 11:  Safety Visit (Day 55 +/- 2 days) 
The following procedures will be performed at this visit: 
• 
Safety check and assess AEs/SAEs 
• 
Collect vital signs (blood pressure & pulse) 
• 
Obtain laboratory studies (Na, K, CO2, creat/GFR, AST/ALT, CBC w/ diff) and HbA1c POC 
• 
Perform a standard 12-lead ECG 
• 
C-SSRS questionnaire 
• 
Provider to see patient at this visit for visit assessment review 
• 
In the event the study site is recommending no non-essential in person clinic contacts, this visit may need to be 
completed as an “essential” visit for safety to document no harm related to the study interventions. Only the VS, 
laboratory studies and ECG will require in-person evaluation, and the study staff and provider can then follow up 
with patient by phone to complete the remaining visit items.  
• 
Study visits 10 and 11 may be combined into 1 visit to conclude the patient’s participation in the study, with as 
many of the data points for both of these visits being obtained at the same visit.  Any assessments that are able 
to be done remotely (such as assessment of AE/SAEs) may be done remotely by phone.  In the event there are 
active or unresolved AE/SAEs at the combined visit 10/11, a separate safety phone call 1 week later will be 
conducted by the study team to assess these AE/SAEs and address as appropriate per investigator. 
7.2 Early Withdrawal 
If subject withdraws from the study after the screening visit, but before visit 2, no further evaluations are necessary.  If 
subject withdraws from the study after visit 2, all safety assessments will be performed (see section 7.3). 
7.3 Safety 
For all safety assessments described below, any clinically significant change will be recorded as an AE or SAE (see section 
11). 
7.3.1 Vital Signs 
Vital signs will be recorded at all clinic visits.  For within subject consistency, brachial artery pressure will be obtained in 
the routine fashion. Weight/height/BMI will be recorded at screening and at end of study treatment period 2.  
7.3.2 ECG 
A standard 12-lead ECG will be performed on subjects at screening and at visit 11 (safety visit). 
7.3.3 Laboratory Samples 
Laboratory tests will be done at screening and at visit 11 (safety visit). 
7.4 Early Withdrawal 
If subject withdraws from the study after the screening visit, but before visit 2, no further evaluations are necessary.  If 
subject withdraws from the study after visit 2, all safety assessments will be performed (see section 7.3). 
7.5 Safety 
For all safety assessments described below, any clinically significant change will be recorded as an AE or SAE (see section 
11). 


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7.5.1 Vital Signs 
Vital signs will be recorded at all clinic visits.  For within subject consistency, brachial artery pressure will be obtained in 
the routine fashion. Weight/height/BMI will be recorded at screening and at end of study treatment period 2.  
7.5.2 ECG 
A standard 12-lead ECG will be performed on subjects at screening and at visit 11 (safety visit). 
7.5.3 Laboratory Samples 
Laboratory tests will be done at screening and at visit 11 (safety visit). 
7.6 Neuropsychological Assessment 
7.6.1 Columbia-Suicide Severity Scale (C-SSRS) 
The Columbia–Suicide Severity Rating Scale (C-SSRS) was designed to quantify the severity of suicidal ideation and 
behavior 41.  In this study, suicidal ideation and behavior will be prospectively assessed using the C-SSRS. The C-SSRS will 
be administered by trained raters at specified time points, as indicated in table 1 as well as when clinically indicated. Any 
subjects demonstrating evidence of suicidality will prompt immediate consultation with the site’s on-call psychiatrist for 
assistance with decision-making and potential referral to behavioral health services.  
7.6.2 Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)  
The RBANS is a brief, individually administered neurocognitive battery measuring immediate and delayed memory, 
attention, language, and visuospatial skills.42 The RBANS Update is a “pencil-and-paper” test and requires only a stimulus 
booklet and record form for administration and scoring. It is specially designed for repeat evaluations and includes 
alternate forms to control for practice effects related to content.  The measure is broadly used for clinical diagnostic 
purposes and has also been increasingly employed as an endpoint in clinical trial investigations of medications believed 
to impact neurocognitive status. Three versions (A, B, and C) will be used for this study and randomized to visit for 
participants. 
7.6.3 Trail Making Test (TMT) Parts A & B 
The TMT Parts A & B is a brief paper and pencil measure of attention, processing speed, and mental flexibility (or set-
shifting).  The test has been well validated for use with a wide range of subject populations, is easy to administer, and 
has been shown to be very sensitive in detecting subtle changes in central nervous system compromise and specifically 
changes in frontal lobe or “executive” functions.  Part A requires subjects to connect a series of numbered dots in order 
as quickly as possible.  Part B requires subjects to connect numbered and lettered dots as quickly as possible by 
alternating back and forth between the two without making mistakes.  Scores include both time to completion and 
various error types. 
8 Investigational Product(s) 
8.1 Description of Investigational Product 
The study will utilize the following investigational products: 
• 
Regular insulin (Humulin-R), intranasal route  
• 
SipNose Intranasal Device (Sections 2, 5 and Investigator brochure) 
8.2 Handling and Storage 
The study drug (insulin or saline) will be given to subject after training for administration. 
Subjects will be instructed to keep unopened and opened study drug at room temperature according to label 
recommendations. 
The study drugs will be kept at study site per label recommendations and institutional Standard Operational Policy. The 
unopened regular insulin will be stored in the refrigerator, and the saline stored at room temperature. The refrigerator 
and storage room used will be connected to the centralized temperature monitoring system, Temp Trak, which monitors 


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temperatures 24/7 and alerts site staff when out of range. Site staff will review and document temperature in Temp 
Trak once daily each day department is open. Study staff will be responsible for safeguarding and maintaining the 
master log. 
8.3 Treatment Assignment 
Randomization to initial drug treatment will use the permuted block method. Investigators will receive sealed envelopes 
containing sequence of insulin and saline for each group.  
8.4 Packaging and Labeling 
All study drug will be labeled according to the following specifications: 
• 
Protocol identifier/IRB approval/account/study number. 
• 
Participant ID # or name. 
• 
“Store at room temperature.” 
• 
“Last day to use” date.” 
• 
“Caution: New Drug--Limited by Federal (or United States) law to investigational use”. 
• 
Study contact # 952-993-3123 
8.5 Occupational Safety:  
No known significant safety risks exist to site personnel in direct or indirect contact with the study drug. 
9 Concomitant Medications and Non-Drug Therapies 
9.1 Permitted Medications 
Any medication not listed in list of Prohibited Medications (Table 3) will be permitted during this study.  A record will be 
kept by site staff detailing doses and indication of any concomitant medications used by subjects. 
9.2 Prohibited Medications 
Subjects taking prohibited medications at time of screening will not be allowed to participate in study, unless such 
treatment is discontinued at least 30 days prior to screening. These medications include opiates, benzodiazepines, and 
barbiturates. Randomized subjects taking a prohibited medication (episodic or PRN) will be considered for study 
participation on an individual basis. 
Table 3: Prohibited Medications 
Barbiturates 
Benzodiazepines 
Opiates 
Any non-insulin therapy to treat diabetes mellitus 
10 Subject Completion, Compensation and Withdrawal 
10.1 Subject Completion 
Subjects completing all 11 study visits (including the 5 phone visits) will be considered to have completed study. 
10.2 Subject Compensation 
Subjects will be paid $50 for the completion of each of the 6 in-clinic visits, up to $300 for the entire study. 
10.3 Subject Withdrawal 
Subject may withdraw from study at any time for any reason without penalty or be terminated from the study by the 
clinical investigator (see provisions for termination by study team.) Investigational team will document the reason(s) for 
withdrawal.  In the event a subject chooses to withdraw from study before Visit 3, the safety procedures described in 
Section 7.3 will be performed ideally within 3 days following subject’s decision to withdraw.  For all subjects who 


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withdraw, all final safety assessments will be collected regardless of time elapsed since previous visit.  In addition to the 
termination visit, subjects who withdraw early will be contacted within 7 days by study staff via telephone to assess 
development of new and/or ongoing AEs and concomitant medications.   
Subject’s participation may be terminated at the discretion of the investigator.  Individuals may be withdrawn for the 
following reasons: 
• 
Clinically significant adverse events 
• 
Lost to follow-up 
• 
Protocol violations 
• 
Inability to tolerate study medication 
• 
Other 
11 Adverse Events (AE) and Serious Adverse Events (SAE) 
11.1 Definition of AE 
An adverse event is any symptom, sign, illness or experience which develops or worsens in severity during the course of 
the study. Intercurrent illnesses or injuries should be regarded as adverse events. Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality: 
• 
Results in study withdrawal 
• 
Is associated with clinical signs or symptoms 
• 
Leads to treatment or to further diagnostic tests 
• 
Is considered by the investigator to be of clinical significance 
11.2 Definition of SAE 
Adverse events are classified as either serious or non-serious. A serious adverse event is any event that results in: 
• 
Severe hypoglycemia  
• 
Severe hyperglycemia 
• 
Diabetic ketoacidosis 
• 
Death 
• 
Life-threatening situation 
• 
Hospitalization or prolongation of hospitalization 
• 
Disability or incapacitation 
• 
Congenital abnormality or birth defect 
• 
Other events determined by investigator to be medically significant in which subject’s well-being is jeopardized  
11.3 Relationship of Adverse Event to Study Treatment 
The study investigator will assess the relationship of any adverse event to be related or unrelated by determining if 
there is a reasonable possibility that the adverse event may have been caused by the study treatment. 
To ensure consistency of adverse event causality assessments, investigators should apply the following general guideline 
when determining whether an adverse event is related: 
• 
Unrelated: The AE is clearly not related to a study drug/device and a likely alternative etiology exists such as an 
underlying disease, environmental or toxic factors or other therapy. 
• 
Unlikely Related: The AE does not follow a reasonable temporal sequence during or after use of study 
drug/device and a more likely alternative etiology exists such as an underlying disease, environmental or toxic 
factors, or other therapy. 
• 
Possibly Related: The AE occurred in a reasonable time during or after use of study drug/device; but could be 
related to another factor such as an underlying disease, environmental or toxic factors, or other therapy; and 
there is a possible, though weak, scientific basis for establishing a causal association between the AE and the 
study drug/device. 


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• 
Probably Related: The AE occurred in a reasonable time during or after use of study drug/device; is unlikely to 
be related to another factor such as an underlying disease, environmental or toxic factors, or other therapy; and 
there is a plausible, though not strong, scientific basis for establishing a causal association between the AE and 
the study drug/device. 
• 
Definitely Related: The AE occurred in a reasonable time during or after use of study drug/device; cannot be 
explained by another factor such as an underlying disease, environmental or toxic factors, or therapy; and there 
is a strong scientific basis for establishing a causal association between the AE and the study drug/device.  
• 
Not Assessable: Causality of an adverse event cannot be judged because information is insufficient or 
contradictory, and which cannot be supplemented or verified. 
11.4 Intensity of Adverse Event 
The intensity of an adverse event will be rated as (1) mild, (2) moderate, or (3) severe. The term “severe” is a measure of 
intensity; thus a severe adverse event is not necessarily serious. For example, itching for several days may be rated as 
severe, but may not be clinically serious. 
• 
MILD: Usually transient, requires no special treatment, and does not interfere with the participant’s daily 
activities. 
• 
MODERATE: Usually causes a low level of inconvenience or concern to the participant and may interfere with 
daily activities, but is usually ameliorated by simple therapeutic measures. 
• 
SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic drug therapy or other 
treatment. 
11.5 Timing of Event Detection and Reporting 
Upon consenting, a subject is considered to be a subject in the study, and until that person either withdraws or 
completes study, AEs and SAEs will be recorded.  The investigational team will promptly report any AE/SAE as required 
per federal guidelines. Each principal investigator is responsible for reporting serious study-related adverse events and 
abiding by any other reporting requirements specific to his/her Institutional Review Board or Ethics Committee. 
11.6 Glycemic Events 
11.6.1 Hypoglycemic Events 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as a serious adverse event (SAE) when the 
following definition for severe hypoglycemia is met: the event required assistance of another person due to altered 
consciousness, and required another person to actively administer carbohydrate, glucagon, or other resuscitative 
actions. This means that the participant was impaired cognitively to the point that he/she was unable to treat 
himself/herself, was unable to verbalize his/her needs, was incoherent, disoriented, and/or combative, or experienced 
seizure or loss of consciousness. These episodes may be associated with sufficient neuroglycopenia to induce seizure or 
loss of consciousness. If plasma glucose measurements are not available during such an event, neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced 
by a low plasma glucose concentration. Non-severe hypoglycemia will not be reported as an AE (but will be captured by 
the data analysis). 
11.6.2 Hyperglycemic/Ketotic Events 
Hyperglycemia/ketoic events not associated with an Adverse Device Effect is only reportable as a serious adverse event 
(SAE) when either of the following criteria are met: 
 
       1. Severe hyperglycemia: 
• 
Blood glucose >300 mg/dL, urine ketones moderate or large (or blood ketone >1.5 mmol/L), or accompanied 
by symptoms of nausea, vomiting or abdominal pain 
 
2. Hyperglycemic events are additionally classified as DKA if all of the following are present: 
• 
Blood glucose >250 mg/dL 


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• 
Symptoms such as polyuria, polydipsia, nausea, vomiting or abdominal pain 
• 
Serum ketones >1.5 mmol/L or large/moderate urine ketones 
• 
Either arterial blood pH <7.30 or venous pH <7.24, or serum bicarbonate <15 mEq/L 
• 
Treatment provided in a health care facility 
Non-severe hyperglycemia will not be reported as an AE as mild hyperglycemia is an expected occurrence in 
the study population. 
11.7 Clinical Laboratory Abnormalities & Other Abnormal Assessments as AEs & SAEs 
Any new abnormal vital sign, examination, or laboratory finding judged clinically significant by the investigator will be 
documented as an AE or SAE, if meeting the definitions for such.  Abnormal lab findings or other abnormal assessments 
associated with the disease under study will not be considered AEs or SAEs unless more severe than expected, as judged 
by the investigator. 
11.8 SipNose Failures and Malfunctions  
All failures and malfunctions of the device will be recorded. All performance issues and malfunctions will be reported to 
SipNose during the study and in the clinical results (e.g., final report). 
11.9 Pregnancy Reporting 
If pregnancy occurs, the participant will be discontinued from the study. Urine pregnancy test may be done at any time if 
pregnancy is suspected. The occurrence of pregnancy will be reported on an AE Form. 
12 Data Analysis and Statistical Considerations 
12.1 Analysis Overview 
Discrete variables will be summarized using frequencies and percentages, while continuous variables will be summarized 
by mean and standard deviation or median and interquartile range, as appropriate. Baseline variables will be compared 
between groups to ensure randomization achieved a balanced design. Distribution of the outcome variables will be 
assessed to determine if the planned analyses are appropriate. All analyses will be performed on an intention-to-treat 
basis. Missing data will be considered to be missing at random and those subjects will be excluded from analysis. If a 
large proportion of data is missing (>10%), we will compare baseline characteristics between subjects with missing and 
non-missing data. No adjustment for multiple comparisons will be done. All statistical analyses will be performed in SAS 
Version 9.4. 
12.2 Statistical Analysis of Primary Outcomes 
The primary objective of this study is to assess non-inferiority of dangerous hypoglycemia with administration of 
intranasal insulin in T1D participants with intact awareness of hypoglycemia. A two-sided 95% confidence interval will be 
reported for the difference between the two treatment periods based on a least squares model. A non-inferiority margin 
Treatment Difference (IN Insulin – Placebo) 
Non-inferior and superior 
Non-inferior and not superior 
Non-inferiority not shown 
Non-inferior and inferior 
0 
-2 
Inferior and not non-inferior 
Figure 14: Possible outcomes of non-inferiority analysis 


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of 2% (approximately 30 minutes per day) will be used (see Section 12.4 for justification). The null hypothesis of 
inequality (difference is greater than or equal to 2%) is rejected in favor of the alternative hypothesis of equality 
(difference is less than margin) if the lower limit of the confidence interval is greater than -2%.  
Since non-inferiority is typically framed in terms of a one-sided test, it is worth noting that the left half of a two-sided 
test at alpha = 0.05 gives the same rejection region as a one-sided test at alpha = 0.025. Therefore, reporting a two-sided 
95% confidence interval will provide flexibility to test for inferiority if non-inferiority cannot be declared while 
maintaining the overall type 1 error rate at 5%. Figure 14 shows the inference to be drawn for various scenarios of the 
two-sided 95% confidence interval.  
12.3 Statistical Analysis of Secondary and Exploratory Outcomes 
The secondary and exploratory objectives are purely descriptive. No inferential statistics will be performed. All measures 
of overall glycemic control, hypoglycemia awareness, and safety endpoints will be reported using the appropriate 
summary statistics. Values will be reported from baseline and conclusion of each dosing period.  
12.4 Power Calculation 
The study is powered on our primary objective of determining non-inferiority of dangerous hypoglycemia with 
administration of intranasal insulin in T1D participants with intact awareness of hypoglycemia. The non-inferiority 
margin of 2% is based solely on clinical judgement. A total sample size of 10 (5 per sequence arm) achieves 79.8% power 
to detect non-inferiority assuming a true mean difference of 0 and a square root of within mean square error of 1.4%. 
This power calculation was conducted using the PASS v16 module for non-inferiority test for the difference between two 
means in a 2x2 cross-over design. 
13 Study Conduct Considerations 
13.1 Regulatory and Ethical Considerations, Including the Informed Consent Process 
The study will be conducted in accordance with GCP.  Subject privacy requirements will also be observed as well as the 
fundamental concepts of the Declaration of Helsinki (e.g. IRB approval of the study, obtaining informed consent from all 
subjects, and meeting reporting requirements). 
13.2 Data Safety Monitoring Board 
The DSMB will be an independent group who are not participating in the trial and have no direct affiliation with 
HealthPartners Center for Memory and Aging or IDC. They will serve as an advisory panel to HealthPartners Center for 
Memory and Aging/IDC. The DSMB will be comprised of three appropriately qualified individuals. The DSMB Charter will 
be established prior to initiation of the study. The DSMB responsibilities include but are not limited to the following: 
• 
Monitoring the study for compliance to the protocol. 
• 
Stopping the study if the rate of SAE’s raises safety concerns.  The details will be specified in the DSMB charter.  
 
The DSMB will convene following the study completion of the 10 subjects in phase 1, or earlier in the case of SAEs.  
During the course of the trial, the DSMB will review accumulating safety data to monitor for incidence of trends that 
would warrant termination of the trial. The frequency of the DSMB meetings, responsibilities, membership, and 
procedures will be documented in the DSMB charter. 
13.3 Quality Assurance 
In the event of a regulatory agency audit or inspection, site will allow the auditor/inspector access to all records 
documented and facilities utilized in conducting the study.  Site will also make accommodations (e.g. time, schedule) to 
discuss findings, concerns, and questions with auditor/inspector. 
13.4 Study Closure 
Upon completion of all subject visits, data entry and analysis, investigator will inform local IRB of study closure. 


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13.5 Records Retention 
All site records will be maintained and stored in a safe and secure location for a minimum of 15 years post study 
completion. 
13.6 Provision of Study Results and Information to Investigators 
Study results will be made available by the study statistician once analysis is complete.   
13.7 Data Management 
Data collection/reporting tools will be developed internally (i.e. CRFs and source documents).  Data collected and stored 
electronically will remain confidential and secure (e.g. secured server, encrypted data, password protected file) 
13.8 Device and Drug Accountability 
A Device Tracking Log will be maintained at the investigational site. SipNose devices will be recorded on the log upon 
delivery to the investigational site and will be stored in a secured area. The Device Tracking Log will be updated as each 
device is delivered, dispensed, returned and the reason for the return.  Batch numbers, expiration date and model 
number of devices delivered to the site will also be recorded. Similarly, a Drug Tracking Log will be maintained at the 
investigational site. Vials of insulin will be secured in the storage area, and stored per manufacturer label.  
14 References 
 
1. 
Feltbower RG, Bodansky HJ, Patterson CC, et al. Acute complications and drug misuse are important causes of 
death for children and young adults with type 1 diabetes: results from the Yorkshire Register of diabetes in 
children and young adults. Diabetes care. 2008;31(5):922-926. 
2. 
Frier BM. Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications. Nature Reviews 
Endocrinology. 2014;10(12):711. 
3. 
Weinstock RS, Xing D, Maahs DM, et al. Severe hypoglycemia and diabetic ketoacidosis in adults with type 1 
diabetes: results from the T1D Exchange clinic registry. The Journal of Clinical Endocrinology & Metabolism. 
2013;98(8):3411-3419. 
4. 
Czyzewska K, Czerniawska E, Szadkowska A. Prevalence of hypoglycemia unawareness in patients with type 1 
diabetes. Pediatr Diabet. 2012;13:77. 
5. 
Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes. 2008;57(12):3169-3176. 
6. 
Weinstock RS, DuBose SN, Bergenstal RM, et al. Risk factors associated with severe hypoglycemia in older adults 
with type 1 diabetes. Diabetes Care. 2016;39(4):603-610. 
7. 
Marathe PH, Gao HX, Close KL. American D iabetes A ssociation S tandards of M edical C are in D iabetes 2017. 
Journal of diabetes. 2017;9(4):320-324. 
8. 
DuBose SN, Weinstock RS, Beck RW, et al. Hypoglycemia in older adults with type 1 diabetes. Diabetes 
technology & therapeutics. 2016;18(12):765-771. 
9. 
Choudhary P, Ramasamy S, Green L, et al. Real-time continuous glucose monitoring significantly reduces severe 
hypoglycemia in hypoglycemia-unaware patients with type 1 diabetes. Diabetes Care. 2013;36(12):4160-4162. 
10. 
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15 Appendices 
15.1 Appendix 1: SipNose Investigator Brochure 
 
15.2 Appendix 2: SipNose Drug-device Compatibility Testing 
 
15.3 Appendix 3: Insulin Full Prescribing Information 
 
15.4 Appendix 4: Questionnaires and Exam Batteries 
 
15.5 Appendix 5: Visit Schedule - Phase 1