IN Insulin in Type 1 Diabetes (T1D) Hypoglycemia Unawareness: Safety Only Phase

Intranasal Insulin: A Novel Therapy for Hypoglycemia Unawareness in Type 1 Diabetes

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.

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

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 self-monitoring of blood glucose (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
• 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

Exclusion Criteria:

• Pregnancy or planning pregnancy
• eGFR ≤ 30 mL/min per 1.73 m2, if available from medical record
• 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.