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

Study Overview
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Brief Summary
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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
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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: Primary: a. To assess non-inferiority of dangerous hypoglycemia with administration of intranasal insulin in T1D participants with intact awareness of hypoglycemia. Secondary: To describe changes in overall glycemic control with administration of intranasal insulin in T1D participants with intact awareness of hypoglycemia To describe changes in hypoglycemia awareness with administration of intranasal insulin in T1D participants with intact awareness of hypoglycemia To describe changes in safety endpoints with administration of intranasal insulin in T1D participants with intact awareness of hypoglycemia. Exploratory: To describe changes in memory, attention and executive function with administration of intranasal insulin in T1D participants with intact awareness of hypoglycemia

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

Conditions
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Type1diabetes

Intervention / Treatment
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* Drug: Regular insulin (Humulin-R), intranasal route
* Device: SipNose intranasal device


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>No active drug | Device: SipNose intranasal device<br>* 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.<br>|
| Experimental: Humulin-R<br>Insulin | Drug: Regular insulin (Humulin-R), intranasal route<br>* Humulin-R insulin is approved by the U.S. Food and Drug Administration (FDA) for the treatment of diabetes.<br>Device: SipNose intranasal device<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Time With Dangerous Hypoglycemia | Defined using percent time below range (<54 mg/dL), from real-time continuous glucose monitoring (CGM) | Two 14-20 day treatment periods | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Time With Blood Glucose 70-180 mg/dL | Defined using percent of Blood Glucose 70-180 mg/dL from real-time continuous glucose monitoring (CGM) | Two 14-20 day treatment periods | 
| Percentage of Time With Blood Glucose <70 mg/dL | Defined using percent of Blood Glucose <70 mg/dL from real-time continuous glucose monitoring (CGM) | Two 14-20 day treatment periods | 
| Percentage of Time Blood Glucose >180 mg/dL | Percentage of time Blood Glucose >180 mg/dL from real-time continuous glucose monitoring (CGM) | Two 14-20 day treatment periods | 
| Percentage of Time With Blood Glucose >250 mg/dL | Percentage of time with Blood Glucose >250 mg/dL from real-time continuous glucose monitoring (CGM) | Two 14-20 day treatment periods | 
| Percentage of Time Participant Had Active Sensor Wear | Percentage of time Participant had Active Sensor Wear from real-time continuous glucose monitoring (CGM) | Two 14-20 day treatment periods | 
| Mean Glucose From the Study Participants | Mean Glucose from the Study Participants from real-time continuous glucose monitoring (CGM) | Two 14-20 day treatment periods | 
| Coefficient of Variation (%CV) of Blood Glucose Values From CGM Data | The Coefficient of variation was calculated by dividing the standard deviation of blood glucose values by the mean of the blood glucose values based on data from the corresponding CGM readings. | Two 14-20 day treatment periods | 
| Glucose Management Indicator (GMI) | An approximate HbA1c based upon real-time continuous glucose monitoring (CGM) values | Two 14-20 day treatment periods |