INHALE-3: Afrezza® Combined With Insulin Degludec Versus Usual Care in Adults With Type 1 Diabetes

Study Overview
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Brief Summary
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INHALE-3 is a Phase 4, randomized controlled trial (RCT) that will randomly assign participants ≥18 years of age with type 1 diabetes (T1D) using multiple daily injections (MDI), an automated insulin delivery (AID) system, or a pump without automation, and continuous glucose monitoring (CGM) 1:1 to an insulin regimen of insulin degludec plus inhaled insulin (Afrezza) and CGM or continuation of usual care. The primary outcome of the RCT is at 17 weeks. The RCT will be followed by a 13-week extension phase in which participants in both groups will use the degludec-inhaled insulin regimen.

Official Title
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INHALE-3: A 17-Week Randomized Trial and a 13-Week Extension, Evaluating the Efficacy and Safety of Inhaled Insulin (Afrezza) Combined With Insulin Degludec Versus Usual Care in Adults With Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Biological: Afrezza
* Biological: insulin degludec
* Biological: Rapid-acting Insulin Analog
* Biological: Basal Insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide informed consent for study participation Clinical diagnosis of T1D (per the Investigator) Treatment with insulin for at least 6 months prior to the collection of the baseline continuous glucose monitoring (CGM) data Same treatment regimen (MDI, an AID system, or an insulin pump without automation) for the 3 months prior to screening Current (at time of screening) rapid-acting insulin analog (RAA) in use for at least 4 weeks If AID system used, automated insulin delivery must be active >85% of the time in the 4 weeks prior to screening If MDI used, participant must be using a long-acting basal insulin plus injecting a RAA bolus for meals, per Investigator Total daily insulin dose 20-100 units Age ≥ 18 years HbA1c <11.0% Participant uses real-time CGM (any type of real-time CGM) on a regular basis (at least 70% of the time in the 4 weeks prior to screening) No use of inhaled insulin in the 3 months prior to screening If female of childbearing potential, willing and able to have pregnancy testing Investigator believes that the participant can safely use the study treatment and will follow protocol No medical, psychiatric,or other conditions, or medications being taken that in the Investigator's judgement would be a safety concern for participation in the study This includes considering the potential impact of medical conditions known to be present including cardiovascular, liver, kidney disease, thyroid disease, adrenal disease, malignancies, vision difficulties, active proliferative retinopathy, and other medical conditions; psychiatric conditions including eating disorders; drug or alcohol abuse. Exclusion Criteria: History of recent blood transfusions (within previous 3 months prior to randomization), hemoglobinopathies, (sickle cell trait is not an exclusion), or any other conditions that affect HbA1c measurements Recent history of asthma (defined as using any medications to treat within the last year), chronic obstructive pulmonary disease (COPD), or any other clinically important pulmonary disease (e.g., cystic fibrosis or bronchopulmonary dysplasia), or significant congenital or acquired cardiopulmonary disease as judged by the Investigator Exposure to any investigational product(s), including drugs or devices, in the 90 days prior to the start of screening Any disease other than diabetes or current use (or anticipated use during the study) of any medication that, in the judgment of the Investigator, may impact glucose metabolism Current or anticipated acute uses of oral, inhaled or injectable glucocorticoids during the time period of the trial (topical glucocorticoid use is acceptable) Use of a non-insulin glucose-lowering medication within 3 months prior to signing informed consent Smoking (includes cigarettes, cigars, pipes, marijuana, and vaping devices) within 3 months prior to screening Pregnant or lactating, planning to become pregnant during the study, or is a woman of childbearing potential and not on an acceptable form of birth control (acceptable includes abstinence, condoms, oral/injectable contraceptives, IUD, or implant); childbearing means that menstruation has started, and the participant is not surgically sterile or greater than 12 months post-menopausal No known stage 4/5 renal failure or on dialysis Taking Hydroxyurea medication An event of severe hypoglycemia, as judged by the Investigator, within the last 90 days prior to screening An episode of diabetic ketoacidosis (DKA) diagnosed at a health care facility within the 90 days prior to screening or severe hypoglycemia event within the 90 days prior to screening Employed by, or having immediate family members employed by MannKind Corporation or JAEB Center for Health Research, or having a direct supervisor at place of employment who is also directly involved in conducting the clinical trial (as Study Investigator, coordinator, etc.); or having a first-degree relative who is directly involved in in conducting the clinical trial

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Afrezza (Technosphere Insulin) + insulin degludec<br>The Afrezza-Degludec group will inhale Afrezza at meals and corrections and will inject insulin degludec once a day for the 17 weeks of the RCT Phase. Dexcom CGM will be provided. The Afrezza-Degludec group will continue to use Afrezza and insulin degludec for an additional 13 weeks in the Extension Phase. | Biological: Afrezza<br>* Pharmaceutical form: powder Route of administration: inhalation<br>* Other names: Technosphere Insulin;Biological: insulin degludec<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>|
| Active Comparator: Usual Care: Insulin delivery with either MDI, a pump without automation, or an AID system and CGM<br>The Usual Care group will continue to receive insulin as they did before the study. This could be by injections or by using an insulin pump with or without automation for the 17 weeks of the RCT Phase. Participants will continue to use their personal CGM as they did before the study. The Usual Care group will then use Afrezza and insulin degludec for 13 weeks in the Extension Phase. Dexcom CGM will be provided during the Extension Phase. | Biological: Rapid-acting Insulin Analog<br>* Pharmaceutical form: clear and colorless solution for injection Route of administration: subcutaneous<br>* Other names: any FDA approved Rapid-acting Insulin Analog;Biological: Basal Insulin<br>* Pharmaceutical form: clear and colorless solution for injection Route of administration: subcutaneous<br>* Other names: any FDA approved Basal Insulin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | Change in HbA1c from baseline to 17 weeks (non-inferiority, non-inferiority margin 0.4%) | 17 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CGM-measured percent time with glucose <54 mg/dL | CGM-measured percent time with glucose <54 mg/dL from baseline to 17 weeks (non-inferiority, margin 0.5%) | 17 weeks | 
| CGM-measured percent time with glucose <70 mg/dL | CGM-measured percent time with glucose <70mg/dL from baseline to 17 weeks (non-inferiority, margin 2.0%) | 17 weeks | 
| CGM-measured daytime (0600-midnight) percent time in range with glucose 70-180 mg/dL | CGM-measured daytime (0600-midnight) percent time in range with glucose 70-180 mg/dL from baseline to 17 weeks, for superiority assessment | 17 weeks | 
| Mean CGM glucose | Mean CGM glucose from baseline to 17 weeks, for superiority assessment | 17 weeks | 
| CGM-measured (24-hours) percent time in range with glucose 70-180 mg/dL | CGM-measured (24-hours) percent time in range with glucose 70-180 mg/dL from baseline to 17 weeks, for superiority assessment | 17 weeks | 
| CGM-measured percent time with glucose >180 mg/dL | CGM-measured percent time with glucose > 180 mg/dL from baseline to 17 weeks, for superiority assessment | 17 weeks | 
| HbA1c | HbA1c from baseline to 17 weeks, for superiority assessment | 17 weeks | 
| CGM-measured time with glucose >250 mg/dL | CGM-measured time with glucose >250 mg/dL from baseline to 17 weeks, for superiority assessment | 17 weeks | 
| CGM-measured time with glucose <70 mg/dL | CGM-measured time with glucose <70 mg/dL from baseline to 17 weeks, for superiority assessment | 17 weeks | 
| CGM-measured time with glucose <54 mg/dL | CGM-measured time with glucose <54 mg/dL from baseline to 17 weeks, for superiority assessment | 17 weeks | 
| CGM-measured coefficient of variation | CGM-measured coefficient of variation from baseline to 17 weeks, for superiority assessment | 17 weeks | 
| Incidence of severe hypoglycemia events | Incidence of severe hypoclycemia events, defined as events requiring assistance of another person due to cognitive impairment to actively administer carbohydrate, glucagon, or other resuscitative actions | 30 weeks | 
| CGM-measured percent time with glucose <54 mg/dL | CGM-measured percent time with glucose <54 mg/dL | 30 weeks | 
| Other serious adverse events, including hospitalizations | Other serious adverse events, including hospitalizations | 30 weeks | 
| Incidence and severity of treatment-emergent adverse events (TEAEs) | Incidence and severity of treatment-emergent adverse events (TEAEs) | 30 weeks | 
| Incidence and severity of adverse events of special interest (AESIs) as well as the number of participants with AESIs and number of individual events | Incidence and severity of adverse events of special interest (AESIs) as well as the number of participants with AESIs and number of individual events | 30 weeks | 
| Change from baseline to 17 weeks in FEV1 | Change from baseline to 17 weeks in FEV1 | 17 weeks | 
| Proportions of participants in each group who have experienced ≥20% reduction in FEV1 from baseline to Week 17 | Proportions of participants in each group who have experienced ≥20% reduction in FEV1 from baseline to Week 17 | 17 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CGM, Diabetes Mellitus, Insulin, Inhaled, Afrezza, Technosphere, Adults, Degludec, Glucose sensors, Insulin pumps