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

• ClinicalTrials.gov Identifier: NCT05904743
• Recruitment Status: Active, not recruiting
• First Posted: June 15, 2023
• Last Update Posted: February 13, 2024
• Sponsor: Mannkind Corporation
• Collaborator: Jaeb Center for Health Research
• Information provided by (Responsible Party): Mannkind Corporation

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1	Biological: Afrezza; Biological: insulin degludec; Biological: Rapid-acting Insulin Analog; Biological: Basal Insulin	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 141 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: July 7, 2023
• Estimated Primary Completion Date: June 2024
• Estimated Study Completion Date: October 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Afrezza (Technosphere Insulin) + insulin degludec; 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; Pharmaceutical form: powder Route of administration: inhalation; Other Name: Technosphere Insulin; Biological: insulin degludec; Pharmaceutical form: solution for injection Route of administration: subcutaneous
Active Comparator: Usual Care: Insulin delivery with either MDI, a pump without automation, or an AID system and CGM; 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; Pharmaceutical form: clear and colorless solution for injection Route of administration: subcutaneous; Other Name: any FDA approved Rapid-acting Insulin Analog; Biological: Basal Insulin; Pharmaceutical form: clear and colorless solution for injection Route of administration: subcutaneous; Other Name: any FDA approved Basal Insulin

Outcome Measures

Primary Outcome Measures :

1. Change in HbA1c [ Time Frame: 17 weeks ]
   Change in HbA1c from baseline to 17 weeks (non-inferiority, non-inferiority margin 0.4%)

Secondary Outcome Measures :

1. CGM-measured percent time with glucose <54 mg/dL [ Time Frame: 17 weeks ]
   CGM-measured percent time with glucose <54 mg/dL from baseline to 17 weeks (non-inferiority, margin 0.5%)
2. CGM-measured percent time with glucose <70 mg/dL [ Time Frame: 17 weeks ]
   CGM-measured percent time with glucose <70mg/dL from baseline to 17 weeks (non-inferiority, margin 2.0%)
3. CGM-measured daytime (0600-midnight) percent time in range with glucose 70-180 mg/dL [ Time Frame: 17 weeks ]
   CGM-measured daytime (0600-midnight) percent time in range with glucose 70-180 mg/dL from baseline to 17 weeks, for superiority assessment
4. Mean CGM glucose [ Time Frame: 17 weeks ]
   Mean CGM glucose from baseline to 17 weeks, for superiority assessment
5. CGM-measured (24-hours) percent time in range with glucose 70-180 mg/dL [ Time Frame: 17 weeks ]
   CGM-measured (24-hours) percent time in range with glucose 70-180 mg/dL from baseline to 17 weeks, for superiority assessment
6. CGM-measured percent time with glucose >180 mg/dL [ Time Frame: 17 weeks ]
   CGM-measured percent time with glucose > 180 mg/dL from baseline to 17 weeks, for superiority assessment
7. HbA1c [ Time Frame: 17 weeks ]
   HbA1c from baseline to 17 weeks, for superiority assessment
8. CGM-measured time with glucose >250 mg/dL [ Time Frame: 17 weeks ]
   CGM-measured time with glucose >250 mg/dL from baseline to 17 weeks, for superiority assessment
9. CGM-measured time with glucose <70 mg/dL [ Time Frame: 17 weeks ]
   CGM-measured time with glucose <70 mg/dL from baseline to 17 weeks, for superiority assessment
10. CGM-measured time with glucose <54 mg/dL [ Time Frame: 17 weeks ]
    CGM-measured time with glucose <54 mg/dL from baseline to 17 weeks, for superiority assessment
11. CGM-measured coefficient of variation [ Time Frame: 17 weeks ]
    CGM-measured coefficient of variation from baseline to 17 weeks, for superiority assessment
12. Incidence of severe hypoglycemia events [ Time Frame: 30 weeks ]
    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
13. CGM-measured percent time with glucose <54 mg/dL [ Time Frame: 30 weeks ]
    CGM-measured percent time with glucose <54 mg/dL
14. Other serious adverse events, including hospitalizations [ Time Frame: 30 weeks ]
    Other serious adverse events, including hospitalizations
15. Incidence and severity of treatment-emergent adverse events (TEAEs) [ Time Frame: 30 weeks ]
    Incidence and severity of treatment-emergent adverse events (TEAEs)
16. Incidence and severity of adverse events of special interest (AESIs) as well as the number of participants with AESIs and number of individual events [ Time Frame: 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
17. Change from baseline to 17 weeks in FEV1 [ Time Frame: 17 weeks ]
    Change from baseline to 17 weeks in FEV1
18. Proportions of participants in each group who have experienced ≥20% reduction in FEV1 from baseline to Week 17 [ Time Frame: 30 weeks ]
    Proportions of participants in each group who have experienced ≥20% reduction in FEV1 from baseline to Week 17
19. Hypoglycemic events from logged BGM measurements: Level 1 events (<70 mg/dL) and Level 2 events (<54 mg/dL) separately [ Time Frame: 30 weeks ]
    Hypoglycemic events from logged BGM measurements: Level 1 events (<70 mg/dL) and Level 2 events (<54 mg/dL)
20. Hyperglycemic events from logged BGM measurements [ Time Frame: 30 weeks ]
    Hyperglycemic events from logged BGM measurements
21. CGM-measured prolonged hyperglycemia events [ Time Frame: 30 weeks ]
    CGM-measured prolonged hyperglycemia events
22. CGM-measured hypoglycemia events (both a safety and efficacy endpoint) [ Time Frame: 17 weeks ]
    CGM-measured hypoglycemia events (both a safety and efficacy endpoint)

Other Outcome Measures:

1. Weight [ Time Frame: 17 weeks ]
   Weight
2. Post prandial glucose for first meal challenge [ Time Frame: 17 weeks ]
   Post prandial glucose for first meal challenge
3. Area under the curve (AUC) for first meal challenge [ Time Frame: 17 weeks ]
   Area under the curve (AUC) for first meal challenge
4. Patient-reported outcome (PRO) questionnaires [ Time Frame: 17 weeks ]

   Type 1 Diabetes Distress Scale (T1-DDS): 28-item validated survey pertaining to distress symptoms related to diabetes (recorded from a scale of 1 to 6).

   Hypoglycemia Confidence Scale (HCS): 9-item validated survey pertaining to situations where hypoglycemia could occur and queries about the participant's level of confidence in those situations (recorded from a scale 1 to 4).

   Insulin Treatment Satisfaction Questionnaire (ITSQ): 22-item survey with a 5-factor structure assessing insulin satisfaction (scores range from 0 to 100).

   Freedom and Flexibility: 6-item non-validated survey pertaining to life experiences impacted by having diabetes (scores range from 6 to 36)

   Insulin Adherence: 1-item non-validated survey pertaining to number of missed boluses in the past week

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

  1. Current (at time of screening) rapid-acting insulin analog (RAA) in use for at least 4 weeks
  2. If AID system used, automated insulin delivery must be active >85% of the time in the 4 weeks prior to screening
  3. 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

  1. 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
• Have a history or current diagnosis of lung cancer

Contacts and Locations

Locations

United States, California

Loma Linda University-Diabetes Treatment Center

Loma Linda, California, United States, 92354

Sansum Diabetes Research

Santa Barbara, California, United States, 93105

United States, Colorado

Barbara Davis Center

Aurora, Colorado, United States, 80045

United States, Georgia

Atlanta Diabetes Associates

Atlanta, Georgia, United States, 30318

United States, Illinois

Northwestern University Division of Endocrinology, Metabolism and Molecular Medicine

Chicago, Illinois, United States, 60611

United States, Iowa

Iowa Diabetes Research

West Des Moines, Iowa, United States, 50265

United States, Massachusetts

Boston Medical Center

Boston, Massachusetts, United States, 02118

Joslin Diabetes Center

Boston, Massachusetts, United States, 02215

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

United States, Nevada

Las Vegas Endocrinology

Henderson, Nevada, United States, 89074

United States, New York

Endocrine Associate of West Village, PC

Long Island City, New York, United States, 11106

Mount Sinai Diabetes Center

New York, New York, United States, 10075

SUNY Upstate Medical University

Syracuse, New York, United States, 13210

United States, North Carolina

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States, 27514

United States, Texas

Texas Diabetes & Endocrinology, P.A.

Austin, Texas, United States, 78731

The University of Texas Southwestern Medical Center

Dallas, Texas, United States, 75390

Diabetes and Glandular Disease Clinic, P.A.

San Antonio, Texas, United States, 78229

United States, Washington

University of Washington Diabetes Institute

Seattle, Washington, United States, 98119

United States, West Virginia

Mountain State Diabetes

Parkersburg, West Virginia, United States, 26101

Sponsors and Collaborators

Mannkind Corporation

Jaeb Center for Health Research

Investigators

• Study Director: Kevin Kaiserman, MD; Mannkind Corporation
• Study Chair: Irl B. Hirsch, MD; University of Washington

More Information

• Responsible Party: Mannkind Corporation
• ClinicalTrials.gov Identifier: NCT05904743
• Other Study ID Numbers: MKC-TI-193
• First Posted: June 15, 2023
• Last Update Posted: February 13, 2024
• Last Verified: June 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mannkind Corporation:

Diabetes Mellitus; Insulin; Inhaled; Afrezza; Technosphere; Adults; Degludec; Glucose sensors; Insulin pumps; CGM

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Insulin; Insulin, Globin Zinc; Insulin, Short-Acting; Hypoglycemic Agents; Physiological Effects of Drugs