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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Biological: Afrezza; Biological: insulin degludec; Biological: Rapid-acting Insulin Analog; Biological: Basal Insulin

• Study Type: Interventional
• Enrollment (Actual): 141
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University-Diabetes Treatment Center
    • Santa Barbara, California, United States, 93105
      • Sansum Diabetes Research
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Barbara Davis Center
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Atlanta Diabetes Associates
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Division of Endocrinology, Metabolism and Molecular Medicine
  • Iowa
    • West Des Moines, Iowa, United States, 50265
      • Iowa Diabetes Research
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Nevada
    • Henderson, Nevada, United States, 89074
      • Las Vegas Endocrinology
  • New York
    • Long Island City, New York, United States, 11106
      • Endocrine Associate of West Village, PC
    • New York, New York, United States, 10075
      • Mount Sinai Diabetes Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina at Chapel Hill
  • Texas
    • Austin, Texas, United States, 78731
      • Texas Diabetes & Endocrinology, P.A.
    • Dallas, Texas, United States, 75390
      • The University of Texas Southwestern Medical Center
    • San Antonio, Texas, United States, 78229
      • Diabetes and Glandular Disease Clinic, P.A.
  • Washington
    • Seattle, Washington, United States, 98119
      • University of Washington Diabetes Institute
  • West Virginia
    • Parkersburg, West Virginia, United States, 26101
      • Mountain State Diabetes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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 Continuous Glucose Monitoring (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 Names: 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 multiple daily injections (MDI) or by using an insulin pump with or without automation for the 17 weeks of the randomized controlled trial (RCT) Phase. Participants will continue to use their personal continuous glucose monitor (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 Names: any FDA approved Rapid-acting Insulin Analog; Biological: Basal Insulin; Pharmaceutical form: clear and colorless solution for injection Route of administration: subcutaneous; Other Names: any FDA approved Basal Insulin

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Continuous Glucose Monitoring (CGM) measured percent time with glucose less than 54 mg/dL	CGM-measured percent time with glucose <54 mg/dL from baseline to 17 weeks (non-inferiority, margin 0.5%)	17 weeks
Continuous Glucose Monitoring (CGM) measured percent time with glucose less than 70 mg/dL	CGM-measured percent time with glucose <70mg/dL from baseline to 17 weeks (non-inferiority, margin 2.0%)	17 weeks
Continuous Glucose Monitoring (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 Continuous Glucose Monitoring (CGM) glucose	Mean CGM glucose from baseline to 17 weeks, for superiority assessment	17 weeks
Continuous Glucose Monitoring (CGM) measured (24-hours) percent time in range (TIR) 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
Continuous Glucose Monitoring (CGM) measured percent time with glucose greater than 180 mg/dL	CGM-measured percent time with glucose > 180 mg/dL from baseline to 17 weeks, for superiority assessment	17 weeks
Change in glycated hemoglobin (HbA1c) for superiority assessment	HbA1c from baseline to 17 weeks, for superiority assessment	17 weeks
Continuous Glucose Monitoring (CGM) measured time with glucose greater than 250 mg/dL	CGM-measured time with glucose >250 mg/dL from baseline to 17 weeks, for superiority assessment	17 weeks
Continuous Glucose Monitoring (CGM) measured time with glucose less than 70 mg/dL	CGM-measured time with glucose <70 mg/dL from baseline to 17 weeks, for superiority assessment	17 weeks
Continuous Glucose Monitoring (CGM) measured time with glucose less than 54 mg/dL	CGM-measured time with glucose <54 mg/dL from baseline to 17 weeks, for superiority assessment	17 weeks
Continuous Glucose Monitoring (CGM) measured coefficient of variation	CGM-measured coefficient of variation from baseline to 17 weeks, for superiority assessment	17 weeks
Change in HbA1c less than 7.0% at 17 weeks	HbA1c <7.0% at 17 weeks	17 weeks
Change in HbA1c from baseline to 17 weeks, with an improvement of greater than 0.5%	HbA1c improvement from baseline to 17 weeks >0.5%	17 weeks
Change in HbA1c from baseline to 17 weeks, with an improvement of greater than 1.0%	HbA1c improvement from baseline to 17 weeks >1.0%	17 weeks
Percent time in range (TIR) with glucose 70-140 mg/dL	Percent time in range with glucose 70-140 mg/dL	17 weeks
Percent time with glucose greater than 300 mg/dL	Percent time with glucose >300 mg/dL	17 weeks
Continuous Glucose Monitoring (CGM) measured prolonged hyperglycemia events	CGM-measured prolonged hyperglycemia events	17 weeks
Continuous Glucose Monitoring (CGM) measured hypoglycemia events	CGM-measured hypoglycemia events	17 weeks
Standard Deviation (SD) of glucose	SD of glucose	17 weeks
"Fasting glucose" by Continuous Glucose Monitoring (CGM)	"Fasting glucose" by CGM (defined as closest value to 6 a.m.; assumed, but not verified, with no food during the prior 4-hour period)	17 weeks
Percent time in range (TIR) with glucose 70-180 mg/dL greater than 70%	Percent time in range with glucose 70-180 mg/dL >70% at 17 weeks	17 weeks
Percent time in range (TIR) with glucose 70-180 mg/dL improvement from baseline to 17 weeks greater than or equal to 5%	Percent time in range with glucose 70-180 mg/dL improvement from baseline to 17 weeks ≥5%	17 weeks
Percent time in range (TIR) with glucose 70-180 mg/dL improvement from baseline to 17 weeks ≥10%	Percent time in range with glucose 70-180 mg/dL improvement from baseline to 17 weeks ≥10%	17 weeks
Percent time with glucose less than 70 mg/dL less than 4%	Percent time with glucose <70 mg/dL <4% at 17 weeks	17 weeks
Percent time with glucose less than 54 mg/dL less than1%	Percent time with glucose <54 mg/dL <1% at 17 weeks	17 weeks
Percent time in range (TIR) 70-180 mg/dL greater than 70% and time less than 54 mg/dL less than 1%	Percent time in range 70-180 mg/dL >70% and time <54 mg/dL <1% at 17 weeks	17 weeks
Continuous Glucose Monitoring (CGM) measured percent time with glucose less than 54 mg/dL	CGM-measured percent time with glucose less than 54 mg/dL	30 weeks
Change from baseline to 17 weeks in Forced Expiratory Volume in one second (FEV1)	Change from baseline to 17 weeks in FEV1	17 weeks
Proportion of participants with Forced Expiratory Volume in one second (FEV1) reduction greater than or equal to 20%	Proportions of participants in each group who have experienced ≥20% reduction in FEV1 from baseline to Week 17	30 weeks
Hypoglycemic events from logged blood glucose measurements (BGM): Level 1 events (less than 70 mg/dL) and Level 2 events (less than 54 mg/dL) separately	Hypoglycemic events from logged BGM measurements: Level 1 events (<70 mg/dL) and Level 2 events (<54 mg/dL)	30 weeks
Hyperglycemic events from logged blood glucose measurements (BGM)	Hyperglycemic events from logged BGM measurements	30 weeks
Continuous Glucose Monitoring (CGM) measured prolonged hyperglycemia events	CGM-measured prolonged hyperglycemia events	30 weeks
Continuous Glucose Monitoring (CGM) measured hypoglycemia events (both a safety and efficacy endpoint)	CGM-measured hypoglycemia events (both a safety and efficacy endpoint)	30 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weight	Weight	17 weeks
Post prandial glucose for first meal challenge	Post prandial glucose for first meal challenge	17 weeks
Area under the curve (AUC) for first meal challenge	Area under the curve (AUC) for first meal challenge	17 weeks
Patient-reported outcome (PRO) questionnaires	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	17 weeks
Change in HbA1c from baseline to 17 weeks, with a worsening of greater than 0.5%	Additional binary HbA1c endpoints, HbA1c worsening from baseline to 17 weeks >0.5%	17 weeks
Change in HbA1c from baseline to 17 weeks, with a worsening of greater than 1.0%	Additional binary HbA1c endpoints, HbA1c worsening from baseline to 17 weeks >1.0%	17 weeks
Percent time in range (TIR) with glucose 70-180 mg/dL worsening from baseline to 17 weeks greater than or equal to 5%	Additional binary CGM endpoints, Percent time in range with glucose 70-180 mg/dL worsening from baseline to 17 weeks ≥5%	17 weeks
Percent time in range (TIR) with glucose 70-180 mg/dL worsening from baseline to 17 weeks greater than or equal to 10%	Additional binary CGM endpoints, Percent time in range with glucose 70-180 mg/dL worsening from baseline to 17 weeks ≥10%	17 weeks

Collaborators and Investigators

• Sponsor: Mannkind Corporation
• Collaborators: Jaeb Center for Health Research
• Investigators: Study Director: Kevin Kaiserman, MD, Mannkind Corporation; Study Chair: Irl B. Hirsch, MD, University of Washington

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2023
• Primary Completion (Actual): March 26, 2024
• Study Completion (Actual): June 24, 2024

Study Registration Dates

• First Submitted: June 2, 2023
• First Submitted That Met QC Criteria: June 6, 2023
• First Posted (Actual): June 15, 2023

Study Record Updates

• Last Update Posted (Actual): August 9, 2024
• Last Update Submitted That Met QC Criteria: August 7, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Insulin; Diabetes Mellitus; Adults; CGM; Glucose sensors; Inhaled; Afrezza; Technosphere; Insulin pumps; Degludec
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc; Insulin, Short-Acting
• Other Study ID Numbers: MKC-TI-193

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No