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

Tracking Information

• First Submitted Date: June 2, 2023
• First Posted Date: June 15, 2023
• Last Update Posted Date: February 13, 2024
• Actual Study Start Date: July 7, 2023
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 6, 2023)

Change in HbA1c [ Time Frame: 17 weeks ]

Change in HbA1c from baseline to 17 weeks (non-inferiority, non-inferiority margin 0.4%)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 9, 2024)

• 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%)
• 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%)
• 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
• Mean CGM glucose [ Time Frame: 17 weeks ]
  Mean CGM glucose from baseline to 17 weeks, for superiority assessment
• 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
• 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
• HbA1c [ Time Frame: 17 weeks ]
  HbA1c from baseline to 17 weeks, for superiority assessment
• 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
• 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
• 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
• CGM-measured coefficient of variation [ Time Frame: 17 weeks ]
  CGM-measured coefficient of variation from baseline to 17 weeks, for superiority assessment
• 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
• CGM-measured percent time with glucose <54 mg/dL [ Time Frame: 30 weeks ]
  CGM-measured percent time with glucose <54 mg/dL
• Other serious adverse events, including hospitalizations [ Time Frame: 30 weeks ]
  Other serious adverse events, including hospitalizations
• Incidence and severity of treatment-emergent adverse events (TEAEs) [ Time Frame: 30 weeks ]
  Incidence and severity of treatment-emergent adverse events (TEAEs)
• 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
• Change from baseline to 17 weeks in FEV1 [ Time Frame: 17 weeks ]
  Change from baseline to 17 weeks in FEV1
• 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
• 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)
• Hyperglycemic events from logged BGM measurements [ Time Frame: 30 weeks ]
  Hyperglycemic events from logged BGM measurements
• CGM-measured prolonged hyperglycemia events [ Time Frame: 30 weeks ]
  CGM-measured prolonged hyperglycemia events
• CGM-measured hypoglycemia events (both a safety and efficacy endpoint) [ Time Frame: 17 weeks ]
  CGM-measured hypoglycemia events (both a safety and efficacy endpoint)

Original Secondary Outcome Measures (submitted: June 6, 2023)

• 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%)
• 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%)
• 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
• Mean CGM glucose [ Time Frame: 17 weeks ]
  Mean CGM glucose from baseline to 17 weeks, for superiority assessment
• 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
• 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
• HbA1c [ Time Frame: 17 weeks ]
  HbA1c from baseline to 17 weeks, for superiority assessment
• 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
• 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
• 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
• CGM-measured coefficient of variation [ Time Frame: 17 weeks ]
  CGM-measured coefficient of variation from baseline to 17 weeks, for superiority assessment
• 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
• CGM-measured percent time with glucose <54 mg/dL [ Time Frame: 30 weeks ]
  CGM-measured percent time with glucose <54 mg/dL
• Other serious adverse events, including hospitalizations [ Time Frame: 30 weeks ]
  Other serious adverse events, including hospitalizations
• Incidence and severity of treatment-emergent adverse events (TEAEs) [ Time Frame: 30 weeks ]
  Incidence and severity of treatment-emergent adverse events (TEAEs)
• 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
• Change from baseline to 17 weeks in FEV1 [ Time Frame: 17 weeks ]
  Change from baseline to 17 weeks in FEV1
• Proportions of participants in each group who have experienced ≥20% reduction in FEV1 from baseline to Week 17 [ Time Frame: 17 weeks ]
  Proportions of participants in each group who have experienced ≥20% reduction in FEV1 from baseline to Week 17

Current Other Pre-specified Outcome Measures (submitted: February 9, 2024)

• Weight [ Time Frame: 17 weeks ]
  Weight
• Post prandial glucose for first meal challenge [ Time Frame: 17 weeks ]
  Post prandial glucose for first meal challenge
• Area under the curve (AUC) for first meal challenge [ Time Frame: 17 weeks ]
  Area under the curve (AUC) for first meal challenge
• 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

Original Other Pre-specified Outcome Measures (submitted: June 6, 2023)

• Fasting glucose by CGM [ Time Frame: 17 weeks ]
  Fasting glucose by CGM
• Insulin: total daily basal insulin dose and total daily bolus insulin dose (average over 7 days) [ Time Frame: 17 weeks ]
  Insulin: total daily basal insulin dose and total daily bolus insulin dose (average over 7 days)
• Weight [ Time Frame: 17 weeks ]
  Weight
• Post prandial glucose for first meal challenge [ Time Frame: 17 weeks ]
  Post prandial glucose for first meal challenge
• Area under the curve (AUC) for first meal challenge [ Time Frame: 17 weeks ]
  Area under the curve (AUC) for first meal challenge
• Patient-reported outcome (PRO) questionnaires [ Time Frame: 17 weeks ]
  Patient-reported outcome (PRO) questionnaires

Descriptive Information

• Brief Title: INHALE-3: Afrezza® Combined With Insulin Degludec Versus Usual Care in Adults With Type 1 Diabetes
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Diabetes Mellitus, Type 1

Intervention

• 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
• 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

Study Arms

• 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.
  Interventions:

  • Biological: Afrezza
  • Biological: insulin degludec
• 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.
  Interventions:

  • Biological: Rapid-acting Insulin Analog
  • Biological: Basal Insulin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: November 28, 2023): 141
• Original Estimated Enrollment (submitted: June 6, 2023): 145
• Estimated Study Completion Date: October 2024
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05904743
• Other Study ID Numbers: MKC-TI-193
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Mannkind Corporation
• Original Responsible Party: Same as current
• Current Study Sponsor: Mannkind Corporation
• Original Study Sponsor: Same as current
• Collaborators: Jaeb Center for Health Research

Investigators

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

• PRS Account: Mannkind Corporation
• Verification Date: June 2023