Afrezza® INHALE-1 Study in Pediatrics (INHALE-1)

• ClinicalTrials.gov Identifier: NCT04974528
• Recruitment Status: Active, not recruiting
• First Posted: July 23, 2021
• Last Update Posted: March 5, 2024
• Sponsor: Mannkind Corporation
• Collaborator: Jaeb Center for Health Research
• Information provided by (Responsible Party): Mannkind Corporation

Tracking Information

• First Submitted Date: June 22, 2021
• First Posted Date: July 23, 2021
• Last Update Posted Date: March 5, 2024
• Actual Study Start Date: September 29, 2021
• Estimated Primary Completion Date: September 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 18, 2022)

Change in HbA1c [ Time Frame: 26 weeks ]

Change in HbA1c from baseline to Week 26, for noninferiority assessment

Original Primary Outcome Measures (submitted: July 13, 2021)

Change in HbA1c After 26 Weeks [ Time Frame: 26 weeks ]

HbA1c change after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA)

Current Secondary Outcome Measures (submitted: November 6, 2023)

• Change in Fasting Plasma Glucose (FPG) [ Time Frame: 26 weeks ]
  Change in FPG from baseline to Week 26, for superiority assessment
• Event rate of pooled level 2 and level 3 hypoglycemia [ Time Frame: 26 weeks ]
  Event rate of pooled level 2 and level 3 hypoglycemia (SMBG < 54 mg/dL and/or severe hypoglycemic events reported on the adverse event CRF) during the 26 -week randomized treatment period, for superiority assessment.
• Change in HbA1c [ Time Frame: 26 weeks ]
  Change in HbA1c from baseline to Week 26, for superiority assessment

Original Secondary Outcome Measures (submitted: July 13, 2021)

• Change in Fasting Plasma Glucose (FPG) After 26 weeks [ Time Frame: 26 weeks ]
  FPG change after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA)
• Rate of Hypoglycemic Events After 26 weeks [ Time Frame: 26 weeks ]
  Event rate of hypoglycemia (SMBG <70 mg/dL) after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA).

Current Other Pre-specified Outcome Measures (submitted: October 17, 2023)

• Event rate of level 1 hypoglycemia (SMBG <70 mg/dL) [ Time Frame: 26 weeks ]
  Event rate of level 1 hypoglycemia during the 26-week randomized treatment period
• Change in percent Time In Range (glucose 70 - 180 mg/dL) [ Time Frame: 26 weeks ]
  Change in percent Time In Range from baseline to Week 26, using Continuous Glucose Monitoring (CGM)-derived data collected over the preceding 30 days for the 24-hour, daytime and nocturnal time periods
• Change in percent time with glucose <54 mg/dL [ Time Frame: 26 weeks ]
  Change in percent time with glucose <54 mg/dL from baseline to Week 26, using CGM-derived data collected over the preceding 30 days for the 24-hour, daytime and nocturnal time periods
• Change in percent Time Below Range (glucose <70 mg/dL) [ Time Frame: 26 weeks ]
  Change in percent Time Below Range from baseline to Week 26, using CGM-derived data collected over the preceding 30 days for the 24-hour, daytime and nocturnal time periods
• Change in percent Time Above Range (glucose >180 mg/dL) [ Time Frame: 26 weeks ]
  Change in percent Time Above Range from baseline to Week 26, using CGM-derived data collected over the preceding 30 days for the 24-hour, daytime and nocturnal time periods
• Percentage of subjects with HbA1c <7.0% [ Time Frame: At Week 26 ]
  Percentage of subjects with HbA1c <7.0% at Week 26
• Score of Diabetes Treatment Satisfaction Questionnaire (DTSQ) Change (c)-Teen [ Time Frame: At Week 26 ]
  Score of DTSQ(c)-Teen at Week 26 in the Afrezza group (score ranges from -24 to 24, with higher score means greater satisfaction)
• Score of Diabetes Treatment Satisfaction Questionnaire (DTSQ) Change (c)-Parent [ Time Frame: At Week 26 ]
  Score of DTSQ(c)-Parent at Week 26 in the Afrezza group (score ranges from -30 to 30, with higher score means greater satisfaction)
• Change in scores of DTSQ Status (s)-Teen [ Time Frame: 26 weeks ]
  Change in scores of DTSQ(s)-Teen from baseline to Week 26 (change in score ranges from -48 to 48, with higher score means greater satisfaction)
• Change in scores of DTSQ Status (s)-Parent [ Time Frame: 26 weeks ]
  Change in scores of DTSQ(s)-Parent from baseline to Week 26 (change in scores ranges from -60 to 60, with higher score means greater satisfaction)
• Change in HbA1c [ Time Frame: 52 weeks (and 26 weeks if required) ]
  Change in HbA1c from baseline to Week 52 (and change from Week 26 to Week 52 if required) in subjects who switch from treatment with RAA injections to Afrezza at Week 26
• Change in FPG [ Time Frame: 52 weeks (and 26 weeks if required) ]
  Change in FPG from baseline to Week 52 (and change from Week 26 to Week 52 if required) in subjects who switch from treatment with RAA injections to Afrezza at Week 26
• Change in percent Time In Range, Time Below Range and Time Above Range [ Time Frame: 52 weeks (and 26 weeks if required) ]
  Change in percent Time In Range, Time Below Range and Time Above Range from baseline to Week 52 (and change from Week 26 to Week 52 if required) in subjects who switch from treatment with RAA injections to Afrezza at Week 26; using CGM-derived data collected over the preceding 30 days for the 24-hour, daytime, and nocturnal periods
• Change in HbA1c [ Time Frame: 52 weeks ]
  Change in HbA1c from baseline to Week 52 in subjects who receive Afrezza in both the randomized treatment period and the treatment extension
• Change in FPG [ Time Frame: 52 weeks ]
  Change in FPG from baseline to Week 52 in subjects who receive Afrezza in both the randomized treatment period and the treatment extension
• Change in percent Time In Range, Time Below Range and Time Above Range [ Time Frame: 52 weeks ]
  Change in percent Time In Range, Time Below Range and Time Above Range from baseline to Week 52 in subjects who receive Afrezza in both the randomized treatment period and the treatment extension; using CGM-derived data collected over the preceding 30 days for the 24-hour, daytime, and nocturnal periods
• Score of DTSQ(c)-Teen at Week 52 [ Time Frame: At Week 52 ]
  Score of DTSQ(c)-Teen at Week 52 (after 6 months of Afrezza treatment) in subjects who switch from RAA injections to Afrezza (score ranges from -24 to 24, with higher score means greater satisfaction)
• Score of DTSQ(c)-Parent at Week 52 [ Time Frame: At Week 52 ]
  Score of DTSQ(c)-Parent at Week 52 (after 6 months of Afrezza treatment) in subjects who switch from RAA injections to Afrezza (score ranges from -30 to 30, with higher score means greater satisfaction)
• Change in scores of DTSQ(s)-Teen [ Time Frame: 52 weeks ]
  Change in scores of DTSQ(s)-Teen from baseline to Week 52 (changes in score ranges from -48 to 48, with higher score means greater satisfaction)
• Change in scores of DTSQ(s)-Parent [ Time Frame: 52 weeks ]
  Change in scores of DTSQ(s)-Parent from baseline to Week 52 (change in scores ranges from -60 to 60, with higher score means greater satisfaction)
• Event rates of hypoglycemic events [ Time Frame: 52 weeks ]
  Event rates and incidence of total, nocturnal, and severe hypoglycemic events from baseline to Week 52
• Incidence of hypoglycemic events [ Time Frame: 52 weeks ]
  Incidence of total, nocturnal, and severe hypoglycemic events from baseline to Week 52
• Incidence and severity of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: 52 weeks ]
  Incidence and severity of TEAEs and SAEs from baseline to Week 52
• Incidence and severity of Adverse Events of Special Interest (AESIs) [ Time Frame: 52 weeks ]
  Incidence and severity of AESIs (i.e., acute bronchospasm, clinically relevant decline in pulmonary function [>15% decline from baseline percent predicted FEV1 accompanied by respiratory symptoms], hypersensitivity reactions [including anaphylaxis], use of asthma reliever medication, initiation or use of asthma controller medication, use of corticosteroid bursts, asthma exacerbations, hospitalization for asthma exacerbation, events of level 3 hypoglycemia, and diabetic ketoacidosis [DKA]) as well as the number of subjects with AESIs and number of individual events
• Change in percent predicted Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: 56 weeks ]
  Change from baseline to Weeks 13, 26, 39, 52, and 56 in percent predicted FEV1

Original Other Pre-specified Outcome Measures (submitted: July 13, 2021)

• Time in Range (70 - 180 mg/dL) [ Time Frame: 26 weeks ]
  Time in Range after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA), based on continuous glucose monitoring derived glucose values.
• Change in Percent Time with Glucose <54 mg/dL [ Time Frame: 26 weeks ]
  Percent Time with Glucose <54 mg/dL after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA), based on continuous glucose monitoring derived values.
• Time Below Range (glucose <70 mg/dL) [ Time Frame: 26 weeks ]
  Time Below Range after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA), based on continuous glucose monitoring derived values.
• Time Above Range (glucose >180 mg/dL) [ Time Frame: 26 weeks ]
  Percent Time with Glucose >180 mg/dL after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA), based on continuous glucose monitoring derived values.
• Percentage of Subjects with HbA1c <7.0% at Week 26 [ Time Frame: 26 weeks ]
  Percentage of Subjects with HbA1c <7.0% after 26 weeks of Afrezza compared to Rapid-Acting Analog (RAA).
• Change in DTSQ score After 26 Weeks of Afrezza [ Time Frame: 26 weeks ]
  Change in Diabetes Treatment Satisfaction Questionnaire (DTSQ) score from before the first dose of Afrezza until after 26 weeks of Afrezza therapy (Week 26 for the Afrezza arm, or Week 52 for the RAA Arm). Scores range from -18 to 18, with higher scores indicating greater treatment satisfaction.
• Change in HbA1c During Extension - RAA arm [ Time Frame: During treatment extension at week 26 to week 52 ]
  Change in HbA1c from Week 26 to Week 52 for the RAA arm only (the RAA arm switches to Afrezza at Week 26)
• Change in HbA1c After 52 Weeks - Afrezza arm [ Time Frame: 52 weeks ]
  Change in HbA1c from baseline to week 52, in subjects who received Afrezza in both the randomized treatment period and the treatment extension.
• Event Rate of Hypoglycemic Events After 52 Weeks [ Time Frame: 52 weeks ]
  Event rate of total, nocturnal, and severe hypoglycemic events; based on the International Society for Pediatric and Adolescent Diabetes criteria.
• Incidence of Hypoglycemic Events After 52 Weeks [ Time Frame: 52 weeks ]
  Incidence of total, nocturnal, and severe hypoglycemic events; based on the International Society for Pediatric and Adolescent Diabetes criteria.
• Incidence and Severity of Adverse Events [ Time Frame: 52 weeks ]
  Incidence and severity of adverse events (AEs): treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and AEs of special interest (AESIs).
• Change in Percent Predicted Forced Expiratory Volume in 1 Second [ Time Frame: 56 weeks ]
  Change in percent predicted forced expiratory volume in 1 second (FEV1) from baseline to Weeks 13, 26, 39, 52, and 56.

Descriptive Information

• Brief Title: Afrezza® INHALE-1 Study in Pediatrics
• Official Title: INHALE-1: A 26-week Primary Treatment Phase, With 26-week Extension, Open-label, Randomized Clinical Trial Evaluating the Efficacy and Safety of Afrezza® Versus Rapid-acting Insulin Analog Injections, Both in Combination With a Basal Insulin, in Pediatric Subjects With Type 1 or Type 2 Diabetes Mellitus

Brief Summary

INHALE-1 is a Phase 3, open-label, randomized clinical study evaluating the efficacy and safety of Afrezza in combination with a basal insulin (i.e., the Afrezza group) versus insulin aspart, insulin lispro or insulin glulisine in combination with a basal insulin (i.e., the Rapid-acting Insulin Analog [RAA] injection group) in pediatric subjects with type 1 or type 2 diabetes mellitus. Following 26 weeks of randomized treatment (i.e., Afrezza or RAA injection combined with a basal insulin), all subjects will enter a treatment extension where subjects will receive Afrezza until Week 52. The purpose of the treatment extension is to assess safety and efficacy with continued use of Afrezza.

Pediatric subjects ≥4 and <18 years of age will be enrolled in this study. Subjects will be randomly assigned in a 1:1 ratio to either the Afrezza group or the RAA injection group.

The study is composed of:

• Up to 5-week screening/run-in period
• 26 week randomized treatment period
• 26-week treatment extension
• 4-week follow-up period

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Diabetes Mellitus, Type 1
• Diabetes Mellitus, Type 2

Intervention

• Biological: Afrezza

  Pharmaceutical form: powder

  Route of administration: inhalation

  Other Name: Technosphere Insulin
• Biological: Rapid-acting Insulin Analog

  Pharmaceutical form: clear and colorless solution for injection

  Route of administration: subcutaneous

  Other Names:

  • insulin aspart
  • insulin lispro
  • insulin glulisine
  • Novolog®
  • Fiasp®
  • Humalog®
  • Admelog®
  • Apidra®
• Biological: Basal Insulin

  Pharmaceutical form: solution for injection

  Route of administration: subcutaneous

  Other Names:

  • insulin glargine
  • insulin degludec
  • insulin detemir
  • Lantus®
  • Abasaglar®
  • Basaglar®
  • Semglee®
  • Toujeo®
  • Tresiba®
  • Levemir®

Study Arms

• Experimental: Afrezza (Technosphere Insulin) + Basal Insulin

  Individualized dose of Afrezza (Technosphere Insulin) for each patient before each meal (breakfast, lunch, and dinner) for 26 weeks.

  Individualized basal insulin (insulin degludec, insulin glargine or insulin detemir) for each patient.

  Interventions:

  • Biological: Afrezza
  • Biological: Basal Insulin
• Active Comparator: RAA Injection + Basal Insulin

  Individualized dose of RAA injection (insulin aspart, insulin lispro or insulin glulisine) for each patient for 26 weeks.

  Individualized basal insulin (insulin degludec, insulin glargine or insulin detemir) for each patient.

  Interventions:

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 3, 2024): 319
• Original Estimated Enrollment (submitted: July 13, 2021): 264
• Estimated Study Completion Date: April 2025
• Estimated Primary Completion Date: September 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Assent from the pediatric subject, as appropriate, and fully informed consent from the parent(s) or legal guardian, as required by both state and federal laws and the local Institutional Review Board (IRB)
• Subjects ≥4 and <18 years of age
• Clinical diagnosis of type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) per the Investigator and have been using insulin for at least 6 months for T1DM, or at least 3 months for T2DM
• Treatment with basal-bolus insulin therapy delivered by multiple daily injections for at least 2 weeks
• Bolus insulins are restricted to the RAAs insulin lispro, insulin aspart or insulin glulisine, including biosimilar products
• Basal insulins are restricted to insulin glargine, insulin degludec or insulin detemir, including biosimilar products
• Access to stable WiFi connection
• HbA1c ≥7.0% and ≤11%
• Average prandial dose of insulin ≥2 units per meal
• Utilized CGM for ≥70% of the time over a consecutive 14-day period preceding randomization

Exclusion Criteria:

• History of recent blood transfusions (within previous 3 months), hemoglobinopathies, or any other conditions that affect HbA1c measurements
• Recent history of asthma (defined as using any medications to treat within the last year), any other clinically important pulmonary disease (e.g., cystic fibrosis or bronchopulmonary dysplasia), or significant congenital or acquired cardiopulmonary disease
• History of serious complications of diabetes (e.g., active proliferative retinopathy or symptomatic autonomic neuropathy), or likely need for specific treatment for diabetic retinopathy (laser photocoagulation, vitrectomy, other) in the next year
• FEV1 and FEV1/forced vital capacity (FVC) ≤80% of predicted Global Lung Function Initiative (GLI) value
• Inability to achieve an acceptable FEV1 and FVC reading for subjects ≥8 years of age would make the subject ineligible
• For subjects <8 years of age who are unable to achieve an acceptable FVC reading, FEV1 only may be assessed; inability to achieve an acceptable FEV1 would make the subject ineligible
• Respiratory tract infection within 14 days before screening (subject may return 14 days after resolution of symptoms for rescreening)
• Inability or unwillingness to perform study procedures
• Exposure to any investigational product(s), including drugs or devices, in the past 30 days
• Any disease other than diabetes or exposure to any medication that, in the judgment of the Investigator, may impact glucose metabolism and current or anticipated acute uses of glucocorticoids or weight loss medications, with the exception of metformin and/or GLP-1 agonists (if GLP-1 agonists used for at least the 3 months prior to enrollment) in subjects with T2DM
• Use of antiadrenergic drugs (e.g., clonidine)
• Any concurrent illness (other than diabetes mellitus) not controlled by a stable therapeutic regimen
• Current uncontrolled eating disorder (e.g., anorexia or bulimia nervosa)
• Current drug or alcohol abuse or a history of drug or alcohol abuse that, in the opinion of the Investigator or the Sponsor, would make the subject an unsuitable candidate for participation in the study
• Smoking (includes cigarettes, cigars, pipes, marijuana, and vaping devices) for the preceding 6 months and/or positive urine cotinine test
• Female subject who is pregnant, breast-feeding, intends to become pregnant, or is of child-bearing potential, sexually active and not using adequate contraceptive methods as required by local regulation or practice
• An event of severe hypoglycemia, as judged by the Investigator, within the last 90 days prior to screening
• An episode of DKA requiring hospitalization within the last 90 days prior to screening

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years to 17 Years (Child)
• 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: NCT04974528
• Other Study ID Numbers: MKC-TI-155 Part 2
• 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; Mannkind Corporation

• PRS Account: Mannkind Corporation
• Verification Date: March 2024