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

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1
• Intervention / Treatment: Biological: Afrezza; Biological: Basal Insulin; Biological: Rapid-acting Insulin Analog

• Study Type: Interventional
• Enrollment (Actual): 319
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Johanna Ulloa; Phone Number: 818-661-5000; Email: inhale1@mannkindcorp.com

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Stanford University
    • Sacramento, California, United States, 95821
      • Sutter Institute for Medical Research (formerly Center of Excellence in Diabetes and Endocrinology)
    • San Diego, California, United States, 92123
      • University of California San Diego, Rady Children's Hospital
    • San Francisco, California, United States, 94158
      • University of California San Francisco
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale New Haven Hospital
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Nemours Children's Hospital, Delaware
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Hollywood, Florida, United States, 33021
      • Joe DiMaggio Children's Hospital
    • Orlando, Florida, United States, 32803
      • Advent Health Orlando
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Emory University, Children's Healthcare of Atlanta
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Rocky Mountain Clinical Research
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
    • West Des Moines, Iowa, United States, 50265
      • Iowa Diabetes Research, IDR
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville, Norton Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
    • Baltimore, Maryland, United States, 21229
      • Dr. Barry J. Reiner
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
  • Michigan
    • Livonia, Michigan, United States, 48152
      • Michigan Pediatric Endocrine and Diabetes Services
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University Of Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • Children's Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Children's Mercy Hospital
  • Nevada
    • Las Vegas, Nevada, United States, 89113
      • The Docs
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Atlantic Health
  • New York
    • Buffalo, New York, United States, 14203
      • UBMD Pediatrics Buffalo
    • New York, New York, United States, 10016
      • NYU Langone, Hassenfeld Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Bartlett, Tennessee, United States, 38133
      • AM Diabetes And Endocrinology Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern
    • Edinburg, Texas, United States, 78539
      • DHR Health
    • San Antonio, Texas, United States, 78229
      • Diabetes & Glandular Disease Clinic, DGD
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53201
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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

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) + 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.	Biological: Afrezza; Pharmaceutical form: powder Route of administration: inhalation; Other Names: Technosphere Insulin; Biological: Basal Insulin; Pharmaceutical form: solution for injection Route of administration: subcutaneous; Other Names: Levemir®; Tresiba®; Lantus®; insulin glargine; insulin degludec; insulin detemir; Abasaglar®; Basaglar®; Semglee®; Toujeo®
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.	Biological: Basal Insulin; Pharmaceutical form: solution for injection Route of administration: subcutaneous; Other Names: Levemir®; Tresiba®; Lantus®; insulin glargine; insulin degludec; insulin detemir; Abasaglar®; Basaglar®; Semglee®; Toujeo®; Biological: Rapid-acting Insulin Analog; Pharmaceutical form: clear and colorless solution for injection Route of administration: subcutaneous; Other Names: Fiasp®; Apidra®; Humalog®; insulin aspart; insulin lispro; insulin glulisine; Novolog®; Admelog®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c	Change in HbA1c from baseline to Week 26, for noninferiority assessment	26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c	Change in HbA1c from baseline to Week 26, for superiority assessment	26 weeks
Change in Fasting Plasma Glucose (FPG)	Change in FPG from baseline to Week 26, for superiority assessment	26 weeks
Event rate of pooled level 2 and level 3 hypoglycemia	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.	26 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event rate of level 1 hypoglycemia (SMBG <70 mg/dL)	Event rate of level 1 hypoglycemia during the 26-week randomized treatment period	26 weeks
Change in percent Time In Range (glucose 70 - 180 mg/dL)	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	26 weeks
Change in percent time with glucose <54 mg/dL	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	26 weeks
Change in percent Time Below Range (glucose <70 mg/dL)	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	26 weeks
Change in percent Time Above Range (glucose >180 mg/dL)	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	26 weeks
Percentage of subjects with HbA1c <7.0%	Percentage of subjects with HbA1c <7.0% at Week 26	At Week 26
Score of Diabetes Treatment Satisfaction Questionnaire (DTSQ) Change (c)-Teen	Score of DTSQ(c)-Teen at Week 26 in the Afrezza group (score ranges from -24 to 24, with higher score means greater satisfaction)	At Week 26
Score of Diabetes Treatment Satisfaction Questionnaire (DTSQ) Change (c)-Parent	Score of DTSQ(c)-Parent at Week 26 in the Afrezza group (score ranges from -30 to 30, with higher score means greater satisfaction)	At Week 26
Change in scores of DTSQ Status (s)-Teen	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)	26 weeks
Change in scores of DTSQ Status (s)-Parent	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)	26 weeks
Change in HbA1c	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	52 weeks (and 26 weeks if required)
Change in FPG	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	52 weeks (and 26 weeks if required)
Change in percent Time In Range, Time Below Range and Time Above Range	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	52 weeks (and 26 weeks if required)
Change in HbA1c	Change in HbA1c from baseline to Week 52 in subjects who receive Afrezza in both the randomized treatment period and the treatment extension	52 weeks
Change in FPG	Change in FPG from baseline to Week 52 in subjects who receive Afrezza in both the randomized treatment period and the treatment extension	52 weeks
Change in percent Time In Range, Time Below Range and Time Above Range	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	52 weeks
Score of DTSQ(c)-Teen 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)	At Week 52
Score of DTSQ(c)-Parent 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)	At Week 52
Change in scores of DTSQ(s)-Teen	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)	52 weeks
Change in scores of DTSQ(s)-Parent	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)	52 weeks
Event rates of hypoglycemic events	Event rates and incidence of total, nocturnal, and severe hypoglycemic events from baseline to Week 52	52 weeks
Incidence of hypoglycemic events	Incidence of total, nocturnal, and severe hypoglycemic events from baseline to Week 52	52 weeks
Incidence and severity of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Incidence and severity of TEAEs and SAEs from baseline to Week 52	52 weeks
Change in percent predicted Forced Expiratory Volume in 1 Second (FEV1)	Change from baseline to Weeks 13, 26, 39, 52, and 56 in percent predicted FEV1	56 weeks
Incidence and severity of Adverse Events of Special Interest (AESIs)	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	52 weeks

Collaborators and Investigators

• Sponsor: Mannkind Corporation
• Collaborators: Jaeb Center for Health Research
• Investigators: Study Director: Kevin Kaiserman, Mannkind Corporation

Study record dates

Study Major Dates

• Study Start (Actual): September 29, 2021
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: June 22, 2021
• First Submitted That Met QC Criteria: July 13, 2021
• First Posted (Actual): July 23, 2021

Study Record Updates

• Last Update Posted (Actual): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 3, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Insulin; Diabetes Mellitus; Pediatric; Inhaled; Afrezza; Technosphere
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc; Insulin Aspart; Insulin Glargine; Insulin Lispro; Insulin glulisine; Insulin Detemir; Insulin, Short-Acting
• Other Study ID Numbers: MKC-TI-155 Part 2

Drug and device information, study documents

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