Afrezza® Dosing Optimization Study (DOS)

DOS [Dosing Optimization Study]: Open-label, Single-arm, Proof-of-Concept Dosing Study of Afrezza® in Adult Subjects 18 Years and Older With Type 1 or Type 2 Diabetes Mellitus

MKC-TI-191 is a Phase 4, single-arm, multicenter, proof-of-concept clinical trial evaluating the efficacy and safety of Afrezza, administered according to the current Afrezza prescribing information (PI) compared to a titrated dose, in combination with a basal insulin in adult subjects (≥18 years of age) with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Eligible subjects will be on a stable regimen consisting of a basal bolus insulin therapy prior to screening. The study is composed of up to 4 clinic visits (screening, 2 treatment visits, and a follow-up visit). Two individual doses of Afrezza will be administered during a meal challenge at Visits 2 and 3. The duration of each subject's participation in the trial is expected to be approximately 2 weeks.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1
• Intervention / Treatment: Combination product: Afrezza Dose 1; Combination product: Afrezza Dose 2

Detailed Description

Screening (Visit 1): Informed consent and California Experimental Subjects Bill of Rights will be signed and eligibility confirmed. Eligible subjects will be enrolled at Visit 1.

Subjects will come into the clinic in a fasting state for a meal challenge and individual dose of Afrezza during Visits 2 and 3. At the beginning of each visit, before their dose of Afrezza, subjects will have FEV1 measurements taken in the clinic. Each meal challenge will consist of 1 to 2 bottles of nutritional shake to be fully consumed within 15 minutes. The nutritional shake will contain approximately 240 calories, 41 g carbohydrate, 10 g protein, and 4 g fat per bottle. Each Afrezza dose will be administered at the start of the meal challenge.

Visit 2: The first dose of Afrezza will be based on the dose of subcutaneous (SC) rapid-acting analogue (RAA) insulin that the subject would normally take, converted according to the guidelines provided in the current Afrezza prescribing information. If subject's normal RAA dose is <4 units or 5 units, subject will be asked to consume enough nutritional shake, per their normal I:C ratio, to cover an RAA dose of 4 units or ≥6 units such that their Afrezza dose at Visit 3 is higher than the dose taken at Visit 2. After completing the standardized meal challenge, the Investigator will decide, based on the subject's glucose excursion at Visit 2, if the subject should proceed to Visit 3 where a second dose of Afrezza will be administered.

Visit 3: The second dose of Afrezza will be based on the dose of SC RAA that the subject would normally take, converted by multiplying their RAA dose by 2 and rounding down to the nearest Afrezza cartridge size.

Follow-up Visit (Visit 4): Subjects will return for safety assessments, including a final FEV1 measurement, 24 to 72 hours after their last dose of Afrezza.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Escondido, California, United States, 92025
      • AMCR Institute
    • Walnut Creek, California, United States, 94598
      • Diablo Clinical Research

Participation Criteria

Eligibility Criteria

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

Description

Subjects will be asked to provide a recent negative COVID-19 test (if available), confirm they have no symptoms of COVID-19, or provide evidence of COVID-19 vaccination.

Inclusion Criteria:

1. Subjects ≥18 years of age at the time of signing the informed consent form
2. Clinical diagnosis of T1DM or T2DM (per the Investigator) and on a stable basal-bolus insulin regimen

Exclusion Criteria:

1. History of asthma, chronic obstructive pulmonary disease, or any other clinically important pulmonary disease (e.g., cystic fibrosis, bronchopulmonary dysplasia), use of any medications to treat such conditions within the last year, or significant congenital or acquired cardiopulmonary disease
2. History of serious complications of diabetes (e.g., active proliferative retinopathy or symptomatic autonomic neuropathy)
3. On dialysis
4. Respiratory tract infection within 14 days before screening (subject may return 14 days after resolution of symptoms for rescreening)
5. Treatment with any investigational drug in the past 30 days or an investigational device in the past 2 weeks
6. Any disease other than diabetes or initiation of any new medication that, in the judgment of the Investigator, could have a direct impact on glycemic control during the study
7. Use of antiadrenergic drugs (e.g., beta blockers and clonidine)
8. Any concurrent illness (other than diabetes mellitus) not controlled by a stable therapeutic regimen
9. History of a significant eating disorder (e.g., anorexia or bulimia nervosa)
10. 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
11. History of smoking (includes cigarettes, cigars, pipes, vaping devices, and marijuana) in the 6 months before screening
12. Female subject who is pregnant, breastfeeding, intends to become pregnant, or is of child-bearing potential and not using adequate contraceptive methods as required by local regulation or practice (may include sexual abstinence)
13. An event of severe hypoglycemia, as judged by the Investigator, within the 90 days before screening
14. An episode of diabetic ketoacidosis (DKA) requiring hospitalization within the 90 days before screening
15. Exposure to Afrezza in the 30 days before screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Afrezza; The test product is defined as Afrezza [insulin human] inhalation powder administered using the Afrezza inhaler. In addition, subjects will take their personal basal insulin while enrolled in the study.

Combination product: Afrezza Dose 1; The first dose of Afrezza will be based on the dose of subcutaneous rapid-acting analogue (RAA) insulin that the subject would normally take for the standardized meal, converted according to the guidelines provided in the current Afrezza U.S. prescribing information.; Combination product: Afrezza Dose 2; The second dose of Afrezza will be based on the dose of subcutaneous rapid-acting analogue that the subject would normally take for the standardized meal, converted by multiplying their RAA dose by 2 and rounding down to the nearest Afrezza cartridge size.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-prandial Glucose Excursion	Mean glucose change from baseline (or postprandial glucose excursion [PPGE]) based on self-monitored blood glucose (SMBG) at 15, 30, 45, 60, 90 and 120 minutes after the dose of Afrezza with baseline defined as SMBG at the time of the dose of Afrezza (t=0)	120 minutes post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With at Least 1 Event of Level 1 Hypoglycemia	Number of subjects with at least 1 event (also referred to as incidence) of Level 1 hypoglycemia (<70mg/dL) within the 120 minutes after Afrezza dosing as confirmed by SMBG.	120 minutes
Percent of Level 1 Hypoglycemia	Percent of total SMBG measurements <70 mg/dL (Level 1 hypoglycemia) within the 120 minutes after Afrezza dosing.	120 minutes
Number of Subjects With at Least 1 Event of Level 2 Hypoglycemia	Number of subjects with at least 1 event (also referred to as incidence) of Level 2 hypoglycemia (<54mg/dL) within the 120 minutes after Afrezza dosing as confirmed by SMBG.	120 minutes
Percent of Level 2 Hypoglycemia	Percent of total SMBG measurements <54 mg/dL (Level 2 hypoglycemia) within the 120 minutes after Afrezza dosing	120 minutes
Number of Subjects With At Least 1 Event of Severe Hypoglycemia	Number of subjects with at least 1 event (also referred to as incidence) of severe hypoglycemia, defined as events requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions within the 120 minutes after Afrezza dosing.	120 minutes
Change in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Between Two Points, Baseline and 120 Minutes Post-Afrezza Dose	Change in percent predicted forced expiratory volume in 1 second (FEV1) between two points (value at 120 minutes post-Afrezza dose minus value at baseline). Standard deviation was not reported.	120 minutes post-dose

Collaborators and Investigators

• Sponsor: Mannkind Corporation
• Investigators: Study Director: Kevin Kaiserman, MD, Mannkind Corporation

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2021
• Primary Completion (Actual): May 28, 2021
• Study Completion (Actual): May 28, 2021

Study Registration Dates

• First Submitted: April 16, 2021
• First Submitted That Met QC Criteria: April 16, 2021
• First Posted (Actual): April 19, 2021

Study Record Updates

• Last Update Posted (Actual): September 18, 2023
• Last Update Submitted That Met QC Criteria: September 14, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Diabetes; Insulin; Dosing; 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
• Other Study ID Numbers: MKC-TI-191

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No