Afrezza® Dosing Optimization Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Combination Product: Afrezza Dose 1
* Combination Product: Afrezza Dose 2


Participation Criteria
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Eligibility Criteria
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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: Subjects ≥18 years of age at the time of signing the informed consent form Clinical diagnosis of T1DM or T2DM (per the Investigator) and on a stable basal-bolus insulin regimen Exclusion Criteria: 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 History of serious complications of diabetes (e.g., active proliferative retinopathy or symptomatic autonomic neuropathy) On dialysis Respiratory tract infection within 14 days before screening (subject may return 14 days after resolution of symptoms for rescreening) Treatment with any investigational drug in the past 30 days or an investigational device in the past 2 weeks 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 Use of antiadrenergic drugs (e.g., beta blockers and clonidine) Any concurrent illness (other than diabetes mellitus) not controlled by a stable therapeutic regimen History of a significant 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 History of smoking (includes cigarettes, cigars, pipes, vaping devices, and marijuana) in the 6 months before screening 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) An event of severe hypoglycemia, as judged by the Investigator, within the 90 days before screening An episode of diabetic ketoacidosis (DKA) requiring hospitalization within the 90 days before screening Exposure to Afrezza in the 30 days before screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Afrezza<br>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<br>* 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.<br>Combination Product: Afrezza Dose 2<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Insulin, Diabetes, Afrezza, Dosing, Technosphere, Inhaled