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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Afrezza | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Afrezza Dose 1 | Combination Product | 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. |
| 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 |
| 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 |
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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:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kevin Kaiserman, MD | Mannkind Corporation | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| AMCR Institute | Escondido | California | 92025 | United States | ||
| Diablo Clinical Research |
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Between April 2021 and May 2021, a total of 20 subjects were enrolled at two investigational sites in the US.
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| ID | Title | Description |
|---|---|---|
| FG000 | Afrezza | The test product was defined as Afrezza [insulin human] inhalation powder administered using the Afrezza inhaler. In addition, subjects took their personal basal insulin while enrolled in the study. The first dose of Afrezza was 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. The second dose of Afrezza was 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Afrezza Dose 1 |
| |||||||||||||
| Afrezza Dose 2 |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Afrezza | The test product was defined as Afrezza [insulin human] inhalation powder administered using the Afrezza inhaler. In addition, subjects took their personal basal insulin while enrolled in the study. Afrezza Dose 1: The first dose of Afrezza was 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. Afrezza Dose 2: The second dose of Afrezza was 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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) | Intent to treat, including all subjects in the safety population, had a baseline value and at least one postbaseline value | Posted | Mean | Standard Error | mg/dL | 120 minutes post-dose |
|
Duration of the two treatment visits (~8 hours)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Afrezza Dose 1 | The test product was defined as Afrezza [insulin human] inhalation powder administered using the Afrezza inhaler. In addition, subjects took their personal basal insulin while enrolled in the study. The first dose of Afrezza was 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cough | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
DOS had no planned or conducted hypothesis testing, and no alpha adjustment was made to account for multiple testing of exploratory endpoints. Instead, DOS aimed to be a small-scale test of the higher dose suggested by previous studies and clinical experience. With no formal hypothesis testing, descriptive statistical comparisons are used to assess the efficacy and safety outcomes of the higher dose for purposes of generating hypothesis for a larger study.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Johanna Ulloa | MannKind Corporation | 818-661-5000 | contact@mannkindcorp.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 15, 2021 | Sep 1, 2022 | Prot_SAP_001.pdf |
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| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| D003924 | Diabetes Mellitus, Type 2 |
| D007333 | Insulin Resistance |
| D053120 | Respiratory Aspiration |
| D003920 | Diabetes Mellitus |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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|
| Afrezza Dose 2 | Combination Product | 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. |
|
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 |
| Walnut Creek |
| California |
| 94598 |
| United States |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| HbA1c | Hemoglobin A1C | Mean | Standard Deviation | percentage of Hemoglobin A1c |
|
| Diabetes type | Count of Participants | Participants |
|
| BMI | Body mass index | Mean | Standard Deviation | kg/m^2 |
|
| OG001 | Afrezza Dose 2 | The test product was defined as Afrezza [insulin human] inhalation powder administered using the Afrezza inhaler. In addition, subjects took their personal basal insulin while enrolled in the study. The second dose of Afrezza was 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. |
|
|
| Secondary | 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. | Intent to treat, including all subjects in the safety population, had a baseline value and at least one postbaseline value | Posted | Count of Participants | Participants | 120 minutes |
|
|
|
| Secondary | Percent of Level 1 Hypoglycemia | Percent of total SMBG measurements <70 mg/dL (Level 1 hypoglycemia) within the 120 minutes after Afrezza dosing. | Intent to treat, including all subjects in the safety population, had a baseline value and at least one postbaseline value | Posted | Number | SMBG Measurements | 120 minutes | SMBG Measurements | SMBG Measurements |
|
|
|
| Secondary | 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. | Intent to treat, including all subjects in the safety population, had a baseline value and at least one postbaseline value | Posted | Count of Participants | Participants | 120 minutes |
|
|
|
| Secondary | Percent of Level 2 Hypoglycemia | Percent of total SMBG measurements <54 mg/dL (Level 2 hypoglycemia) within the 120 minutes after Afrezza dosing | Intent to treat, including all subjects in the safety population, had a baseline value and at least one postbaseline value | Posted | Number | SMBG Measurements | 120 minutes | SMBG Measurements | SMBG Measurements |
|
|
|
| Secondary | 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. | Intent to treat, including all subjects in the safety population, had a baseline value and at least one postbaseline value | Posted | Count of Participants | Participants | 120 minutes |
|
|
|
| Secondary | 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. | Intent to treat, including all subjects in the safety population, had a baseline value and at least one postbaseline value | Posted | Mean | Standard Deviation | change in percent predicted FEV1 | 120 minutes post-dose |
|
|
|
| 0 |
| 20 |
| 0 |
| 20 |
| 1 |
| 20 |
| EG001 | Afrezza Dose 2 | The test product was defined as Afrezza [insulin human] inhalation powder administered using the Afrezza inhaler. In addition, subjects took their personal basal insulin while enrolled in the study. The second dose of Afrezza was 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. | 0 | 20 | 0 | 20 | 2 | 20 |
The PI cannot disclose any of the results arising out of or in connection with the clinical trial without the prior express written consent of the Sponsor.
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D006946 | Hyperinsulinism |
| D012120 | Respiration Disorders |
| D012140 | Respiratory Tract Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |