Type 1 Diabetes
Conditions
Keywords
Diabetes Mellitus, Insulin, Inhaled Insulin, Afrezza, Technosphere Insulin
Brief summary
A phase 4 study evaluating the efficacy of mealtime control with Afrezza in combination with an automated insulin pump or insulin degludec in adult subjects with type 1 diabetes
Detailed description
MKC-TI-192 is a Phase 4, 90-day, randomized, three-arm, multicenter clinical trial evaluating the treatment paradigm and efficacy of Afrezza in controlling postprandial glucose in adult subjects (≥18 years of age) with Type 1 Diabetes Mellitus (T1DM). Subjects will be randomized to one of three treatment groups (two Afrezza groups and one control group): * Afrezza + AID: Subjects in this group will use Afrezza for their bolus (mealtime) insulin and a continuous subcutaneous insulin infusion (CSII) pump with an automatic insulin delivery (AID) algorithm using rapid acting analogs (RAA) for their basal and correction insulin coverage. * Afrezza + Insulin Degludec: Subjects in this group will use Afrezza for their bolus (mealtime and correction) insulin and insulin degludec for basal insulin coverage. * AID Control: Subjects in this group will use a CSII pump with an AID algorithm using RAA for all bolus (mealtime and correction) and basal insulin coverage (control group). The study is composed of up to 5 clinic visits (screening, 3 treatment visits, and an end-of-treatment visit) and 9 telephone visits.
Interventions
BIOLOGICALAfrezza (insulin human) Inhalation Powder
Pharmaceutical form: powder Route of administration: inhalation
BIOLOGICALinsulin degludec
Pharmaceutical form: solution for injection Route of administration: subcutaneous
DEVICEContinuous Subcutaneous Insulin Infusion (CSII) pump with Automatic Insulin Delivery (AID)
Acceptable AID systems in this study are Medtronic 670G/770G and Tandem Control IQ
Sponsors
Mannkind Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects ≥18 years of age at the time of signing the informed consent form * Clinical diagnosis of Type 1 Diabetes * HbA1c ≥7.0% and \<11.0% * Treatment with a CSII pump with an AID algorithm (Medtronic 670G/770G or Tandem Control IQ) for at least 3 months * Ability to pay for their own RAA used in the insulin pump or injections, either through co-pay or self-pay, for the duration of the study * Willingness to follow study procedures including discontinuing their insulin pump and transitioning to insulin degludec injections plus Afrezza
Exclusion criteria
* A recent history of asthma (defined as using any medications to treat within the last year), chronic obstructive pulmonary disease (COPD), or any other clinically important pulmonary disease (e.g., cystic fibrosis, bronchopulmonary dysplasia), or significant congenital or acquired cardiopulmonary disease * History of serious complications of diabetes (e.g., active proliferative retinopathy or symptomatic autonomic neuropathy) * History of hypersensitivity to insulin or any of the Afrezza excipients * On dialysis * Respiratory tract infection within 14 days before screening (subject may return 14 days after resolution of symptoms for rescreening) * Exposure to any investigational drug in the past 30 days or an investigational device in the past 2 weeks * Adrenal insufficiency, active use of steroids or planned steroid use * Hypothyroidism not controlled, as defined by thyroid stimulating hormone (TSH) outside the upper limit of the reference range by \>1.5 × in the last 6 months, according to the local laboratory reference range * Hyperthyroidism not controlled, as defined by TSH below the normal reference range, according to the local laboratory * 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, breast-feeding, 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 reported by the patient, within the last 180 days before screening * An episode of diabetic ketoacidosis (DKA), as determined by the Investigator, requiring hospitalization within the last 180 days before screening * Exposure to Afrezza in the 30 days before screening * Abnormal TSH or creatinine levels above 2.0 mg/dL
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c | 90 days | Change in glycated hemoglobin (HbA1c) from baseline to end of study |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Events of Severe Hypoglycemia | 90 days | Events of severe hypoglycemia requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions |
| Change in Time Below Range (Glucose <70 mg/dL) | baseline and 90 days | Change from baseline to end of study in Time Below Range (TBR), defined as the percentage of time spent with glucose \<70 mg/dL, based on continuous glucose monitoring derived glucose values |
| Change in Percentage of Time With Glucose <54 mg/dL | baseline and 90 days | Change from baseline to end of study in percentage of time spent with glucose \<54 mg/dL, based on continuous glucose monitoring derived glucose values |
| Change in Time Above Range (Glucose >180 mg/dL) | baseline and 90 days | Change from baseline to end of study in Time Above Range (TAR), defined as the percentage of time spent with glucose \>180 mg/dL, based on continuous glucose monitoring derived glucose values |
| Change in Percentage of Time With Glucose >250 mg/dL | baseline and 90 days | Change from baseline to end of study in percentage of time spent with glucose \>250 mg/dL, based on continuous glucose monitoring derived glucose values |
| Change in Coefficient of Variation (CV) | baseline and 90 days | Change from baseline to end of study in glycemic variability as measured by coefficient of variation (CV), based on continuous glucose monitoring derived glucose values |
| Events of Level 1 Hypoglycemia (SMBG < 70mg/dL) | 90 days | Events of hypoglycemia (SMBG \<70 mg/dL for SMBG values more than 30 minutes apart) |
| Events of Level 2 Hypoglycemia (SMBG < 54 mg/dL) | 90 days | Events of hypoglycemia (SMBG \<54 mg/dL for SMBG values more than 30 minutes apart) |
| Change in Time in Range (Glucose of 70 - 180 mg/dL) | baseline and 90 days | Change from baseline to end of study in Time in Range (TIR), defined as the percentage of time spent with glucose in the range of 70 to 180 mg/dL, based on continuous glucose monitoring derived glucose values |
Other
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Serious Adverse Events | 90 days | Total Number of Serious Adverse Events (SAEs) |
| Total Number of Adverse Events of Special Interest | 90 days | Total Number of Adverse Events of Special Interest (AESIs) |
| Total Number of Device Complaints | 90 days | Total Number of Device Complaints |
| Change in Percent Predicted Forced Expiratory Volume in 1 Second | baseline and 90 days | Change in percent predicted forced expiratory volume in 1 second (FEV1) from baseline to end of study |
| Total Number of Treatment-Emergent Adverse Events | 90 days | Total Number of Treatment-Emergent Adverse Events (TEAEs) |
Countries
United States
Participant flow
Pre-assignment details
Per protocol, participants who complete the informed consent process are enrolled in the study. In this study, 33 participants were enrolled in the study. The study has a run-in period of up to 28 days. After completion of the run-in period, and confirmation of all eligibility requirements, the participant may be assigned to a study arm/group. In this study, only 28 participants started the treatment phase and were assigned to a study arm/group (5 participants are considered PreRand drops).
Participants by arm
| Arm | Count |
|---|---|
| Afrezza + Automatic Insulin Delivery (AID) Subjects in this group will use Afrezza for their bolus (mealtime) insulin and a Continuous Subcutaneous Insulin Infusion (CSII) pump with an AID algorithm using Rapid Acting Insulin Analogs (RAA) for their basal and correction insulin coverage.
Afrezza (insulin human) Inhalation Powder: Pharmaceutical form: powder
Route of administration: inhalation
CSII pump with AID: Acceptable AID systems in this study are Medtronic 670G/770G and Tandem Control IQ | 13 |
| Afrezza + Insulin Degludec Subjects in this group will use Afrezza for their bolus (mealtime and correction) insulin and insulin degludec for basal insulin coverage.
Afrezza (insulin human) Inhalation Powder: Pharmaceutical form: powder
Route of administration: inhalation
insulin degludec: Pharmaceutical form: solution for injection
Route of administration: subcutaneous | 10 |
| AID Control Subjects in this group will use a CSII pump with an AID algorithm using RAA for all bolus (mealtime and correction) and basal insulin coverage (control group).
CSII pump with AID: Acceptable AID systems in this study are Medtronic 670G/770G and Tandem Control IQ | 5 |
| Total | 28 |
Baseline characteristics
| Characteristic | Afrezza + Automatic Insulin Delivery (AID) | Afrezza + Insulin Degludec | AID Control | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 10 Participants | 5 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 10 Participants | 5 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 10 Participants | 5 Participants | 28 Participants |
| Region of Enrollment United States | 13 participants | 10 participants | 5 participants | 28 participants |
| Sex: Female, Male Female | 7 Participants | 9 Participants | 3 Participants | 19 Participants |
| Sex: Female, Male Male | 6 Participants | 1 Participants | 2 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 10 | 0 / 5 |
| other Total, other adverse events | 7 / 13 | 8 / 10 | 1 / 5 |
| serious Total, serious adverse events | 2 / 13 | 1 / 10 | 0 / 5 |
Outcome results
Primary
Change in HbA1c
Change in glycated hemoglobin (HbA1c) from baseline to end of study
Time frame: 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Change in HbA1c | 0.32 percent of glycated hemoglobin | Standard Deviation 0.55 |
| Afrezza + Insulin Degludec | Change in HbA1c | 0.35 percent of glycated hemoglobin | Standard Deviation 0.58 |
| AID Control | Change in HbA1c | 0.52 percent of glycated hemoglobin | Standard Deviation 0.29 |
Secondary
Change in Coefficient of Variation (CV)
Change from baseline to end of study in glycemic variability as measured by coefficient of variation (CV), based on continuous glucose monitoring derived glucose values
Time frame: baseline and 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Change in Coefficient of Variation (CV) | 1 percent of coefficient of variation | Standard Deviation 5 |
| Afrezza + Insulin Degludec | Change in Coefficient of Variation (CV) | 4 percent of coefficient of variation | Standard Deviation 9 |
| AID Control | Change in Coefficient of Variation (CV) | -5 percent of coefficient of variation | Standard Deviation 3 |
Secondary
Change in Percentage of Time With Glucose >250 mg/dL
Change from baseline to end of study in percentage of time spent with glucose \>250 mg/dL, based on continuous glucose monitoring derived glucose values
Time frame: baseline and 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Change in Percentage of Time With Glucose >250 mg/dL | -1.04 percent of time with glucose >250mg/dL | Standard Deviation 23.57 |
| Afrezza + Insulin Degludec | Change in Percentage of Time With Glucose >250 mg/dL | 0.84 percent of time with glucose >250mg/dL | Standard Deviation 9.86 |
| AID Control | Change in Percentage of Time With Glucose >250 mg/dL | -4.47 percent of time with glucose >250mg/dL | Standard Deviation 3.03 |
Secondary
Change in Percentage of Time With Glucose <54 mg/dL
Change from baseline to end of study in percentage of time spent with glucose \<54 mg/dL, based on continuous glucose monitoring derived glucose values
Time frame: baseline and 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Change in Percentage of Time With Glucose <54 mg/dL | 0.03 percent of time with glucose <54mg/dL | Standard Deviation 0.43 |
| Afrezza + Insulin Degludec | Change in Percentage of Time With Glucose <54 mg/dL | 0.88 percent of time with glucose <54mg/dL | Standard Deviation 2.04 |
| AID Control | Change in Percentage of Time With Glucose <54 mg/dL | -0.1 percent of time with glucose <54mg/dL | Standard Deviation 0.12 |
Secondary
Change in Time Above Range (Glucose >180 mg/dL)
Change from baseline to end of study in Time Above Range (TAR), defined as the percentage of time spent with glucose \>180 mg/dL, based on continuous glucose monitoring derived glucose values
Time frame: baseline and 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Change in Time Above Range (Glucose >180 mg/dL) | -4.63 percent of TAR | Standard Deviation 28.69 |
| Afrezza + Insulin Degludec | Change in Time Above Range (Glucose >180 mg/dL) | 1.97 percent of TAR | Standard Deviation 17.89 |
| AID Control | Change in Time Above Range (Glucose >180 mg/dL) | -1.81 percent of TAR | Standard Deviation 10.17 |
Secondary
Change in Time Below Range (Glucose <70 mg/dL)
Change from baseline to end of study in Time Below Range (TBR), defined as the percentage of time spent with glucose \<70 mg/dL, based on continuous glucose monitoring derived glucose values
Time frame: baseline and 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Change in Time Below Range (Glucose <70 mg/dL) | -0.06 percent of TBR | Standard Deviation 1.72 |
| Afrezza + Insulin Degludec | Change in Time Below Range (Glucose <70 mg/dL) | 1.92 percent of TBR | Standard Deviation 4.23 |
| AID Control | Change in Time Below Range (Glucose <70 mg/dL) | -0.18 percent of TBR | Standard Deviation 0.44 |
Secondary
Change in Time in Range (Glucose of 70 - 180 mg/dL)
Change from baseline to end of study in Time in Range (TIR), defined as the percentage of time spent with glucose in the range of 70 to 180 mg/dL, based on continuous glucose monitoring derived glucose values
Time frame: baseline and 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Change in Time in Range (Glucose of 70 - 180 mg/dL) | 4.69 percent of TIR | Standard Deviation 27.61 |
| Afrezza + Insulin Degludec | Change in Time in Range (Glucose of 70 - 180 mg/dL) | -3.89 percent of TIR | Standard Deviation 16 |
| AID Control | Change in Time in Range (Glucose of 70 - 180 mg/dL) | 1.99 percent of TIR | Standard Deviation 10.12 |
Secondary
Events of Level 1 Hypoglycemia (SMBG < 70mg/dL)
Events of hypoglycemia (SMBG \<70 mg/dL for SMBG values more than 30 minutes apart)
Time frame: 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Events of Level 1 Hypoglycemia (SMBG < 70mg/dL) | 12 Count of events | Standard Deviation 12 |
| Afrezza + Insulin Degludec | Events of Level 1 Hypoglycemia (SMBG < 70mg/dL) | 20 Count of events | Standard Deviation 12 |
| AID Control | Events of Level 1 Hypoglycemia (SMBG < 70mg/dL) | 14 Count of events | Standard Deviation 7 |
Secondary
Events of Level 2 Hypoglycemia (SMBG < 54 mg/dL)
Events of hypoglycemia (SMBG \<54 mg/dL for SMBG values more than 30 minutes apart)
Time frame: 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Events of Level 2 Hypoglycemia (SMBG < 54 mg/dL) | 3 Count of events | Standard Deviation 3 |
| Afrezza + Insulin Degludec | Events of Level 2 Hypoglycemia (SMBG < 54 mg/dL) | 5 Count of events | Standard Deviation 4 |
| AID Control | Events of Level 2 Hypoglycemia (SMBG < 54 mg/dL) | 4 Count of events | Standard Deviation 5 |
Secondary
Events of Severe Hypoglycemia
Events of severe hypoglycemia requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Events of Severe Hypoglycemia | 0 Count of events |
| Afrezza + Insulin Degludec | Events of Severe Hypoglycemia | 0 Count of events |
| AID Control | Events of Severe Hypoglycemia | 0 Count of events |
Other Pre-specified
Change in Percent Predicted Forced Expiratory Volume in 1 Second
Change in percent predicted forced expiratory volume in 1 second (FEV1) from baseline to end of study
Time frame: baseline and 90 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Change in Percent Predicted Forced Expiratory Volume in 1 Second | -2 percent predicted FEV1 | Standard Deviation 5 |
| Afrezza + Insulin Degludec | Change in Percent Predicted Forced Expiratory Volume in 1 Second | 2 percent predicted FEV1 | Standard Deviation 6 |
| AID Control | Change in Percent Predicted Forced Expiratory Volume in 1 Second | -2 percent predicted FEV1 | Standard Deviation 6 |
Other Pre-specified
Total Number of Adverse Events of Special Interest
Total Number of Adverse Events of Special Interest (AESIs)
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Total Number of Adverse Events of Special Interest | 3 count of AESIs |
| Afrezza + Insulin Degludec | Total Number of Adverse Events of Special Interest | 0 count of AESIs |
| AID Control | Total Number of Adverse Events of Special Interest | 0 count of AESIs |
Other Pre-specified
Total Number of Device Complaints
Total Number of Device Complaints
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Total Number of Device Complaints | 0 Count of Device Complaints |
| Afrezza + Insulin Degludec | Total Number of Device Complaints | 0 Count of Device Complaints |
| AID Control | Total Number of Device Complaints | 0 Count of Device Complaints |
Other Pre-specified
Total Number of Serious Adverse Events
Total Number of Serious Adverse Events (SAEs)
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Total Number of Serious Adverse Events | 2 count of SAEs |
| Afrezza + Insulin Degludec | Total Number of Serious Adverse Events | 1 count of SAEs |
| AID Control | Total Number of Serious Adverse Events | 0 count of SAEs |
Other Pre-specified
Total Number of Treatment-Emergent Adverse Events
Total Number of Treatment-Emergent Adverse Events (TEAEs)
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afrezza + Automatic Insulin Delivery (AID) | Total Number of Treatment-Emergent Adverse Events | 26 count of TEAEs |
| Afrezza + Insulin Degludec | Total Number of Treatment-Emergent Adverse Events | 12 count of TEAEs |
| AID Control | Total Number of Treatment-Emergent Adverse Events | 1 count of TEAEs |