Diabetes Mellitus, Type 1
Conditions
Keywords
diabetes, time in range, inhaled insulin, continuous glucose monitoring, type 1 diabetes, hypoglycemia, post prandial hypergylcemia
Brief summary
This is an investigator-initiated, prospective, randomized, multicenter, parallel, open-label, pilot clinical trial evaluating the efficacy of TI for PPBG, PPGE, and time-in-range on CGM download in patients with T1D. TI is an inhaled ultra-rapid-acting insulin, approved by the FDA for use in patients with diabetes. This is a pilot, real-life study where patients will continue their routine diabetes care and use post-meal correction dosages as deemed necessary for normalizing PPBG as per the protocol. This multi-center study will enroll 60 patients with T1D, A1c values between 6.5 to 10%. The patients will be randomized in 1:1 fashion to either TI or NL. Patients who are randomized into the NL arm will continue using their usual prandial insulin dose before meals. Patients who are randomized into the TI arm will be instructed to dose before the meals and take necessary corrections at 1- and 2-hours after meals to optimize PPBG (Table 1B). There will be a total of 7 study visits (screening visit, randomization visit, 2 clinic, and 3 phone visits). There will be a 4-week treatment comparison between TI and NL and 1-week of post-study follow up. (Phone visit; Figure-1). Standard lab tests (A1c, complete metabolic panel {CMP}, complete blood count {CBC}) will be performed at the screening visit. All patients will use real-time CGM (Dexcom G5®, San Diego, CA), which will be provided at the randomization visit for their day-to-day diabetes care. CGM data will be downloaded at every clinic visit on a secured computer. The data will be analyzed after the study for different primary and secondary end points. All patients will be allowed to keep the CGM after the study is over for their day-to-day diabetes care.
Interventions
This multi-center study will enroll 60 patients with T1D, A1c values between 6.5 to 10%. The patients will be randomized in 1:1 fashion to either TI or NL. Patients who are randomized into the NL arm will continue using their usual prandial insulin dose before meals. Patients who are randomized into the TI arm will be instructed to dose before the meals and take necessary corrections at 1- and 2-hours after meals to optimize PPBG (Table 1B). There will be a total of 7 study visits (screening visit, randomization visit, 2 clinic, and 3 phone visits). There will be a 4-week treatment comparison between TI and NL and 1-week of post-study follow up. (Phone visit; Figure-1). Standard lab tests (A1c, complete metabolic panel {CMP}, complete blood count {CBC}) will be performed at the screening visit.
Sponsors
Atlanta Diabetes Associates
University of Southern California
Rainier Clinical Research Center
Mannkind Corporation
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
1. Signed informed consent before any study-related activities, 2. Male or female aged 18-70 years, 3. Type 1 diabetes mellitus (T1D) duration more than six months 4. Treatment with multiple daily injections (MDI) for at least three months before screening visit; stable insulin dose for the last one month, 5. No use of any oral anti-diabetics, any other form of insulin other than mentioned in the protocol, or any other type of injections such as glucagon-like-peptide-1 (GLP-1) analogs, pramlintide or insulin/GLP-1 analog combinations, 6. A1c between 6.5 to 10%, 7. Willingness to routinely collect at least two blood glucose measurements per day needed to calibrate the CGM. Beyond the calibrations, patients may use CGM for necessary action without having to confirm with fingersticks self-monitoring blood glucose (SMBG), as approved by the Food and Drug Administration (FDA), 8. BMI ≤35 kg/m2, 9. Ability and willingness to adhere to the protocol including clinical and phone visits and 4-week-long CGM wear, 10. Using insulin glargine or insulin degludec as basal insulin, 11. Able to use and understand CGM data, 12. Willing to complete phone and clinic visits, 13. Patients who eat three main meals in a day (breakfast, lunch, and dinner), 14. Patients who use insulin-carb ratio for bolus, 15. Ability to speak, read, and write English, and 16. Patients prandial insulin need must be \<18 units per meal
Exclusion criteria
1. Use of any other diabetic medication other than allowed in the protocol, 2. Pregnant or intention to become pregnant during the study, or not using adequate birth control methods, 3. Severe unexplained hypoglycemia requiring emergency treatment in the previous three months, 4. Use of systemic or inhaled corticosteroids, 5. History of hemoglobinopathies, 6. Diagnosis of anemia, 7. Post-renal transplantation, currently undergoing dialysis, creatinine \>2.0 mg/dl or a calculated creatinine clearance of \<50 mL/min, 8. Advanced or unstable retinopathy needing laser procedure or vitrectomy, 9. History of pancreatitis, 10. Extensive skin changes/diseases that inhibit wearing a sensor on normal skin, 11. Known allergy to adhesives, 12. Known allergy to study medication, 13. Participation in another investigational study protocol within 30 days before enrollment, 14. Known chronic obstructive pulmonary disease, pulmonary hypertension, asthma, pulmonary fibrosis, or any chronic pulmonary infection, or any systemic disease that primarily affects the lungs. History of any pulmonary nodule will be excluded to participate in the study, 15. Active smokers, 16. Marijuana users, 17. Insulin pump users, 18. Using insulin detemir or NPH as basal insulin, and 19. Any other condition, as determined by the investigator, which could make the subject unsuitable for the trial, impairs the subject's suitability for the trial, or impairs the validity of the informed consent -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Time in Range (%) (70-180 mg/dl) With TI on CGM | 4 weeks | Difference between Time in range for TI group (treatment) and for Aspart group (control) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glucose Variability (GV) (mg/dl) (Standard Deviation and/or Coefficient Variation) | 4 weeks | Difference of glucose variability metrics between treatment and control groups |
| The Area Under the Curve Calculation (AUC) (Min*mg/dl) in the PPBG and PPGE, | 0, 1, 2, 3, 4 hours post-dose at 4 weeks | Difference of area under curve between treatment and control groups. ( 0 to 4 hours duration) |
| Change in Post-prandial Glucose Excursion (mg/dl) (1-4 Hours After Meals) With TI | 4 weeks | Difference in postprandial blood glucose between treatment and control group |
| Change in Above the Target Time (%) (>180 mg/dl) on CGM | 4 weeks | Difference of time above range between treatment and control group |
| Hypoglycemia Frequency (%) (Below the Target <70mg/dl) on CGM | 4 weeks | Difference of hypoglycemia frequency between treatment and control groups. |
| Change in HbA1c (%) in One-month Treatment | 4 weeks | Difference in HbA1c between treatment and control group |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Technosphere Insulin (TI, Afrezza) -Treatment Arm This group received Technosphere insulin for bolus insulin with meals and corrections | 26 |
| Insulin Aspart ( Novolog) -Control Arm This group received insulin aspart for bolus insulin with meals and corrections | 34 |
| Total | 60 |
Baseline characteristics
| Characteristic | Insulin Aspart ( Novolog) -Control Arm | Total | Technosphere Insulin (TI, Afrezza) -Treatment Arm |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants | 60 Participants | 26 Participants |
| Age, Continuous | 42 years STANDARD_DEVIATION 14 | 41 years STANDARD_DEVIATION 15 | 41 years STANDARD_DEVIATION 16 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 60 Participants | 26 Participants |
| Region of Enrollment United States | 34 participants | 60 participants | 26 participants |
| Sex: Female, Male Female | 12 Participants | 22 Participants | 10 Participants |
| Sex: Female, Male Male | 22 Participants | 38 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 34 |
| other Total, other adverse events | 3 / 26 | 0 / 34 |
| serious Total, serious adverse events | 0 / 26 | 0 / 34 |
Outcome results
Primary
Change in Time in Range (%) (70-180 mg/dl) With TI on CGM
Difference between Time in range for TI group (treatment) and for Aspart group (control)
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Aspart ( Novolog) -Control Arm | Change in Time in Range (%) (70-180 mg/dl) With TI on CGM | 53.5 percent time in range | Standard Deviation 1.8 |
| Technosphere Insulin (TI, Afrezza) -Treatment Arm | Change in Time in Range (%) (70-180 mg/dl) With TI on CGM | 58.4 percent time in range | Standard Deviation 2.2 |
Secondary
Change in Above the Target Time (%) (>180 mg/dl) on CGM
Difference of time above range between treatment and control group
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Aspart ( Novolog) -Control Arm | Change in Above the Target Time (%) (>180 mg/dl) on CGM | 38.1 percent time above target | Standard Deviation 0.3 |
| Technosphere Insulin (TI, Afrezza) -Treatment Arm | Change in Above the Target Time (%) (>180 mg/dl) on CGM | 41.2 percent time above target | Standard Deviation 1.8 |
Secondary
Change in Glucose Variability (GV) (mg/dl) (Standard Deviation and/or Coefficient Variation)
Difference of glucose variability metrics between treatment and control groups
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Aspart ( Novolog) -Control Arm | Change in Glucose Variability (GV) (mg/dl) (Standard Deviation and/or Coefficient Variation) | 57.8 mg/dl | Standard Deviation 2.4 |
| Technosphere Insulin (TI, Afrezza) -Treatment Arm | Change in Glucose Variability (GV) (mg/dl) (Standard Deviation and/or Coefficient Variation) | 66.3 mg/dl | Standard Deviation 1.9 |
Secondary
Change in HbA1c (%) in One-month Treatment
Difference in HbA1c between treatment and control group
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Aspart ( Novolog) -Control Arm | Change in HbA1c (%) in One-month Treatment | 0.25 percentage (%) | Standard Deviation 0.31 |
| Technosphere Insulin (TI, Afrezza) -Treatment Arm | Change in HbA1c (%) in One-month Treatment | 0.02 percentage (%) | Standard Deviation 0.36 |
Secondary
Change in Post-prandial Glucose Excursion (mg/dl) (1-4 Hours After Meals) With TI
Difference in postprandial blood glucose between treatment and control group
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Aspart ( Novolog) -Control Arm | Change in Post-prandial Glucose Excursion (mg/dl) (1-4 Hours After Meals) With TI | 45 mg/dl | Standard Deviation 6 |
| Technosphere Insulin (TI, Afrezza) -Treatment Arm | Change in Post-prandial Glucose Excursion (mg/dl) (1-4 Hours After Meals) With TI | 60 mg/dl | Standard Deviation 8 |
Secondary
Hypoglycemia Frequency (%) (Below the Target <70mg/dl) on CGM
Difference of hypoglycemia frequency between treatment and control groups.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Aspart ( Novolog) -Control Arm | Hypoglycemia Frequency (%) (Below the Target <70mg/dl) on CGM | 2.2 percent time below range | Standard Deviation 0.7 |
| Technosphere Insulin (TI, Afrezza) -Treatment Arm | Hypoglycemia Frequency (%) (Below the Target <70mg/dl) on CGM | 4.0 percent time below range | Standard Deviation 0.6 |
Secondary
The Area Under the Curve Calculation (AUC) (Min*mg/dl) in the PPBG and PPGE,
Difference of area under curve between treatment and control groups. ( 0 to 4 hours duration)
Time frame: 0, 1, 2, 3, 4 hours post-dose at 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Aspart ( Novolog) -Control Arm | The Area Under the Curve Calculation (AUC) (Min*mg/dl) in the PPBG and PPGE, | 15020 min*mg/dl | Standard Deviation 560 |
| Technosphere Insulin (TI, Afrezza) -Treatment Arm | The Area Under the Curve Calculation (AUC) (Min*mg/dl) in the PPBG and PPGE, | 20020 min*mg/dl | Standard Deviation 680 |