Type 1 Diabetes Mellitus
Conditions
Brief summary
Primary Objective: -To assess the safety and tolerability of Afrezza in children ages 4 to 17 years with type 1 diabetes mellitus (T1DM). Secondary Objectives: * To assess the ability to titrate the prandial and supplemental doses of Afrezza at each meal. * To assess pharmacokinetics (PK) following a prandial dose of Afrezza in children ages 4 to 17 years with T1DM.
Detailed description
The patients are expected to participate in the study for approximately 6 to 8 weeks from Screening to final follow-up visit.
Interventions
BIOLOGICALAfrezza
Pharmaceutical form: powder Route of administration: inhalation
Sponsors
Mannkind Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
: 1. Written or oral assent from the pediatric subject and written informed consent from the parent(s) or legal guardian and a witness, as required by both state and federal laws and the local Institutional Review Board; 2. Children aged ≥4 and ≤17 years (enrolled sequentially into 3 age cohorts: 13 to 17, 8 to 12, and 4 to 7 years); 3. Clinical diagnosis of T1DM and using insulin for at least 1 year; 4. Currently receiving a regimen of basal/bolus insulin administered by MDI for at least 6 weeks prior to enrollment; 5. Subjects with pre-breakfast self monitored blood glucose values between 80 and 250 mg/dL for 5 of 7 documented daily readings obtained in the week prior to Visit 2 (readings to be taken using glucometer provided at Screening Visit 1) and reported via the e Diary; 6. Subjects on a regimen of insulin via continuous SC insulin infusion may be enrolled if they satisfy all other enrollment criteria and are willing to convert to MDI for the duration of the study, beginning 6 weeks prior to enrollment. They must continue to meet all enrollment criteria after converting to the MDI regimen; 7. Total daily insulin dose ≤1.5 units/kg/day with a minimum of 3 units of RAA at every meal. 8. Hemoglobin A1c (HbA1c) ≥7.0% to \<10.0% at the time of screening; 9. Fasting serum C-peptide ≤0.3 ng/mL; 10. Forced expiratory volume in 1 second (FEV1) ≥70% of National Health and Nutrition Examination Survey (NHANES) III predicted for children ≥8 years of age or Wang predicted for children \<8 years of age; 11. Forced vital capacity ≥70% of NHANES III predicted for children ≥8 years of age or Wang predicted for children \<8 years of age; 12. Females of childbearing potential, must use highly effective methods of contraception throughout conduct of the trial
Exclusion criteria
1. Body mass index below 25th or above 95th percentile for age and gender according to Centers for Disease Control and Prevention growth charts; 2. History of physician diagnosis of asthma or any other clinically important pulmonary disease, or use of any medications to treat such conditions within the last year; 3. Allergy or known hypersensitivity for AFREZZA or to drugs with similar chemical structure; 4. Unstable diabetes control, defined as 2 or more episodes of severe hypoglycemia (i.e., an episode associated with a seizure, coma, or loss of consciousness) or any hospitalization or emergency room visit for poor diabetes control, ketoacidosis, hypoglycemia, or hyperglycemia within the preceding 3 months from screening; 5. Serum creatinine ≥ the upper limit of normal for age; 6. Respiratory tract infection within 30 days before screening or between screening and initiation of treatment period; subject may return 4 weeks after resolution of the infection for rescreening; 7. Evidence of any complication of diabetes (proliferative retinopathy, autonomic neuropathy, nephropathy, etc), or likelihood of requiring laser photocoagulation, vitrectomy, or other specific treatment for diabetic retinopathy in the coming year; 8. Smoking of tobacco or other substances or positive urine cotinine testing (\>100 ng/mL); 9. Positive urine drug screen; 10. Positive urine pregnancy test for female subjects of childbearing potential; 11. Inability to perform study procedures including pulmonary function testing; 12. Exposure to any investigational product(s) in the past 3 months or 5 half-lives, whichever is more; 13. History of eating disorder; 14. Any disease or exposure to any medication which, in the judgment of the principal Investigator, may impact glucose metabolism; 15. Any concurrent medical or major psychiatric condition that makes the subject unsuitable for the clinical study or impairs the subject's ability to participate in the study. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Maximum Observed Concentration (Cmax) | 250 minutes post-dose | Insulin Cmax after a dose of Afrezza |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Time to Reach Cmax (Tmax) | 250 minutes post-dose | Insulin Tmax after a dose of Afrezza |
| Insulin Area Under Concentration Time Curve (AUC) | 250 minutes post-dose | Insulin AUC after a dose of Afrezza |
| Assessment of Fumaryl Diketopiperazine (FDKP) Elimination Half-life (t1/2) | Using PK data collected over 250 minutes post-dose of Afrezza | FDKP (inert carrier excipient) calculated half life t1/2 |
Countries
United States
Participant flow
Pre-assignment details
A total of 48 subjects were screened for the study, of which 30 subjects were enrolled in the study (15 subjects each in Cohort 1 and Cohort 2)
Participants by arm
| Arm | Count |
|---|---|
| Afrezza Cohort 1 (Ages 13-17) Individualized dose of Afrezza (Technosphere Insulin) for each patient at each meal (breakfast, lunch, and dinner) for 30 days.
During the trial, all patients will receive daily injections of basal long acting insulin, in general at bedtime every day.
Afrezza: Pharmaceutical form: powder
Route of administration: inhalation | 15 |
| Afrezza Cohort 2 (Ages 8-12) Individualized dose of Afrezza (Technosphere Insulin) for each patient at each meal (breakfast, lunch, and dinner) for 30 days.
During the trial, all patients will receive daily injections of basal long acting insulin, in general at bedtime every day.
Afrezza: Pharmaceutical form: powder
Route of administration: inhalation | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | Afrezza Cohort 1 (Ages 13-17) | Total | Afrezza Cohort 2 (Ages 8-12) |
|---|---|---|---|
| Age, Continuous | 15.0 years STANDARD_DEVIATION 1.73 | 12.7 years STANDARD_DEVIATION 2.84 | 10.4 years STANDARD_DEVIATION 1.55 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 28 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| 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 | 2 Participants | 3 Participants | 1 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 | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 12 Participants | 25 Participants | 13 Participants |
| Region of Enrollment United States | 15 participants | 30 participants | 15 participants |
| Sex: Female, Male Female | 8 Participants | 18 Participants | 10 Participants |
| Sex: Female, Male Male | 7 Participants | 12 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 12 / 15 | 11 / 15 |
| serious Total, serious adverse events | 1 / 15 | 1 / 15 |
Outcome results
Primary
Insulin Maximum Observed Concentration (Cmax)
Insulin Cmax after a dose of Afrezza
Time frame: 250 minutes post-dose
Population: All subjects without any major deviations related to study drug administration, and for whom any PK parameters are available, will be included in the PK population.~Subjects who sneeze or cough right after AFREZZA inhalation for PK profiling will be considered as important deviations related to IMP and will be excluded for PK analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Afrezza Cohort 1 (Ages 13-17) | Insulin Maximum Observed Concentration (Cmax) | 12 unit cartridge | 201 μU/mL | Standard Deviation 118 |
| Afrezza Cohort 1 (Ages 13-17) | Insulin Maximum Observed Concentration (Cmax) | 8 unit cartridge | 101 μU/mL | Standard Deviation 42.1 |
| Afrezza Cohort 1 (Ages 13-17) | Insulin Maximum Observed Concentration (Cmax) | 16 unit cartridge | 105 μU/mL | — |
| Afrezza Cohort 1 (Ages 13-17) | Insulin Maximum Observed Concentration (Cmax) | 4 unit cartridge | 28.5 μU/mL | Standard Deviation 5.77 |
| Afrezza Cohort 2 (Ages 8-12) | Insulin Maximum Observed Concentration (Cmax) | 8 unit cartridge | 133 μU/mL | Standard Deviation 91 |
| Afrezza Cohort 2 (Ages 8-12) | Insulin Maximum Observed Concentration (Cmax) | 4 unit cartridge | 102 μU/mL | Standard Deviation 31.4 |
| Afrezza Cohort 2 (Ages 8-12) | Insulin Maximum Observed Concentration (Cmax) | 12 unit cartridge | 251 μU/mL | — |
Secondary
Assessment of Fumaryl Diketopiperazine (FDKP) Elimination Half-life (t1/2)
FDKP (inert carrier excipient) calculated half life t1/2
Time frame: Using PK data collected over 250 minutes post-dose of Afrezza
Population: All subjects without any major deviations related to study drug administration, and for whom any PK parameters are available, will be included in the PK population.~Subjects who sneeze or cough right after AFREZZA inhalation for PK profiling will be considered as important deviations related to IMP and will be excluded for PK analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Afrezza Cohort 1 (Ages 13-17) | Assessment of Fumaryl Diketopiperazine (FDKP) Elimination Half-life (t1/2) | 12 unit cartridge | 109 minutes | Standard Deviation 25.9 |
| Afrezza Cohort 1 (Ages 13-17) | Assessment of Fumaryl Diketopiperazine (FDKP) Elimination Half-life (t1/2) | 8 unit cartridge | 123 minutes | Standard Deviation 31.3 |
| Afrezza Cohort 1 (Ages 13-17) | Assessment of Fumaryl Diketopiperazine (FDKP) Elimination Half-life (t1/2) | 16 unit cartridge | 144 minutes | — |
| Afrezza Cohort 1 (Ages 13-17) | Assessment of Fumaryl Diketopiperazine (FDKP) Elimination Half-life (t1/2) | 4 unit cartridge | 103 minutes | Standard Deviation 23 |
| Afrezza Cohort 2 (Ages 8-12) | Assessment of Fumaryl Diketopiperazine (FDKP) Elimination Half-life (t1/2) | 8 unit cartridge | 86.5 minutes | Standard Deviation 15.8 |
| Afrezza Cohort 2 (Ages 8-12) | Assessment of Fumaryl Diketopiperazine (FDKP) Elimination Half-life (t1/2) | 4 unit cartridge | 86.8 minutes | Standard Deviation 6.35 |
| Afrezza Cohort 2 (Ages 8-12) | Assessment of Fumaryl Diketopiperazine (FDKP) Elimination Half-life (t1/2) | 12 unit cartridge | 95.5 minutes | — |
Secondary
Insulin Area Under Concentration Time Curve (AUC)
Insulin AUC after a dose of Afrezza
Time frame: 250 minutes post-dose
Population: All subjects without any major deviations related to study drug administration, and for whom any PK parameters are available, will be included in the PK population.~Subjects who sneeze or cough right after AFREZZA inhalation for PK profiling will be considered as important deviations related to IMP and will be excluded for PK analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Afrezza Cohort 1 (Ages 13-17) | Insulin Area Under Concentration Time Curve (AUC) | 8 unit cartridge | 4488 min*μU/mL | Standard Deviation 2644 |
| Afrezza Cohort 1 (Ages 13-17) | Insulin Area Under Concentration Time Curve (AUC) | 4 unit cartridge | 1468 min*μU/mL | Standard Deviation 1272 |
| Afrezza Cohort 1 (Ages 13-17) | Insulin Area Under Concentration Time Curve (AUC) | 12 unit cartridge | 6400 min*μU/mL | Standard Deviation 3009 |
| Afrezza Cohort 1 (Ages 13-17) | Insulin Area Under Concentration Time Curve (AUC) | 16 unit cartridge | 5778 min*μU/mL | — |
| Afrezza Cohort 2 (Ages 8-12) | Insulin Area Under Concentration Time Curve (AUC) | 12 unit cartridge | 5971 min*μU/mL | — |
| Afrezza Cohort 2 (Ages 8-12) | Insulin Area Under Concentration Time Curve (AUC) | 4 unit cartridge | 2931 min*μU/mL | Standard Deviation 1011 |
| Afrezza Cohort 2 (Ages 8-12) | Insulin Area Under Concentration Time Curve (AUC) | 8 unit cartridge | 4975 min*μU/mL | Standard Deviation 2921 |
Secondary
Insulin Time to Reach Cmax (Tmax)
Insulin Tmax after a dose of Afrezza
Time frame: 250 minutes post-dose
Population: All subjects without any major deviations related to study drug administration, and for whom any PK parameters are available, will be included in the PK population.~Subjects who sneeze or cough right after AFREZZA inhalation for PK profiling will be considered as important deviations related to IMP and will be excluded for PK analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Afrezza Cohort 1 (Ages 13-17) | Insulin Time to Reach Cmax (Tmax) | 12 unit cartridge | 15.3 minutes | Standard Deviation 3.27 |
| Afrezza Cohort 1 (Ages 13-17) | Insulin Time to Reach Cmax (Tmax) | 8 unit cartridge | 13.5 minutes | Standard Deviation 5.47 |
| Afrezza Cohort 1 (Ages 13-17) | Insulin Time to Reach Cmax (Tmax) | 16 unit cartridge | 20.0 minutes | — |
| Afrezza Cohort 1 (Ages 13-17) | Insulin Time to Reach Cmax (Tmax) | 4 unit cartridge | 12.5 minutes | Standard Deviation 3.54 |
| Afrezza Cohort 2 (Ages 8-12) | Insulin Time to Reach Cmax (Tmax) | 8 unit cartridge | 14.1 minutes | Standard Deviation 5.44 |
| Afrezza Cohort 2 (Ages 8-12) | Insulin Time to Reach Cmax (Tmax) | 4 unit cartridge | 9.5 minutes | Standard Deviation 4.04 |
| Afrezza Cohort 2 (Ages 8-12) | Insulin Time to Reach Cmax (Tmax) | 12 unit cartridge | 10.0 minutes | — |