Afrezza Safety and Pharmacokinetics Study in Pediatric Patients

• Sponsor: Mannkind Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02527265
• Collaborator: (none)
• Enrollment: 30
• Locations: 13
• Arm: 1
• Actual Duration (Months): 32.9
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus	Biological: Afrezza	Phase 2

Detailed Description

The patients are expected to participate in the study for approximately 6 to 8 weeks from Screening to final follow-up visit.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label, Single-arm, Multiple-dose Safety, Titration, and Pharmacokinetic Trial of Afrezza® in Pediatric Patients Ages 4 to 17 Years With Type 1 Diabetes Mellitus
• Actual Study Start Date: Sep 28, 2017
• Actual Primary Completion Date: Mar 17, 2020
• Actual Study Completion Date: Jun 25, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Afrezza (Technosphere Insulin) 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 multiple injections of basal long acting insulin, in general at bedtime every day.	Biological: Afrezza; Pharmaceutical form: powder Route of administration: inhalation; Other Names: Technosphere Insulin

Outcome Measures

Primary Outcome Measures

1. Insulin Maximum Observed Concentration (Cmax) [250 minutes post-dose]

   Insulin Cmax after a dose of Afrezza

Secondary Outcome Measures

1. Insulin Time to Reach Cmax (Tmax) [250 minutes post-dose]

   Insulin Tmax after a dose of Afrezza

2. Insulin Area Under Concentration Time Curve (AUC) [250 minutes post-dose]

   Insulin AUC after a dose of Afrezza

3. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
2	Barbara Davis Center for Childhood Diabetes	Aurora	Colorado	United States	80045
3	Yale University Hospital	New Haven	Connecticut	United States	06510
4	University of Florida	Gainesville	Florida	United States	32610
5	USF Diabetes Center	Tampa	Florida	United States	33612
6	Atlanta Diabetes Associates	Atlanta	Georgia	United States	30318
7	Van Meter Pediatric Endocrinology, P.C.	Atlanta	Georgia	United States	30318
8	Emory University Children's Center	Atlanta	Georgia	United States	30322
9	Indiana University, Riley Hospital for Children	Indianapolis	Indiana	United States	46202
10	Barry J. Reiner, MD, LLC	Baltimore	Maryland	United States	21229
11	Diabetes, Obesity, Cardiovascular Clinical Specialists (DOCS)	Las Vegas	Nevada	United States	89113
12	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
13	Le Bonheur Children's Hospital	Memphis	Tennessee	United States	38105

Sponsors and Collaborators

• Mannkind Corporation

Investigators

• Study Director: Clinical Operations, Mannkind Corporation

Study Documents (Full-Text)

• Study Protocol - Feb 14, 2018
• Statistical Analysis Plan - Jan 17, 2020

More Information

Publications

None provided.

• Responsible Party: Mannkind Corporation
• ClinicalTrials.gov Identifier: NCT02527265
• Other Study ID Numbers: MKC-TI-155 Part 1; U1111-1166-5528
• First Posted: Aug 18, 2015
• Last Update Posted: Apr 6, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin

Study Results

Participant Flow

Pre-assignment Detail	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)

Arm/Group Title	Afrezza Cohort 1 (Ages 13-17)	Afrezza Cohort 2 (Ages 8-12)
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	15	15
COMPLETED	13	11
NOT COMPLETED	2	4

Baseline Characteristics

Arm/Group Title	Afrezza Cohort 1 (Ages 13-17)	Afrezza Cohort 2 (Ages 8-12)	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	15	15	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15.0 (1.73)	10.4 (1.55)	12.7 (2.84)
Sex: Female, Male (Count of Participants)
Female	8 53.3%	10 66.7%	18 60%
Male	7 46.7%	5 33.3%	12 40%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 13.3%	2 6.7%
Not Hispanic or Latino	15 100%	13 86.7%	28 93.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 13.3%	1 6.7%	3 10%
White	12 80%	13 86.7%	25 83.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 6.7%	1 6.7%	2 6.7%
Region of Enrollment (participants) [Number]
United States	15 100%	15 100%	30 100%

Outcome Measures

1. Primary Outcome

Title	Insulin Maximum Observed Concentration (Cmax)
Description	Insulin Cmax after a dose of Afrezza
Time Frame	250 minutes post-dose

Outcome Measure Data

Analysis Population Description

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/Group Title	Afrezza Cohort 1 (Ages 13-17)	Afrezza Cohort 2 (Ages 8-12)
Arm/Group Description	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 multiple injections of basal long acting insulin, in general at bedtime every day. Afrezza: Pharmaceutical form: powder Route of administration: inhalation	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 multiple injections of basal long acting insulin, in general at bedtime every day. Afrezza: Pharmaceutical form: powder Route of administration: inhalation
Measure Participants	15	13
4 unit cartridge	28.5 (5.77)	102 (31.4)
8 unit cartridge	101 (42.1)	133 (91.0)
12 unit cartridge	201 (118)	251 (NA)
16 unit cartridge	105 (NA)

2. Secondary Outcome

Title	Insulin Time to Reach Cmax (Tmax)
Description	Insulin Tmax after a dose of Afrezza
Time Frame	250 minutes post-dose

Outcome Measure Data

Analysis Population Description

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/Group Title	Afrezza Cohort 1 (Ages 13-17)	Afrezza Cohort 2 (Ages 8-12)
Arm/Group Description	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 multiple injections of basal long acting insulin, in general at bedtime every day. Afrezza: Pharmaceutical form: powder Route of administration: inhalation	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 multiple injections of basal long acting insulin, in general at bedtime every day. Afrezza: Pharmaceutical form: powder Route of administration: inhalation
Measure Participants	15	13
4 unit cartridge	12.5 (3.54)	9.5 (4.04)
8 unit cartridge	13.5 (5.47)	14.1 (5.44)
12 unit cartridge	15.3 (3.27)	10.0 (NA)
16 unit cartridge	20.0 (NA)

3. Secondary Outcome

Title	Insulin Area Under Concentration Time Curve (AUC)
Description	Insulin AUC after a dose of Afrezza
Time Frame	250 minutes post-dose

Outcome Measure Data

Analysis Population Description

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/Group Title	Afrezza Cohort 1 (Ages 13-17)	Afrezza Cohort 2 (Ages 8-12)
Arm/Group Description	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 multiple injections of basal long acting insulin, in general at bedtime every day. Afrezza: Pharmaceutical form: powder Route of administration: inhalation	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 multiple injections of basal long acting insulin, in general at bedtime every day. Afrezza: Pharmaceutical form: powder Route of administration: inhalation
Measure Participants	15	13
4 unit cartridge	1468 (1272)	2931 (1011)
8 unit cartridge	4488 (2644)	4975 (2921)
12 unit cartridge	6400 (3009)	5971 (NA)
16 unit cartridge	5778 (NA)

4. Secondary Outcome

Title	Assessment of Fumaryl Diketopiperazine (FDKP) Elimination Half-life (t1/2)
Description	FDKP (inert carrier excipient) calculated half life t1/2
Time Frame	Using PK data collected over 250 minutes post-dose of Afrezza

Outcome Measure Data

Analysis Population Description

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/Group Title	Afrezza Cohort 1 (Ages 13-17)	Afrezza Cohort 2 (Ages 8-12)
Arm/Group Description	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 multiple injections of basal long acting insulin, in general at bedtime every day. Afrezza: Pharmaceutical form: powder Route of administration: inhalation	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 multiple injections of basal long acting insulin, in general at bedtime every day. Afrezza: Pharmaceutical form: powder Route of administration: inhalation
Measure Participants	15	13
4 unit cartridge	103 (23.0)	86.8 (6.35)
8 unit cartridge	123 (31.3)	86.5 (15.8)
12 unit cartridge	109 (25.9)	95.5 (NA)
16 unit cartridge	144 (NA)

Adverse Events

Time Frame	4 weeks
Arm/Group Title	Afrezza Cohort 1 (Ages 13-17)		Afrezza Cohort 2 (Ages 8-12)
Arm/Group Description	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 multiple injections of basal long acting insulin, in general at bedtime every day. Afrezza: Pharmaceutical form: powder Route of administration: inhalation		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 multiple injections of basal long acting insulin, in general at bedtime every day. Afrezza: Pharmaceutical form: powder Route of administration: inhalation
All Cause Mortality
	Afrezza Cohort 1 (Ages 13-17)		Afrezza Cohort 2 (Ages 8-12)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Afrezza Cohort 1 (Ages 13-17)		Afrezza Cohort 2 (Ages 8-12)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/15 (6.7%)		1/15 (6.7%)
Infections and infestations
Gastroenteritis viral	0/15 (0%)	0	1/15 (6.7%)	1
Metabolism and nutrition disorders
Diabetic ketoacidosis	1/15 (6.7%)	1	0/15 (0%)	0
Other (Not Including Serious) Adverse Events
	Afrezza Cohort 1 (Ages 13-17)		Afrezza Cohort 2 (Ages 8-12)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/15 (80%)		11/15 (73.3%)
Gastrointestinal disorders
Constipation	1/15 (6.7%)	1	0/15 (0%)	0
Diarrhoea	1/15 (6.7%)	1	0/15 (0%)	0
Vomiting	0/15 (0%)	0	1/15 (6.7%)	1
General disorders
Asthenia	0/15 (0%)	0	1/15 (6.7%)	1
Tenderness	0/15 (0%)	0	1/15 (6.7%)	1
Immune system disorders
Seasonal allergy	0/15 (0%)	0	1/15 (6.7%)	1
Infections and infestations
Gastroenteritis	1/15 (6.7%)	1	0/15 (0%)	0
Upper respiratory tract infection	1/15 (6.7%)	1	3/15 (20%)	3
Urinary tract infection	1/15 (6.7%)	1	0/15 (0%)	0
Injury, poisoning and procedural complications
Limb injury	0/15 (0%)	0	1/15 (6.7%)	1
Investigations
Blood pressure increased	0/15 (0%)	0	1/15 (6.7%)	1
Urine cotinine test positive	1/15 (6.7%)	1	0/15 (0%)	0
Metabolism and nutrition disorders
Hyperglycemia	0/15 (0%)	0	1/15 (6.7%)	1
Hypoglycemia	10/15 (66.7%)	48	10/15 (66.7%)	45
Musculoskeletal and connective tissue disorders
Arthralgia	1/15 (6.7%)	1	0/15 (0%)	0
Flank pain	0/15 (0%)	0	1/15 (6.7%)	1
Nervous system disorders
Dizziness	0/15 (0%)	0	1/15 (6.7%)	1
Headache	1/15 (6.7%)	1	1/15 (6.7%)	1
Reproductive system and breast disorders
Dysmenorrhea	2/15 (13.3%)	2	0/15 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	7/15 (46.7%)	7	5/15 (33.3%)	5
Throat irritation	1/15 (6.7%)	2	0/15 (0%)	0
Tonsillar hypertrophy	0/15 (0%)	0	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Erythema	0/15 (0%)	0	1/15 (6.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.