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
Phase: PHASE2
Conditions: Type 1 Diabetes Mellitus
Sponsor: Mannkind Corporation

MKC-TI-155 Part 1 
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CLINICAL STUDY PROTOCOL AMENDMENT 3: MKC-TI-155 
 
 
Study Title: 
Open-label, single-arm, multiple-dose safety, titration, and 
pharmacokinetic study of AFREZZA® in pediatric subjects ages 
4 to 17 years with type 1 diabetes mellitus 
Study Number: 
MKC-TI-155 Part 1 
Study Phase: 
2 
Product Name: 
AFREZZA® (insulin human) Inhalation Powder 
(Technosphere® Insulin Inhalation Powder) 
IND Number: 
061729 
Indication: 
Diabetes Mellitus 
Sponsor: 
MannKind Corporation 
One Casper Street 
Danbury, CT 06810 
Sponsor Contact: 
David J. Klein MD, PhD 
Senior Director, Clinical Development 
Office: 203-790-3174 
dklein@mannkindcorp.com 
Original Date 
Amendment 1 Date: 
11 February 2014 (TDR 14323 V2) 
13 February 2017 
Amendment 2 Date: 
11 May 2017 
Amendment 3 Date: 
14 February 2018 
 
 
Confidentiality Statement 
By receipt of this document, you acknowledge that it is MannKind Corporation 
confidential information. You shall not directly or indirectly publish, disseminate or 
otherwise disclose, deliver or make available to any third party any part of this 
document and shall not use it other than in furtherance of the purpose for which it 
was made available to you. You may disclose this information only with the prior 
written consent of MannKind Corporation, or to a governmental authority related 
to the subject matter herein, or by order of a court of competent jurisdiction. Any 
disclosure of this document, whether authorized or not, shall be reported to 
  
MannKind Corporation immediately 
 

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NAMES AND ADDRESSES OF 
 
CLINICAL OPERATIONS 
STUDY TEAM LEADER 
Name: 
David Gash 
MannKind Corporation 
One Casper Street 
Danbury, CT 06810 
973-744-5292 
dgash@mannkindcorp.com 
Address: 
Tel: 
E-mail: 
MEDICAL MONITOR 
Name: 
David J. Klein MD, PhD 
MannKind Corporation 
One Casper Street 
Danbury, CT 06810 
203-790-3174 
dklein@mannkindcorp.com 
Address: 
Tel: 
E-mail: 
CLINICAL STUDY 
MANAGEMENT 
Name: 
PPD 
929 North Front Street 
Wilmington, NC 28401-331 
1-910-251-0081 
1-910-762-5820 
Address: 
Tel: 
Fax: 
SPONSOR’S MEDICAL 
DIRECTOR 
Name: 
David J. Klein MD, PhD 
MannKind Corporation 
One Casper Street 
Danbury, CT 06810 
203-790-3174 
dklein@mannkindcorp.com 
Address: 
Tel: 
E-mail: 
SPONSOR 
Company: 
MannKind Corporation 
One Casper Street 
Danbury, CT 06810 
Address: 

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CLINICAL STUDY SUMMARY 
The AFREZZA pediatric study MKC-TI-155 consists of 2 parts: 
• Part 1 is a Phase 2, open-label, single-arm, multiple-dose safety, titration, and pharmacokinetic (PK) 
study of AFREZZA in pediatric subjects ages 4 to 17 years with type 1 diabetes mellitus (T1DM). 
• Part 2 is a Phase 3, 52-week, open-label, randomized, multinational, clinical study evaluating the 
efficacy and safety of AFREZZA (insulin human) inhalation powder in combination with a basal 
insulin versus insulin aspart in combination with a basal insulin in pediatric subjects with type 1 or 
type 2 diabetes mellitus. The design of the Phase 3 study may be modified based on the results from 
Part 1. Design for the Phase 3 study is in development (Section 18.3 - Appendix C). 
 
 
STUDY NUMBER 
MKC-TI-155 Part 1 
COMPOUND: 
AFREZZA® (insulin human) Inhalation Powder 
STUDY TITLE 
Open-label, single-arm, multiple-dose safety, titration, and 
pharmacokinetic study of AFREZZA® in pediatric subjects ages 
4 to 17 years with type 1 diabetes mellitus 
INVESTIGATOR/STUDY 
LOCATION 
United States 
PHASE OF DEVELOPMENT 
2 
STUDY OBJECTIVES 
• 
Assess the safety and tolerability of AFREZZA in children 
ages 4 to 17 years with T1DM 
• 
Assess PK following a prandial dose of AFREZZA in 
children ages 4 to 17 years with T1DM 
• 
Assess the ability to titrate the prandial and supplemental 
dose of AFREZZA at each meal using postprandial 
self-monitored blood glucose values obtained 120 to 
150 minutes after each prandial dose of AFREZZA in 
children ages 4 to 17 years with T1DM 
STUDY DESIGN 
Part 1 of the study will be a single-arm, multi-center, open-label, 
uncontrolled study to evaluate PK, safety, and ability to titrate 
AFREZZA® in children ages 4 to 17 years with T1DM, who 
were previously on a regimen of basal-bolus insulin therapy 
administered by multiple daily injections (MDI). 
On Day 1, subjects will receive a single dose of AFREZZA prior 
to PK sampling. There will be 3 different doses of AFREZZA for 
the PK study. The AFREZZA® dose (4, 8, or 12 units) will be 
based on the dose of subcutaneous (SC) rapid-acting analog 
(RAA) that the subject would usually receive with breakfast. 
During the 4-week titration period following the PK visit, each 
subject will be titrated with AFREZZA according to the titration 

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rules given. 
The study will be conducted sequentially in age cohorts 
beginning with Cohort 1 and then proceeding to Cohort 2 and 
Cohort 3 in parallel. Approximately 46 subjects will be enrolled 
into 3 age cohorts: 
Cohort 1: 13 to 17 years; approximately 18 subjects distributed 
across 4, 8, and 12 unit starting dose groups. Before proceeding 
to Cohort 2 and Cohort 3, at least 14 subjects must be dosed 
(complete PK Visit 2). Of those, at least 6 subjects must receive 
at least the 8 unit dose. 
Cohort 2: 8 to 12 years; approximately 14 subjects distributed 
across 4, 8, and 12 unit starting dose groups, as derived from the 
insulin:carb ratio – Figure 1 (the sample size may be adapted 
after taking the PK data from Cohort 1 into account).. 
Cohort 3: 4 to 7 years; approximately 14 subjects will be treated 
and assessed for AFREZZA with a starting dose of distributed 
across 4, 8, and 12 unit starting dose groups, as derived from the 
insulin:carb ratio – Figure 1. The sample size may be adapted 
after evaluating the PK data from Cohort 1 and Cohort 2. 
The study consists of: 
• 
Up to 3-week screening period 
• 
PK assessment period: 1 day, after a single dose of 
AFREZZA® 
• 
Dose titration period: approximately a 4-week period with 
multiple doses of AFREZZA 
• 
A follow-up visit will occur approximately 1 week after the 
end of AFREZZA treatment for safety assessments 
(duration 1 day) 
Stopping rules 
• 
Administration of AFREZZA in any dose group(s) of an 
age cohort may be halted if the Sponsor or data safety 
monitoring committee (DMC) considers a dose group or age 
cohort to be unsafe or that it is unreasonable to continue. 
• 
The study may also be stopped if the Sponsor or DMC 
considers it not appropriate to proceed to the next age 
cohorts based on safety, PK, or titration data. 
STUDY POPULATION 
Main selection criteria 
Inclusion criteria 
1. Written consent or oral assent from the pediatric subject and 

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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 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. Subjects of childbearing potential must use “highly 
effective” methods of contraception. These include, for 
example, a state after surgical sterilization, hormonal 
intrauterine devices (coil), oral hormonal contraceptives, 
sexual abstinence or a surgically sterilized partner. “Highly 
effective” methods are considered those with a low failure 
rate (i.e., less than 1% undesired pregnancies per year). 
During the entire trial females of childbearing potential 

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must use two contraceptive methods which are independent 
from each other, e.g. an intrauterine contraceptive coil or 
oral hormonal contraceptive plus a vaginal diaphragm or a 
condom coated with a spermicidal substance. The use of a 
condom in combination with spermicidal creams, however, 
is not sufficiently reliable. 
 
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: 
https://www.cdc.gov/growthcharts/html_charts/bmiagerev.h 
tm 
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; 

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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. 
Total expected number of 
subjects 
Approximately 46 subjects will be enrolled in the Part 1 of the 
study (18 subjects for 13 to 17-year-old cohort, 14 subjects for 
8 to 12-year-old cohort, and 14 subjects for 4 to 7-year-old 
cohort). 
STUDY TREATMENTS 
Investigational medicinal product AFREZZA® (insulin human) Inhalation Powder and Inhaler 
Formulation 
Recombinant DNA origin 
Each milligram of formulation contains 3.0 units of human 
insulin 
Route of administration 
Inhalation 
Dose regimen 
At the beginning of each meal 
Non-investigational medicinal 
product 
Basal insulin (e.g., insulin glargine) 
Formulation 
Long acting insulin analog 
Route of administration 
Subcutaneous injection 
Dose regimen 
Daily dose as instructed by Physician 
ENDPOINTS 
Pharmacokinetic endpoints 
• 
Insulin Cmax (maximum observed concentration after 
correction for baseline) 
• 
Insulin AUC0-tlast (area under the baseline-corrected 
concentration-time curve from time 0 to the last measurable 
concentration) 
• 
Insulin tmax (time to Cmax) 
• 
Insulin apparent clearance (CL/F) 
• 
Insulin apparent volume of distribution (Vss/F) 
• 
Fumaryl diketopiperazine (FDKP) elimination half-life (t1/2) 
• 
Insulin AUC (area under the serum concentration versus 

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time curve extrapolated to infinity according to the 
following equation: 
AUC = AUClast + Clast/λz 
Safety endpoints: 
• 
Adverse events, serious adverse events, treatment-emergent 
adverse events 
• 
Adverse Events of Special Interest (AESI), which include 
the following events: 
• 
Acute bronchospasm 
• 
Clinically relevant decline in pulmonary function 
• 
Hypersensitivity reactions, including anaphylaxis, which 
can occur with insulin products, including AFREZZA® 
• 
Diabetic ketoacidosis 
• 
Vital sign measurements 
• 
Abnormal clinical laboratory assessments 
• 
Hypoglycemia: asymptomatic, symptomatic, nocturnal, and 
severe hypoglycemia according to the 2014 International 
Society for Pediatric and Adolescent Diabetes guideline 
• 
Anti-insulin antibodies 
ASSESSMENT SCHEDULE 
The schedule of study-related procedures/assessments is detailed 
in the study flow chart. 
STATISTICAL 
CONSIDERATIONS 
Sample size determination: 
Sample size calculation is based on a total standard deviation 
(SDTotal) of 0.725 for the log-transformed apparent total body 
clearance (CL/F). The sample size is planned to target the 
maximum imprecision of the 95% confidence interval for the 
geometric mean estimates of CL/F in each age cohort within 
40%, with at least 80% power. 
A sample size of 14 subjects in the first cohort will provide at 
least 80% power in order to target the maximum imprecision of 
the 95% confidence interval of the geometric mean estimates 
within 40%, assuming an SDTotal of 0.725 as the most 
conservative approach. For Cohort 2 and Cohort 3, the sample 
size may be adjusted to enable taking the PK variability in 
previous cohorts into account. 
Analysis population: 
All subjects in the clinical study who receive a dose of 

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AFREZZA will be included in the safety population. 
All subjects without any major deviations related to study drug 
administration (no sneezing or coughing right after AFREZZA 
inhalation on Day 1), and for whom any PK parameters are 
available, will be included in the PK population. 
Pharmacokinetic analysis: 
All analyses will be performed in a descriptive manner based on 
the PK population. 
Safety analyses: 
Analyses will be performed in a descriptive manner by age 
cohort. 
The safety analysis will be conducted on the safety population 
and will be based on the review of the individual values 
(clinically significant abnormalities) and descriptive statistics 
(summary tables and plots if appropriate). Individual values will 
be flagged for potentially clinically significant abnormalities 
and treatment-emergent adverse events will be tabulated (counts 
and percent).The details of the analyses for the study will be 
specified in the Statistics and Analysis Plan (SAP) for the study. 
DURATION OF STUDY 
PERIOD (per subject) 
The total duration of the study will be approximately 6 to 
8 weeks per subject through the 4-week titration period. 
STUDY COMMITTEES 
Data Monitoring Committee: an independent group of experts 
will be responsible for monitoring the safety of the subjects 
enrolled in the clinical trial on an on-going basis in order to 
provide, in a timely fashion, appropriate recommendations to the 
Sponsor. 

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1 
FLOW CHARTS 
 
1.1 
STUDY FLOW CHART FOR PK AND TITRATION PHASE 
 
 
Phase 
Screening 
PK 
Titration period 
Follow-up 
Early 
Terminationa 
End of 
Titration 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Day 
D–21 to 
D–7 
D1 
D2 
D4 
D6 
D8 
D10 
D12 
D15 
D17 
D19 
D22 
D24 
D26 
D29 
D36 
Visit window 
(days) 
0 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 3 
Visit at clinical 
site 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone 
contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed 
consent/Assent 
X 
Review 
inclusion/ 
exclusion criteria 
X 
X 
Enrollment 
X 
Medical/ surgical 
history 
X 
Demography 
X 
HbA1c 
X 
X 
X 
Fasting serum 
C-peptide 
X 

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Phase 
Screening 
PK 
Titration period 
Follow-up 
Early 
Terminationa 
End of 
Titration 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Day 
D–21 to 
D–7 
D1 
D2 
D4 
D6 
D8 
D10 
D12 
D15 
D17 
D19 
D22 
D24 
D26 
D29 
D36 
Visit window 
(days) 
0 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 3 
Serology test b 
X 
Full physical 
examination 
including Tanner 
stage, body 
weight and 
height, body 
temperature 
X 
Abbreviated 
physical 
examination, 
body weight 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
Urine drug 
screen, alcohol 
breath, or plasma 
test 
X 
Urine cotinine 
X 
X 
X 
X 
X 
X 
X 
X 
Urine β-HCG 
(females of 
childbearing 
potential) c 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometry 
(FEV1) d 
X 
X 
X 
X 
X 
X 

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Phase 
Screening 
PK 
Titration period 
Follow-up 
Early 
Terminationa 
End of 
Titration 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Day 
D–21 to 
D–7 
D1 
D2 
D4 
D6 
D8 
D10 
D12 
D15 
D17 
D19 
D22 
D24 
D26 
D29 
D36 
Visit window 
(days) 
0 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 3 
Hematology, 
biochemistry , 
urinalysis 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BG and SMBG 
Blood glucose 
samples during 
4 hr PKe 
X 
Remind subject 
to obtain 7 
Fasting SMBGs 
in week prior to 
Visit 2, PK 
X 
Dispense glucose 
meter, test stripsf 
X 
Training on both 
the study 
supplied Glucose 
Meter and e-diary 
X 
Remind subject 
to obtain 7-point 
glucose data for 
X 
X 
X 
X 
X 

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Phase 
Screening 
PK 
Titration period 
Follow-up 
Early 
Terminationa 
End of 
Titration 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Day 
D–21 to 
D–7 
D1 
D2 
D4 
D6 
D8 
D10 
D12 
D15 
D17 
D19 
D22 
D24 
D26 
D29 
D36 
Visit window 
(days) 
0 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 3 
next site visit g 
Blood glucose 
via glucose meter 
reading 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review subject’s 
7-point glucose 
data 
X 
X 
X 
X 
AFREZZA® and basal insulin 
BluHale 
inspiratory 
training 
X 
Training on use 
and storage of 
AFREZZA® 
inhaler and 
cartridge 
X 
Dispense new 
Afrezza inhalers 
and cartridges as 
necessary i 
X 
X 
X 
X 
X 
Breakfast and 
lunch at site 
X 
AFREZZA® 
inhalation 
X 
Dose titration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Phase 
Screening 
PK 
Titration period 
Follow-up 
Early 
Terminationa 
End of 
Titration 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Day 
D–21 to 
D–7 
D1 
D2 
D4 
D6 
D8 
D10 
D12 
D15 
D17 
D19 
D22 
D24 
D26 
D29 
D36 
Visit window 
(days) 
0 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 3 
based on SMBG 
values 
Provide 
nutritional 
information 
X 
Prescription for 
usual prandial 
RAA 
X 
X 
Pharmacokinetics 
Insulin PK 
sampling for 
4 hours 
X 
FDKP PK 
sampling for 
4 hours 
X 
Anti-insulin 
antibody 
X 
X 
X 
Abbreviations: β-HCG, beta human chorionic gonadotropin; BG, blood glucose; ECG, electrocardiogram; FDKP, fumaryl diketopiperazine; HbA1c, glycated hemoglobin 
A1c; PK, pharmacokinetic(s); RAA, rapid-acting analog; SMBG, self-monitored blood glucose. 
a. Early termination is defined as withdrawal or discontinuation at any point between AFREZZA® administration on Day 1 (Visit 2) and end of 28-day titration. 
b. Tests for hepatitis B antigen, hepatitis C antibodies, anti-HIV-1, and anti-HIV- 2. 
c. Urine β-HCG test to be done in female subjects of childbearing potential in Cohorts 1 and 2. 
d. Spirometry: on Day 1 Spirometry test will be conducted at approximately –25, 18, 55, 125, and 245 minutes. 
e. Blood glucose sample for 4 hours: glucose reading to be done locally via a table top glucose meter (eg, YSI) at Investigator site. Central laboratory will be used only if local 
reading (i.e., table top glucose meter) is not available. 
f. Additional test strips may be provided as needed at Visits 6, 9, 12, 15 and every 3 months during the extension treatment period. 

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g. Once per week in the week prior to the next clinic visit, subjects will obtain 7-point glucose data (pre-meal and 120-150 minutes post-dose at breakfast, lunch, dinner, and 
pre-bedtime). On these days, the starting and ending time for each meal will be recorded in the e-Diary, in addition to the dosing time. 
h. If the fasting plasma glucose (FPG) value is ≥80 mg/dL at Visit 2, the subject will undergo a 4-hour PK assessment after eating his/her usual breakfast and receiving his/her 
breakfast dose of AFREZZA®. 
i. One inhaler, which may be used for up to 15 days, and replacements will be available if necessary. 

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1.2 
SCHEDULE FOR DAY 1 
 
Day 
D1 
Time (minute) 
-30 
-25 
-15 
0 
5 
10 
15 
18 
20 
30 
45 
55 
60 
90 
120 
125 
180 
240 
245 
250 
Indicative clock time 
7:30 
am 
7:35 
am 
7:45 
am 
8:00 
am 
8:05 
am 
8:10 
am 
8:15 
am 
8:18
am 
8:20 
am 
8:30 
am 
8:45 
am 
8:55 
am 
9:00 
am 
9:30 
am 
10:00 
am 
10:05 
am 
11:00 
am 
12:00 
pm 
12:05
pm 
12:10
pm 
Concomitant medications 
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
> 
Adverse event collection 
< 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
> 
Blood glucose via glucose meter 
readinga 
X 
X 
Glucose value via local or central 
laboratoryb 
G00 
G01 
G02 
G03 
G04 
G05 
G06 
Spirometry (FEV1) 
X 
X 
X 
X 
X 
Study treatment administration 
AFREZZA® inhalation 
X c 
X e 
Meal 
X d 
X e 
Pharmacokinetics 
Human insulin 
S00 
S01 
S02 
S03 
S04 
S05 
S06 
S07 
S08 
S09 
S10 
S11 
S12 
S13 
FDKP 
SF00 
SF01 
SF02 
SF03 
SF04
Abbreviations: FEV1,forced expiratory volume in 1 second; FDKP, fumaryl diketopiperazine; 
a. If the FPG value is ≥80 mg/dL at Visit 2, the subject will undergo a 4-hour PK assessment after eating his/her usual breakfast and receiving his/her breakfast dose of AFREZZA®. 
b. Glucose value via local or central laboratory: glucose reading to be done locally via a table top glucose meter (e.g., YSI) at Investigator site. Central laboratory will be used only if local 
reading (i.e., table top glucose meter) is not available. 
c. Subject will inhale a dose of AFREZZA® under the supervision of the Investigator after the glucose sample has been taken and immediately before the first mouthful of food. The 
AFREZZA® dose will be calculated based on the conversion table. The AFREZZA® dosing time will be recorded in the electronic case report form (e-CRF). 
d. Subject will receive a breakfast that is typical for that subject based on his/her usual patterns of eating and activity. The starting and ending time of breakfast will be recorded in the e-CRF. 
e. At the conclusion of the PK test, plasma glucose concentration will be assessed and subjects will receive a lunch. The lunch should correspond in size and composition to the subject’s 
usual lunch, and should be accompanied by an AFREZZA® dose corresponding to the subject’s usual dose of prandial insulin with an adjustment (if necessary) based on the results of the 
glucose profile during the PK test and the pre-lunch plasma glucose value. 

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2 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL AMENDMENT 3: MKC-TI-155.......................................................... 1 
CLINICAL STUDY SUMMARY ....................................................................................................... 3 
1 
FLOW CHARTS ........................................................................................................... 10 
1.1 
STUDY FLOW CHART FOR PK AND TITRATION PHASE ................................................. 10 
1.2 
SCHEDULE FOR DAY 1................................................................................................ 16 
2 
TABLE OF CONTENTS ................................................................................................ 17 
3 
LIST OF ABBREVIATIONS ........................................................................................... 21 
4 
INTRODUCTION AND RATIONALE ............................................................................... 22 
4.1 
INTRODUCTION .......................................................................................................... 22 
4.2 
RATIONALE ................................................................................................................ 22 
4.3 
POTENTIAL BENEFITS ................................................................................................ 23 
4.4 
IMPORTANT POTENTIAL RISKS AND ASSESSMENT PLAN ............................................ 23 
5 
STUDY OBJECTIVES................................................................................................... 27 
6 
STUDY DESIGN .......................................................................................................... 28 
6.1 
DESCRIPTION OF THE PROTOCOL .............................................................................. 28 
6.2 
STOPPING RULES ...................................................................................................... 28 
6.3 
DURATION OF STUDY PARTICIPATION FOR EACH SUBJECT ........................................ 29 
6.5 
DETERMINATION OF END OF CLINICAL STUDY (ALL SUBJECTS) .................................. 29 
6.6 
INTERIM ANALYSIS ..................................................................................................... 29 
7 
SELECTION OF PARTICIPANTS ................................................................................... 30 
7.1 
NUMBER OF SUBJECTS PLANNED .............................................................................. 30 
7.2 
INCLUSION CRITERIA ................................................................................................. 30 
7.3 
EXCLUSION CRITERIA ................................................................................................ 31 
8 
STUDY TREATMENTS ................................................................................................. 33 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT.................................................................... 33 
8.1.1 
AFREZZA (Insulin Human) inhalation powder and inhaler ................................................... 33 
8.1.2 
AFREZZA inhalation training ........................................................................................... 33 
8.1.3 
Initial dose for PK assessment ........................................................................................ 33 
8.1.4 
Dose titration ............................................................................................................... 34 

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8.1.5 
Postprandial dosing (follow-on doses) .............................................................................. 34 
8.1.6 
Additional dosing of AFREZZA for snacks ......................................................................... 34 
8.1.7 
Basal insulin dose adjustment......................................................................................... 35 
8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS.......................................................... 35 
8.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS .................................... 35 
8.4 
PACKAGING AND LABELING ........................................................................................ 35 
8.5 
STORAGE CONDITIONS AND SHELF LIFE .................................................................... 35 
8.5.1 
AFREZZA inhalation powder ........................................................................................... 35 
8.5.2 
AFREZZA inhaler ......................................................................................................... 35 
8.5.3 
Handling...................................................................................................................... 36 
8.6 
RESPONSIBILITIES ..................................................................................................... 36 
8.7 
CONCOMITANT TREATMENT....................................................................................... 36 
8.8 
TREATMENT ACCOUNTABILITY AND COMPLIANCE ...................................................... 37 
8.9 
RETURN AND/OR DESTRUCTION OF TREATMENTS ..................................................... 37 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ....................................... 38 
9.1 
PHARMACOKINETICS ................................................................................................. 38 
9.1.1 
Sampling times............................................................................................................. 38 
9.1.2 
Number of PK samples.................................................................................................. 38 
9.1.3 
Sample handling procedure............................................................................................ 38 
9.1.4 
Bioanalytical methods ................................................................................................... 39 
9.1.5 
Pharmacokinetic parameters .......................................................................................... 39 
9.2 
SAFETY...................................................................................................................... 39 
9.2.1 
Baseline demographic characteristics .............................................................................. 39 
9.2.2 
Medical history ............................................................................................................. 40 
9.2.3 
Screening assessment .................................................................................................. 40 
9.2.4 
Safety assessment during the study ................................................................................ 42 
9.2.5 
Self-measured blood glucose (SMBG) ............................................................................. 42 
9.2.6 
Mandatory SMBG ......................................................................................................... 42 
9.2.6.1 
Fasting pre-breakfast SMBG .......................................................................................... 42 
9.2.6.2 
Routine SMBG monitoring.............................................................................................. 43 
9.2.6.3 
7-point SMBG profiles ................................................................................................... 43 
9.2.6.4 
Self-monitored blood glucose during symptomatic hypoglycemia.......................................... 43 
9.2.7 
Recording of SMBG into the e-CRF ................................................................................. 43 
9.2.8 
Recording of insulin doses into the e-CRF ........................................................................ 43 
9.3 
OTHER ASSESSMENT................................................................................................. 44 
10 
SUBJECT SAFETY ...................................................................................................... 45 

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10.1 
ADVERSE EVENT MONITORING................................................................................... 45 
10.2 
DEFINITIONS OF ADVERSE EVENTS............................................................................ 45 
10.2.1 
Adverse event .............................................................................................................. 45 
10.2.2 
Serious adverse event ................................................................................................... 46 
10.2.3 
Adverse event of special interest..................................................................................... 46 
10.2.4 
Hypoglycemia .............................................................................................................. 46 
10.2.4.1 Definitions and reporting for hypoglycemia and severe hypoglycemia ................................... 46 
10.2.4.2 Non-severe hypoglycemic episodes................................................................................. 47 
10.2.4.3 Severe hypoglycemic episodes ....................................................................................... 47 
10.2.4.4 Guidelines for treating hypoglycemia................................................................................ 48 
10.2.5 
Cough......................................................................................................................... 48 
10.3 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ...................... 48 
10.3.1 
General guidelines for reporting adverse events ................................................................ 48 
10.3.2 
Guidelines for reporting SAEs ......................................................................................... 49 
10.3.3 
Guidelines for reporting adverse events of special interest .................................................. 50 
10.4 
OBLIGATIONS OF THE SPONSOR ................................................................................ 50 
11 
HANDLING OF SUBJECT WITHDRAWAL ...................................................................... 51 
11.1 
LIST OF TREATMENT WITHDRAWAL CRITERIA............................................................. 51 
11.2 
REASONS FOR TREATMENT WITHDRAWAL ................................................................. 51 
11.3 
TREATMENT WITHDRAWAL FOLLOW-UP PROCEDURE ................................................ 51 
12 
STUDY PROCEDURES ................................................................................................ 53 
12.1 
VISIT SCHEDULE ........................................................................................................ 53 
12.1.1 
Screening period .......................................................................................................... 53 
12.1.2 
PK assessment period (Visit 2) ....................................................................................... 54 
12.1.3 
Dose titration period ...................................................................................................... 56 
12.1.3.1 Telephone contact (Visits 3, 4, and 5) .............................................................................. 57 
12.1.3.2 Clinical site visits (Visits 6, 9, and 12)............................................................................... 57 
12.1.3.3 Telephone contact (Visits 7, 8, 10, 11, 13, and 14) ............................................................. 58 
12.1.3.4 End of titration (Visit 15) ................................................................................................. 58 
12.1.3.5 Follow-up (Visit 16) ....................................................................................................... 59 
12.1.6 
Early termination........................................................................................................... 59 
12.2 
STUDY RECORD KEEPING .......................................................................................... 60 
12.2.1 
Site essential documents ............................................................................................... 60 
13 
STATISTICAL CONSIDERATIONS ................................................................................ 62 
13.1 
DETERMINATION OF SAMPLE SIZE ............................................................................. 62 
13.2 
SUBJECT DESCRIPTION ............................................................................................. 64 
13.2.1 
Disposition, demographics, and baseline characteristics of subjects ..................................... 64 

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13.3 
ANALYSIS POPULATION.............................................................................................. 64 
13.3.1 
Safety population .......................................................................................................... 64 
13.3.2 
Pharmacokinetics population .......................................................................................... 64 
13.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .................................................... 64 
13.4.1 
Subject demographic characteristics, medical history, and diagnoses ................................... 64 
13.4.2 
Baseline pharmacodynamic parameters ........................................................................... 65 
13.4.3 
Baseline safety parameters ............................................................................................ 65 
13.5 
EXTENT OF STUDY TREATMENT EXPOSURE AND COMPLIANCE.................................. 65 
13.6 
PRIOR/CONCOMITANT MEDICATION/THERAPY............................................................ 65 
13.7 
ANALYSIS OF PHARMACODYNAMIC VARIABLES .......................................................... 65 
13.8 
ANALYSIS OF SAFETY DATA ....................................................................................... 65 
13.9 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS .................................................. 66 
13.10 
INTERIM ANALYSIS ..................................................................................................... 66 
14 
ETHICAL AND REGULATORY CONSIDERATIONS......................................................... 67 
14.1 
ETHICAL AND REGULATORY STANDARDS................................................................... 67 
15 
STUDY MONITORING AND QUALITY ............................................................................ 68 
15.1 
INVESTIGATOR QUALITY AND REGULATORY RESPONSIBILITIES ................................. 68 
15.1.1 
Protocol deviations........................................................................................................ 68 
15.2 
SPONSOR QUALITY ASSURANCE AND REGULATORY RESPONSIBILITIES .................... 68 
15.3 
DATA MONITORING COMMITTEE ................................................................................. 69 
15.4 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE ........................................................................................................................ 69 
15.5 
CLINICAL STUDY RESULTS ......................................................................................... 69 
16 
BIBLIOGRAPHIC REFERENCES................................................................................... 70 
17 
INVESTIGATOR’S SIGNATURE .................................................................................... 71 
18 
APPENDICES.............................................................................................................. 72 
18.1 
APPENDIX A ............................................................................................................... 72 
18.2 
APPENDIX B ............................................................................................................... 72 
18.3 
APPENDIX C - PHASE 3 STUDY (PART 2 OF THE AFREZZA PEDIATRIC 
DEVELOPMENT PROGRAM) ........................................................................................ 72 

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3 
LIST OF ABBREVIATIONS 
AE 
: 
adverse event 
AESI 
: 
adverse event of special interest 
AUC 
: 
area under the serum concentration versus time curve extrapolated to 
infinity 
AUC0-tlast 
: 
area under the baseline-corrected concentration-time curve from time 0 to 
the last measurable concentration 
CL/F 
: 
apparent total body clearance 
Cmax 
: 
maximum observed concentration after correction for baseline 
CSR 
: 
clinical study report 
DMC 
: 
data safety monitoring committee 
e-CRF 
: 
electronic case report form 
FDA 
: 
Food and Drug Administration (USA) 
FDKP 
: 
fumaryl diketopiperazine 
FEV1 
: 
forced expiratory volume in 1 second 
GCP 
: 
Good Clinical Practice 
HbA1c 
: 
glycated hemoglobin A1c 
ICH 
: 
International Council for Harmonisation 
IMP 
: 
investigational medicinal product 
ISPAD 
: 
International Society for Pediatric and Adolescent Diabetes 
MDI 
: 
multiple daily injections 
NHANES 
: 
National Health and Nutrition Examination Survey 
NIMP 
: 
non-investigational medicinal product 
PK 
: 
pharmacokinetic(s) 
RAA 
: 
rapid-acting analog 
SAE 
: 
serious adverse event 
SAP 
: 
statistical analysis plan 
SC 
: 
subcutaneous 
SDTotal 
: 
total standard deviation 
SMBG 
: 
self-monitored blood glucose 
T1DM 
: 
type 1 diabetes mellitus 
tmax 
: 
time to Cmax 
Vss/F 
: 
apparent volume of distribution 

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4 
INTRODUCTION AND RATIONALE 
 
4.1 
INTRODUCTION 
In type 1 diabetes mellitus (T1DM), the therapeutic objective is to optimally control blood 
glucose levels and this objective is fundamentally the same in all subjects with T1DM. However, 
individual circumstances and needs dictate what those optimal levels should be. Children and 
adolescents with T1DM are dependent on insulin for survival (1), (2), (3), (4). Children and 
adolescents experience phases of growth and pubertal development associated with substantial 
changes in metabolism and, consequently, insulin requirements (5), (6). 
 
AFREZZA® inhalation powder (hereafter referred to as AFREZZA®) consists of recombinant 
human insulin adsorbed onto fumaryl diketopiperazine (FDKP), a novel excipient which, at 
acidic pH, self-assembles into particles, and polysorbate 80. AFREZZA® is administered by oral 
inhalation using a breath-powered inhaler. AFREZZA® particles have a median diameter of 
approximately 2 to 2.5 µm, a size appropriate for inhalation into the lung. Following inhalation, 
AFREZZA® particles dissolve immediately at the physiologic pH of the lung, and insulin and 
FDKP are absorbed systemically. 
 
AFREZZA® is currently available in cartridges labeled as “4 units”, “8 units”, and “12 units”. 
The actual contents are 10 units human insulin in a “4 unit cartridge”, 20 units in an “8 unit 
cartridge”, and 30 units in a “12 unit cartridge”. 
 
AFREZZA® received Food and Drug Administration (FDA) approval for the treatment of adults 
18 years or older with T1DM or type 2 diabetes. In subjects with T1DM, AFREZZA® must be 
used with a long-acting basal insulin formulation. After administration of AFREZZA® in adults, 
the maximum serum insulin concentration occurs in approximately 12 to 15 minutes (versus 45 
to 60 minutes for rapid-acting analog [RAA] insulin via subcutaneous [SC] route) and returns to 
near baseline levels in approximately 180 minutes (versus about 5 hours for RAA) (7). 
 
Because of its more rapid kinetics, AFREZZA® may be potentially more useful as a first-phase 
prandial insulin replacement than injectable prandial insulins. Basing AFREZZA® dosing on 
self-monitored blood glucose (SMBG) readings done 120 to 150 minutes post-dose takes both 
the pre-meal glucose and the rise of blood glucose after a meal into account, and represents a new 
treatment and monitoring paradigm. Postprandial or “follow-on” AFREZZA® dosing following 
meals based on these postprandial SMBG readings may also offer the possibility to correct 
postprandial glucose elevations without the “stacking” of insulin. 
 
4.2 
RATIONALE 
MKC-TI-155 Part 1 is designed to assess the pharmacokinetics (PK), safety, and tolerability of 
AFREZZA® in children with T1DM ages 4 to 17 years who are on a stable regimen of 
basal-bolus insulin therapy administered by multiple daily injections (MDI). The study is 
intended to gain initial experience with AFREZZA® regarding the ability to dose-titrate in 
children. The data from this study will help determine the appropriate age range for inclusion, 

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and recommended dosing for a 1-year pediatric efficacy and safety study (MKC-TI-155 Part 2). 
The study design for Part 2 is in development (Section 18.3– Appendix C). 
 
 
4.3 
POTENTIAL BENEFITS 
The potential benefits of AFREZZA® over current treatment modalities with SC insulin include 
an improved compliance to treatment and a reduced incidence of hypoglycemia with similar 
overall glycemic control as assessed by glycated hemoglobin A1c (HbA1c) levels. 
 
 
4.4 
IMPORTANT POTENTIAL RISKS AND ASSESSMENT PLAN 
Safety of AFREZZA® has not been evaluated in children. The potential risk(s) of AFREZZA® 
based on the results of the studies done in adults may include the following (Table 1): 
 
Table 1 
Risk and Assessment/Mitigation plan 
 
Risk 
Assessment/mitigation plan 
Important Identified risks 
Bronchospasm in patients with chronic obstructive 
pulmonary disease 
The long-term safety and efficacy of AFREZZA® in 
subjects with chronic lung disease has not been 
established. Acute bronchospasm has been observed in 
subjects with asthma and chronic obstructive pulmonary 
disease (COPD) using AFREZZA®. Because of the risk 
of acute bronchospasm, AFREZZA® is contraindicated 
in subjects with chronic lung disease such as asthma or 
COPD. The FDA-approved label has a boxed warning 
explaining the risk of acute bronchospasm in subjects 
with chronic lung disease. 
Subjects with asthma or any other clinically important 
pulmonary disease will not be enrolled in the study. 
Severe hypoglycemia 

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Risk 
Assessment/mitigation plan 
In T1DM, the incidence of mild/moderate hypoglycemia 
was significantly lower in TI Inhalation Powder-treated 
subjects than in those treated with sc insulin comparator. 
The incidence of severe hypoglycemia was comparable 
between treatment groups (24.2% for TI Inhalation 
Powder and 28.3% for sc insulin comparator). Event 
rates for severe hypoglycemia were also comparable 
between the 2 groups (5.63 per 100 subject-month and 
6.39 per 100 subject- month, respectively). Event rates 
per 100 subject-month for mild/moderate and severe 
hypoglycemia were not significantly different between 
the 2 groups. 
Blood glucose will be monitored using self-monitored 
blood glucose. 
Dose titration and supplement dose instruction will be 
given to subjects. 
Hyperglycemia during initiation of treatment 
During the clinical development program, some subjects 
treated with TI Inhalation Powder presented with events 
of hyperglycemia. Most of these events were reported 
during the first 4 weeks of treatment initiation and were 
associated with insufficient titration. As is the case 
during initiation of any insulin therapy, blood glucose 
concentrations should be closely monitored on an 
individual basis and dose adjustments should be made as 
necessary during initiation of TI Inhalation Powder. 
Blood glucose will be monitored using self-monitored 
blood glucose. 
Dose titration and supplement dose instruction will be 
given to subjects. 
Important potential risks 
Diabetic Ketoacidosis 
In clinical studies in adults with type 1 diabetes mellitus, 
diabetic ketoacidosis was more common in subjects 
receiving AFREZZA® (0.43%; n=13) than in subjects 
receiving comparators (0.14%; n=3). In subjects at risk 
for diabetic ketoacidosis, such as those with an acute 
illness or infection, increase the frequency of glucose 
monitoring and consider delivery of insulin using an 
alternate route of administration if indicated. 
Blood glucose will be monitored using self-monitored 
blood glucose. 
Dose titration and supplement dose instruction will be 
given to subjects. 
Lung Cancer 

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Risk 
Assessment/mitigation plan 
In clinical studies in adults, 2 cases of lung cancer, 1 in 
controlled studies and 1 in uncontrolled studies (2 cases 
in 2750 subject-years of exposure), were observed in 
participants exposed to AFREZZA®, while no cases of 
lung cancer were observed in comparators (0 cases in 
2169 subject-years of exposure). In both cases, a prior 
history of heavy tobacco use was identified as a risk 
factor for lung cancer. Two additional cases of lung 
cancer (squamous cell) occurred in non-smokers 
exposed to AFREZZA® and were reported by 
investigators after clinical study completion. These data 
are insufficient to determine whether AFREZZA® has 
an effect on lung or respiratory tract tumors. 
Cotinine is test at screening as part of entry criteria and 
monitored throughout the study. 
Dyspnea 
Dyspnea is an uncommon AE occurring in 1.7% and 
0.1% of TI Inhalation Powder subjects and comparator- 
treated subjects with T1DM, respectively, and in 1.2% 
and 0.4% of TI Inhalation Powder and comparator- 
treated subjects with T2DM, respectively. A relatively 
higher incidence of dyspnea in TI Inhalation Powder- 
treated subjects may have been influenced by the open- 
label design of these trials. It is possible that subjects 
receiving an inhaled product were more self-aware and 
reported more signs and symptoms than did those on 
usual sc injection or oral treatments. 
All adverse events will be collected and monitored 
throughout the study 
Hyperglycemia during acute illness or change of 
treatment 
TI Inhalation Powder may be used during intercurrent 
illnesses, including upper respiratory tract infection. At 
such times, more frequent monitoring of blood glucose 
concentrations and dose adjustment may be required. If 
administration by inhalation is not feasible, substitution 
with an injectable insulin may be needed. It  is  
important that a patient’s insulin be continued. Transfer 
from  TI  Inhalation  Powder  treatment  to  other insulin 
therapies  requires  close  monitoring  of  blood  glucose 
Blood glucose will be monitored using self-monitored 
blood glucose. 
Dose titration and supplement dose instruction will be 
given to subjects. 

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Risk 
Assessment/mitigation plan 
concentrations to reduce the risk of hypoglycemia or 
hyperglycemia during the transition period. These 
changes should be made under close medical 
supervision and the frequency of blood glucose 
monitoring should be increased. Concomitant oral 
antidiabetic treatment may need to be adjusted. 
Additional safety consideration: 
Decline in FEV1 
In clinical studies excluding subjects with chronic lung 
disease and lasting up to 2 years, AFREZZA® treated 
subjects experienced a small (40 mL [95% confidence 
interval (CI): -80, -1]) but greater forced expiratory 
volume in 1 second (FEV1) decline than comparator- 
treated subjects. The FEV1 decline was noted within the 
first 3 months, and persisted for the entire duration of 
therapy (up to 2 years of observation). In this 
population, the annual rate of FEV1 decline did not 
appear to worsen with increased duration of use. The 
effects of AFREZZA® on pulmonary function for 
treatment duration longer than 2 years have not been 
established. 
To enter the study, subjects must have 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, and forced 
vital capacity (FVC) ≥70% of NHANES III predicted 
for children ≥8 years of age or Wang predicted for 
children <8 years of age. 
Spirometry (FEV1) will be done to assess pulmonary 
function at the screening visit and at 5 time points during 
pharmacokinetic 
assessment 
before 
and 
after 
AFREZZA® dose at Visit 2 to evaluate any acute change 
in lung function after dosing. In addition, FEV1 
assessment will take place at Visits 9, 15, and the follow 
up visit (Visit 16), and/or Early Termination Visit. 

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5 
STUDY OBJECTIVES 
The objectives of the study, MKC-TI-155 Part 1, are to: 
 
• Assess the safety and tolerability of AFREZZA® in children ages 4 to 17 years with 
T1DM 
• Assess PK following a prandial dose of AFREZZA® in children ages 4 to 17 years with 
T1DM 
• Assess the ability to titrate the prandial and supplemental doses of AFREZZA® at each 
meal using postprandial SMBG values obtained 120 to 150 minutes after each prandial 
dose of AFREZZA® in children ages 4 to 17 years with T1DM 

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6 
STUDY DESIGN 
 
6.1 
DESCRIPTION OF THE PROTOCOL 
MKC-TI-155 Part 1 will be a single-arm, multi-center, open-label, uncontrolled study to evaluate 
PK, safety, and ability to titrate AFREZZA® in children ages 4 to 17 years with T1DM, who were 
previously on a regimen of basal-bolus insulin therapy administered by MDI. 
 
The structure of the study is as follows: 
 
• Single dose PK at breakfast 
• 4-week titration period starting at lunch after PK evaluation 
 
On Day 1, subjects will receive a single dose of AFREZZA® prior to PK sampling. There will be 
3 different doses of AFREZZA® for the PK study. The AFREZZA® dose (4, 8, or 12 units) will 
be based on the dose of SC RAA that the subject would usually receive with breakfast (Section 
8.1.3). After this starting dose, each subject will be titrated with AFREZZA® TI according to the 
titration rules given. 
 
The study will begin with Cohort 1 then proceed to Cohort 2 and Cohort 3 in parallel. Approximately 46 
subjects will be enrolled into 3 age cohorts: 
• Cohort 1: 13 to 17 years; approximately 18 subjects distributed across 4, 8, and 12 unit 
starting dose groups. Before proceeding to subsequent cohorts, at least 14 subjects must 
be dosed (i.e., complete PK Visit 2). Of those, at least 6 subjects must receive at least the 8 
unit dose. 
• Cohort 2: 8 to 12 years; approximately 14 subjects distributed across 4 ,8 and 12 unit 
starting doses, as derived from the insulin:carb ratio – Figure 1.The sample size may be 
adapted after evaluating the PK data from Cohort 1. 
• Cohort 3: 4 to 7 years; approximately 14 subjects will be treated and assessed for 
AFREZZA® distributed across 4, 8, and 12 unit starting doses, as derived from the insulin:carb 
ratio table – Figure 1.. The sample size may be adapted after evaluating the PK data from 
Cohort 1 and Cohort 2. 
 
 
6.2 
STOPPING RULES 
Administration of AFREZZA® in any dose group(s) of an age cohort may be halted if the 
Sponsor or data safety monitoring committee (DMC) considers a dose group or age cohort to be 
unsafe or that it is unreasonable to continue. 
 
The study may also be stopped if the Sponsor or DMC considers it not appropriate to proceed to 
the next age cohorts based on safety, PK, or titration data. 

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6.3 
DURATION OF STUDY PARTICIPATION FOR EACH SUBJECT 
The study consists of: 
 
• Up to a 3-week screening period 
• PK assessment period: 1 day, after a single dose of AFREZZA® 
• Dose titration period: approximately a 4-week period with multiple daily doses of 
AFREZZA® 
• A follow-up visit will occur approximately 1 week after the end of AFREZZA® 
treatment for safety assessments (duration of 1 day) 
 
The total duration of the study through the 4-week titration period and follow-up will be 
approximately 6 to 8 weeks per subject. 
 
 
6.4 
DETERMINATION OF END OF CLINICAL STUDY (ALL SUBJECTS) 
The end of the clinical study is defined as the day the last subject completed his/her last visit 
planned in the protocol. 
 
 
6.5 
INTERIM ANALYSIS 
An interim analyses will be conducted on a cohort by cohort basis as each cohort completes PK 
and 4-week Titration Phase of this protocol. 
 
Pharmacokinetics and safety data for Cohort 1 will be reviewed on a rolling basis by the Sponsor 
and the DMC in order to allow enrollment into Cohorts 2 and 3 as described in Section 6.1. 

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7 
SELECTION OF PARTICIPANTS 
 
7.1 
NUMBER OF SUBJECTS PLANNED 
Approximately 46 subjects will be enrolled in Part 1 of the study (18 subjects for 13 to 17-year- 
old cohort, 14 subjects for 8 to 12-year-old cohort, and 14 subjects for 4 to 7-year-old cohort). 
 
7.2 
INCLUSION CRITERIA 
Eligible subjects must meet all the following inclusion criteria for Part 1 of the study: 
 
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 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 SMBG values between 80 and 250 mg/dL for 5 of 7 documented 
daily readings obtained in the week prior to Visit 2 (reading 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. 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 (8), (9); 
 
11. Forced vital capacity ≥70% of NHANES III predicted for children ≥8 years of age or Wang 
predicted for children <8 years of age (8), (9); 
 
12. Subjects of childbearing potential must use “highly effective” methods of contraception. 
These include, for example, a state after surgical sterilization, hormonal intrauterine devices 
(coil), oral hormonal contraceptives, sexual abstinence or a surgically sterilized partner. 

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“Highly effective” methods are considered those with a low failure rate (i.e., less than 1% 
undesired pregnancies per year). During the entire trial females of childbearing potential 
must use two contraceptive methods which are independent from each other, e.g. an 
intrauterine contraceptive coil or oral hormonal contraceptive plus a vaginal diaphragm or a 
condom coated with a spermicidal substance. The use of a condom in combination with 
spermicidal creams, however, is not sufficiently reliable. 
 
7.3 
EXCLUSION CRITERIA 
 
Subjects who have met all the above inclusion criteria listed in Section 7.2 will be screened for 
the following 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 
https://www.cdc.gov/growthcharts/html_charts/bmiagerev.htm 
 
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 to 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 

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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. 

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8 
STUDY TREATMENTS 
 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT 
 
8.1.1 AFREZZA (Insulin Human) inhalation powder and inhaler 
AFREZZA consists of single-use plastic cartridges filled with a white powder containing insulin, 
which is administered via oral inhalation using the AFREZZA Inhaler only. 
 
AFREZZA Inhalation Powder is a dry powder supplied as 4, 8, or 12 unit cartridges. 
 
The AFREZZA Inhaler is breath-powered by the subject. When the subject inhales through the 
device, the powder is aerosolized and delivered to the lung. 
 
 
8.1.2 AFREZZA inhalation training 
At Visit 2, subjects will receive AFREZZA inhalation training using the BluHale system, which 
consists of an AFREZZA inhaler, an empty cartridge, and a pressure-sensing jacket that slips 
onto each inhaler. The jacket is designed for repeated use on multiple inhalers and does not 
require sterilization between subjects. Therefore, subjects may use the same jacket during 
training. Empty cartridges will be provided for training and practice. Subjects must demonstrate 
the ability to adequately perform the inspiratory maneuver utilizing the empty cartridge to 
continue in the study. 
 
If, in the opinion of the Investigator, a subject cannot adequately perform the inspiratory 
maneuver after second repeated training, the subject will be withdrawn from the study. 
 
 
8.1.3 Initial dose for PK assessment 
Dosing is individualized for each subject. For PK assessment, the AFREZZA dose for the 
breakfast will be calculated based on the dosage chart (Figure 1). AFREZZA should be taken 
under Investigator’s supervision, immediately before the first bite of breakfast. The starting and 
ending time of breakfast will be recorded. 
 
A standardized meal will be provided to the subjects for their first dose of 
Afrezza. Carbohydrate should account for 50% of the meal content up to a maximum of 70 
grams of carbohydrate. Each cohort will likely fall in the following ranges for grams of 
carbohydrate at the initial breakfast: 
Cohort 1: 50 - 70g; 
Cohort 2: 40 - 60g; and, 
Cohort 3: 30 - 40g. 
The appropriate dose of Afrezza will be determined by using the subjects insulin/carbohydrate 
ratio in conjunction the with carb content of the meal per Figure 1. 

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Figure 1 
Dosage chart to determine AFREZZA unit cartridges 
 
Breakfast 
Carbs (g) 
Breakfast Carbohydrate Ratio (units of insulin/g Carb) 
1/5* 
1/7 
1/10 
1/12 
1/15 
40 
12 
8 
4 
4 
4 
50 
16** 
8 
8 
4 
4 
60 
16** 
12 
8 
8 
4 
70 
20** 
12 
12 
8 
8 
*Consider dosing at 1:7 ratio recommendation in insulin resistant subjects 
**Consider lowering carbohydrate intake since supplemental dose (second cartridge inhalation) 
may be indicated. 
 
 
 
8.1.4 Dose titration 
AFREZZA® should be taken at the beginning of the meal. An individualized postprandial dose 
will be administered 120 to 150 minutes after the initial dose if the SMBG exceeds 180 mg/dL. 
For dose titration, initial doses for lunch and dinner on Day 1 will also be determined based on 
the conversion table (Figure 1). 
 
Throughout the study, doses for each of the following 3 days’ meals will be titrated at the end of 
the current 3-day period based on the median SMBG (120 to 150 minutes post-dose) (Table 2). 
In other words, the subject will measure his/her 120 to 150 minute post-lunch SMBG for 3 days. 
The median dose (not the average dose, but the middle – between highest and lowest - of the 3 
test values) will be used for dose adjustment per Table 2. This new dose should be used for the 
next 3 days. This process will be duplicated for both the post breakfast and dinner SMBG 
values. 
 
 
Table 2 
Recommended AFREZZA dose adjustments 
 
Median 120-150 minute PPG value (mg/dL) 
AFREZZA dose adjustment for that meal 
<110 
Decrease dose by 4 units 
110-180 
Maintain current dose 
>180 
Increase dose by 4 units 
 
8.1.5 Postprandial dosing (follow-on doses) 
If a subject’s SMBG is greater than or equal to 180 mg/dL, 120 to 150 minutes after the prandial 
dose, the subject should take an additional, individualized postprandial or follow-on dose. The 
dose should be sufficient to reduce blood glucose below 120 mg/dL based on the subject’s 
individualized dose-response. 
 
 
8.1.6 Additional dosing of AFREZZA for snacks 
Additional AFREZZA dosing may or may not be required with snacks. The need for a dose and 
the size of the dose depends on the size and content of the snack and the individual’s 
dose-response. 

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8.1.7 Basal insulin dose adjustment 
The basal insulin dose should be adjusted, as necessary, to achieve a fasting SMBG of 
80 to 130 mg/dL. 
 
 
8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
During the study, all subjects will receive daily injections of basal long-acting insulin. 
 
 
8.3 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS 
In MKC-TI-155 Part 1, subjects will be assigned to their cohort based on their age. 
 
8.4 
PACKAGING AND LABELING 
 
AFREZZA will be provided in 4, 8, and 12 unit cartridges with AFREZZA inhalers. 
Empty AFREZZA cartridges are provided for training with the AFREZZA inhaler. 
AFREZZA will be packaged and labeled per the FDA-approved prescribing information and for 
clinical trial use. 
 
 
8.5 
STORAGE CONDITIONS AND SHELF LIFE 
AFREZZA should be refrigerated (2ºC to 8ºC or 36ºF to 46ºF). When in transit by a commercial 
carrier, the product may be shipped refrigerated or frozen (–25ºC to –15ºC or –13ºF to 5ºF). See 
Site Operations Manual for further information. 
 
 
8.5.1 AFREZZA inhalation powder 
When not in use: it should be stored in refrigerator at 2°C to 8°C (36°F to 46°F). Sealed 
(unopened) foil packages may be stored at 2°C to 8°C (36°F to 46°F) until the expiration date. If 
a foil package is not refrigerated, the contents must be used within 10 days. 
 
When in use: it should be stored at room temperature at 25°C (77°F), excursions permitted to 
15°C to 30°C (59°F to 86°F). Sealed (unopened) blister cards and strips must be used within 10 
days, and opened strips must be used within 3 days. 
 
 
8.5.2 AFREZZA inhaler 
Store at 2°C to 25°C (36°F to 77°F): excursions permitted. Inhaler may be stored refrigerated, 
but should be at room temperature before use. 

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8.5.3 Handling 
Before use, cartridges should be at room temperature for 10 minutes. 
 
 
8.6 
RESPONSIBILITIES 
 
The Investigator, the clinical site pharmacist, or other personnel allowed to store and dispense 
investigational medicinal product (IMP) will be responsible for ensuring that the IMP used in 
the clinical study is securely maintained in a temperature-controlled environment as specified by 
the Sponsor. 
 
All IMP shall be dispensed in accordance with the protocol, and it is the Investigator’s 
responsibility to ensure that up to date and accurate records of IMP issued and returned are 
maintained. 
 
Any IMP-related quality issues should be recorded and reported to the Sponsor by the means of 
a procedure on product technical complaint forms (refer to Site Operations Manual). 
 
A potential defect in the quality of IMP provided by the Sponsor may initiate a recall procedure 
by the Sponsor. In this case, the Investigator will be responsible for promptly addressing any 
request made by the Sponsor to recall IMP and eliminate potential hazards. 
 
Under no circumstances will the Investigator supply IMP provided by the Sponsor to a third 
party, allow the IMP provided by the Sponsor to be used other than as directed by this clinical 
study protocol, or dispose of IMP provided by the Sponsor in any other manner. 
 
 
8.7 
CONCOMITANT TREATMENT 
A concomitant medication is any treatment used by the subject at the same time they are using 
the study IMP. Any treatment which is continued during the study and/or initiated or changed 
during the study must be recorded in source data and in the electronic case report form (e-CRF), 
including the name of the medication, indication for which the medication is being given, daily 
dosage, and duration of use. 
 
During the study, all subjects will receive daily injections of basal long-acting insulin. 
 
With the exception of ibuprofen and over the counter cold remedies, the use of any other 
concomitant medications (including herbal supplements) in the period from 2 weeks before the 
screening visit to the conclusion of the subject’s participation in this study should be discussed 
with the Sponsor’s medical monitor. 
 
Subjects who have an intercurrent illness (including respiratory tract infections) will be treated 
at the discretion of the Investigator or a designee. After consultation with the Sponsor medical 
monitor, the subject may be discontinued from the study treatment. 

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During intercurrent illnesses, including upper respiratory tract infection, it is important that a 
subject’s insulin be continued. At such times, more frequent monitoring of blood glucose 
concentrations and dose titration may be required. AFREZZA may be continued unless, in the 
judgment of the Investigator, temporary substitution with injectable insulin is needed. 
 
Drugs or herbal preparations known to modify glucose metabolism, that may, in the opinion of 
the Investigator, interfere with the clinical study results should be discussed with the Sponsor’s 
medical monitor. Dose adjustment and increased frequency of glucose monitoring may be 
required when AFREZZA is co-administered with drugs that may increase risk of hypoglycemia 
(ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, 
monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, 
somatostatin analogs [e.g., octreotide], and sulfonamide antibiotics). 
 
 
8.8 
TREATMENT ACCOUNTABILITY AND COMPLIANCE 
At each contact with the subject, either by telephone or during on-site visits, the Investigator or 
his/her delegate must ask the subject about administered doses of IMP and non-investigational 
medicinal product (NIMP). 
 
Treatment units are returned by the subject at each on-site visit. The Investigator or delegate has 
to inspect IMP remaining in the returned packs and compare it to the dosing records documented 
in the subjects’ diaries. Discrepancies have to be addressed with the subject for clarification of 
actual treatment administration. However, as subjects with T1DM require insulin, the level of 
glycemia as reflected by SMBG and HbA1c is a sensitive marker of adherence to insulin 
treatment. 
 
The Investigator or delegate fills the treatment log form per subject and records the dosing 
information on the appropriate page(s) of the e-CRF. 
 
The monitor will check the e-CRF data by comparing them with the subject’s diary entries, 
treatment log forms, and unused treatment kits. 
 
 
8.9 
RETURN AND/OR DESTRUCTION OF TREATMENTS 
Investigational medicinal product reconciliation must be performed at the site by the 
Investigator and the monitoring team using treatment log forms and documented on the center 
IMP inventory countersigned by the Investigator and the monitoring team. 
 
A written authorization for destruction will be given by the clinical study team once the IMP 
reconciliation is achieved. This destruction can be performed at site depending on IMP 
specificities and local requirements or IMP can be returned to the Sponsor for destruction. 

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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
All protocol-defined biological safety analysis, except SMBG, will be performed by a Central 
Laboratory. Detailed information on samples drawing, management, and analysis will be 
provided in a specific Central Lab Specifications (CLS). 
 
 
9.1 
PHARMACOKINETICS 
All insulin PK parameters will be based on baseline-corrected insulin concentration. The 
baseline insulin concentration due to residual basal insulin will be estimated from the pre-dose 
blood samples. Insulin concentrations will be determined by validated radioimmunoassay. The 
FDKP serum levels will be determined by LC-MS and anti-insulin antibodies will be determined 
by radioimmunoprecipitation assay. 
 
9.1.1 Sampling times 
The sampling times for blood collection can be found in the Flow Chart 1.2. 
 
9.1.2 Number of PK samples 
The number of samples per subject and by study is indicated in Table 3. 
 
 
Table 3 
Number of serum samples 
 
AFREZZA® insulin 
FDKP 
Anti-insulin antibody 
By subject 
14 
5 
2a 
Total for study 
(n subjects) 
14 × 46 = 644 
5 × 46 = 230 
2 × 46 = 92 
a. Anti-insulin antibody samples to be collected at screening and end of treatment/early termination. 
 
9.1.3 Sample handling procedure 
 
The sample handling procedure is summarized in Table 4. 
 
Special procedures for collection, storage, and shipment will be provided in the CLS. 

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Table 4 
Summary of handling procedures 
 
AFREZZA® Insulin 
FDKP 
Anti-insulin antibody 
Blood sample volume 
2 mL 
2 mL 
2 mL 
Serum aliquot split 
1 aliquot 
1 aliquot 
1 aliquot 
Serum storage conditions 
–70°C 
–70°C 
–20°C 
Serum shipment conditions 
Dry ice 
Dry ice 
Dry ice 
 
9.1.4 Bioanalytical methods 
 
A brief outline of the bioanalytical assay is provided in Table 5 below. 
 
Table 5 
Summary of bioanalytical methods 
 
Analyte 
AFREZZA® Insulin 
FDKP 
Anti-insulin antibody 
Matrix 
Serum 
Serum 
Plasma 
Analytical technique 
Radioimmunoassay 
LC-MS/MS 
Radioimmunoprecipitation 
Lower limit of 
quantification 
8 µU/mL 
1 ng/mL 
NA 
Assay volume 
100 µL serum 
200 µL serum 
250 µL plasma 
 
9.1.5 Pharmacokinetic parameters 
The following PK parameters will be calculated, using non-compartmental methods using 
baseline-corrected serum insulin concentrations obtained after AFREZZA single dose. The 
parameters will include, but may not be limited to, the following: 
 
• Insulin Cmax (maximum observed concentration after correction for baseline) 
• Insulin AUC0-tlast (area under the baseline-corrected concentration-time curve from time 0 
to the last measurable concentration) 
 
• Insulin tmax (time to reach Cmax) 
• Insulin AUC (area under the serum concentration versus time curve extrapolated to 
infinity) according to the following equation: 
 
AUC = AUClast + Clast/λz 
 
• Apparent total body clearance (CL/F) and apparent volume of distribution (Vss/F) 
calculated by standard non-compartmental methods 
 
• Fumaryl diketopiperazine elimination half-life (t1/2) 
 
9.2 
SAFETY 
 
9.2.1 Baseline demographic characteristics 
 
Baseline demographic characteristics at screening will consist of: 

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1. Age (years) 
 
2. Height (cm): should be measured when the subject’s shoes are off, feet together, and arms by 
the sides. Heels, buttocks, and upper back should also be in contact with the wall when the 
measurement is made. 
 
3. Body weight (kg): should be obtained with the subject wearing undergarments or very light 
clothing and no shoes, and with an empty bladder. The floor surface on which the scale rests 
must be hard and should not be carpeted or covered with other soft material. The same scale 
should be used throughout the study, and calibrated on a regular basis as recommended by 
the manufacturer. 
 
4. Body mass index 
 
5. Race and/or ethnicity 
 
6. Gender 
 
9.2.2 Medical history 
 
Medical history along with subject demographics will be obtained at screening, including history 
of diabetes (e.g., age at onset of diabetes, start and stop dates of previous insulin treatments, 
treatment name, dose(s), frequency and method of dose delivery, date of clinical diagnosis of 
T1DM). 
 
Determination of the relevance of the medical history, and its impact on subject eligibility, will 
be made by the Investigator or designee. The Investigator may consult with the Sponsor medical 
monitor if necessary. 
 
9.2.3 Screening assessment 
Informed Consent/Assent will be obtained prior to performing any screening procedures. The 
safety assessment at screening will be performed according to the Flow Chart 1.1 and will 
include: 
 
• Assessment of inclusion and exclusion criteria 
• Physical examination (at screening): full physical examination, including ear, nose, 
throat, lung and cardiac auscultation, recording of Tanner stages of pubertal development 
and excluding genitourinary and rectal examinations 
 
• Oral body temperature, body weight, and height 
• Vital signs (respiratory rate, sitting blood pressure, and pulse measurements) will be 
recorded with the subject in a sitting position for 5 minutes before the measurement is 
taken. 
 
• HbA1c 

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• Fasting serum C-peptide 
• Laboratory tests: 
o Serology tests: hepatitis B antigen, hepatitis C antibodies, anti-HIV-1 and anti-HIV-2 
antibodies 
 
o Anti-Insulin Antibody 
o Pregnancy test: females of childbearing potential 
o Urine cotinine 
o Urine drug screening: amphetamines/methamphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, and opiates 
 
o Alcohol breath or plasma test 
o Hematology: red blood cell count, hematocrit, hemoglobin, white blood cell count 
with differential count (neutrophils, eosinophils, basophils, monocytes, and 
lymphocytes), platelets 
 
o Biochemistry: 
1. Plasma/serum electrolytes: sodium, potassium, chloride, calcium, phosphorus, 
carbon dioxide 
 
2. Liver function: aspartate aminotransferase, alanine transaminase, alkaline 
phosphatase, total and conjugated bilirubin 
 
3. Renal function: blood urea nitrogen, creatinine, uric acid 
 
4. Metabolism: albumin, total proteins, total cholesterol, low-density lipoprotein, 
triglycerides 
 
5. Potential muscle toxicity: creatinine phosphokinase, lactate dehydrogenase 
 
o Urinalysis: albumin/creatinine ratio, ketones, glucose, erythrocytes, and leucocytes 
count, pH, urobilinogen, nitrates, specific gravity 
 
• A standard 12-lead electrocardiogram recorded after at least 10 minutes in a supine 
position 
 
• FEV1 testing: Spirometry (FEV1) will be done to assess pulmonary function. Another 
pulmonary function test may be done after consultation with a pediatric pulmonologist if 
the subject is unable to perform spirometry 
 
• Adverse events (AEs) spontaneously reported by the subject or observed by the 
Investigator will be monitored 
 
• Prior/concomitant medications reported by the subject or by the Investigator will be 

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recorded 
 
9.2.4 Safety assessment during the study 
 
Safety assessments during the study will be done according to the Flow Chart 1.1 and will 
include, but is not limited to: 
 
• Physical examination: the abbreviated physical examinations will include, but not limited 
to, general appearance, mental status, respiratory and cardiovascular systems, and other 
evaluations deemed appropriate by the Investigator for safety reasons 
 
• Body weight (kg) 
• Vital signs (respiratory rate, sitting blood pressure, and pulse measurements) will be 
recorded after the subject has been sitting for 5 minutes 
 
• Laboratory tests: 
o Urine pregnancy test: females of childbearing potential 
o Urine cotinine 
• Adverse events spontaneously reported by the subject or observed by the Investigator 
will be monitored 
 
• FEV1 testing: Spirometry will be done to assess pulmonary function. Another pulmonary 
function test may be done after the consultation of a pediatric pulmonologist if the 
subject is unable to perform spirometry 
 
• Concomitant medications reported by the subject or by the Investigator will be recorded 
 
9.2.5 Self-measured blood glucose (SMBG) 
Blood glucose values will be self-measured by the subject using the Sponsor-provided blood 
glucose meter and corresponding supplies (lancets, control solutions, test strips, etc). Subjects 
will enter their SMBG data in the Sponsor-provided e-Diary. 
 
Post-dose SMBG will be used to adjust the bolus insulin. The frequency of monitoring, including 
ad hoc values, can be adjusted by the Investigator. 
 
All SMBG values will be used by the Investigator to monitor glycemia. 
 
 
9.2.6 Mandatory SMBG 
 
9.2.6.1 Fasting pre-breakfast SMBG 
Fasting pre-breakfast SMBG will be measured daily during the study and used, among other 
things, to titrate basal insulin doses. 

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9.2.6.2 Routine SMBG monitoring 
In addition to performing fasting SMBG every morning before breakfast, subjects or parents will 
perform SMBG monitoring 120-150 minutes post-dose at each meal. AFREZZA® doses will be 
adjusted based on these measurements (Table 2). 
 
 
9.2.6.3 7-point SMBG profiles 
Once during the screening period in the week prior to the PK visit (Visit 2) and once per week 
during the treatment period 7-point glucose data (pre-meal and 120-150 minutes post-dose at 
breakfast, lunch, and dinner as well as at bedtime) will be obtained via SMBG readings. These 
data will be reviewed by the site and may be used to prescribe a regular supplemental post-meal 
AFREZZA® dose as per Section 8.1.5. 
On these days, the starting and ending time for each meal will be reported in the e-Diary and 
in the e-CRF. 
 
 
9.2.6.4 Self-monitored blood glucose during symptomatic hypoglycemia 
Whenever the subjects feel hypoglycemic symptoms, glucose should be measured by the subject 
(or others, if applicable) if possible. Subjects should be instructed to measure plasma glucose 
levels prior to carbohydrate intake/administration of glucose whenever symptomatic 
hypoglycemia is suspected, unless safety considerations necessitate immediate 
carbohydrate/glucose rescue prior to confirmation. 
 
Subjects have to document hypoglycemic events appropriately in their diaries and contact the 
Investigator as soon as possible following severe events for review and for decision on any 
necessary measures to be taken. 
 
All hypoglycemia episodes will be documented on the “hypoglycemia specific form” in the e- 
CRF. This includes all symptomatic hypoglycemia events and asymptomatic hypoglycemia. 
 
Hypoglycemia events fulfilling the criteria of a serious adverse event (SAE) will be documented 
on the SAE form in the e-CRF. 
 
 
9.2.7 Recording of SMBG into the e-CRF 
All mandatory SMBG readings will be recorded in the e-CRF. Subjects will record SMBG 
readings in the e-Diary. Refer to the Site Operations Manual regarding SMBG data upload. 
 
 
9.2.8 Recording of insulin doses into the e-CRF 
To assess the change in daily AFREZZA and basal insulin dose, appropriate documentation of 
administration times and doses in corresponding pages of the e-CRF is requested. 
 
Subjects will document the doses and times of administration of AFREZZA® and basal insulin in 
the e-Diary on a daily basis. 

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9.3 
OTHER ASSESSMENT 
Information on the ability to use the AFREZZA inhalation device will be collected in the e-Diary. 

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10 
SUBJECT SAFETY 
The Investigator is the primary person responsible for taking all clinically relevant decisions on 
safety issues. 
 
If judged necessary, the opinion of a specialist should be sought in a timely manner (e.g., acute 
renal failure, convulsions, skin rashes, angioedema, cardiac arrest, electrocardiographic 
modifications, etc). 
 
 
10.1 ADVERSE EVENT MONITORING 
All events will be managed and reported in compliance with all applicable regulations and 
included in the final clinical study report (CSR). 
 
 
10.2 DEFINITIONS OF ADVERSE EVENTS 
 
10.2.1 Adverse event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and which does not necessarily have to have a causal relationship with this treatment. An AE 
can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a drug, and does not imply any judgment about 
causality. 
 
• Mild = no modification of daily activities and does not require corrective/symptomatic 
treatment. 
 
• Moderate = hinders normal daily activities and/or requires corrective/symptomatic 
treatment. 
 
• Severe = prevents daily activities and requires corrective/symptomatic treatment. 

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10.2.2 Serious adverse event 
 
A SAE is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect, or 
• Is a medically important event: 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
definition above. Note: Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias, convulsions, that do not result in 
inpatient hospitalization, or the development of drug dependence or drug abuse. 
 
10.2.3 Adverse event of special interest 
An AESI is an adverse event (serious or nonserious) of scientific and medical concern, specific 
to the IMP or program, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor may be appropriate. Such events may require further investigation in 
order to characterize and understand them. 
 
For AESIs, the Sponsor must be informed immediately (i.e., within 24 hours), per SAE 
notification guidelines described in Section 10.3.2, even if not fulfilling a seriousness criterion as 
an SAE. 
 
The following adverse events are considered AESIs: 
 
• Acute bronchospasm 
• Clinically relevant decline in pulmonary function 
• Hypersensitivity reactions, including anaphylaxis, which can occur with insulin products, 
including AFREZZA 
 
• Diabetic ketoacidosis 
 
10.2.4 Hypoglycemia 
 
10.2.4.1 Definitions and reporting for hypoglycemia and severe hypoglycemia 
The general symptoms of hypoglycemia most subjects experience include 1 or more of the 
following: headache, dizziness, general feeling of weakness, drowsiness, confusion, pallor, 

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irritability, trembling, sweating, lightheadedness, shaky, increased appetite, rapid heartbeat and a 
cold, clammy feeling. In severe cases, seizure, loss of consciousness, or even coma can occur. 
 
The definitions used in this protocol are based on the Clinical Practice Consensus Guidelines 2014 
of the International Society for Pediatric and Adolescent Diabetes (ISPAD) (10). In the adult 
population, severe hypoglycemia is defined as an event requiring assistance of another person to 
actively administer carbohydrates, glucagon, or take other corrective actions. In childhood, this 
definition is problematic as most young children require assistance to correct even mild 
hypoglycemia. As a result, in the pediatric population, severe hypoglycemia is generally defined 
as an event associated with severe neuroglycopenia usually resulting in loss of consciousness, 
coma, or seizure. 
 
 
10.2.4.2 Non-severe hypoglycemic episodes 
Non-severe hypoglycemia is defined according to the ISPAD Clinical Practice Consensus 
Guidelines 2014 (10) as follows: 
 
• SMBG levels <70 mg/dL and/or 
• Symptoms of hypoglycemia that are relieved by the administration of carbohydrates 
All episodes of hypoglycemia that meet this definition of non-severe hypoglycemia are to be 
recorded in the e-Diary, and will be reported on the hypoglycemia page in the e-CRF. 
 
 
10.2.4.3 Severe hypoglycemic episodes 
Severe hypoglycemia in children is defined according to the ISPAD Clinical Practice Consensus 
Guidelines 2014 (10) as an event associated with a seizure, coma, or loss of consciousness and 
will be considered an SAE (see below). If glucose measurements are not available during such an 
event, the neurological recovery attributable to the restoration of glucose to normal will be 
considered sufficient evidence that the event was induced by a low glucose concentration. 
 
The following episodes of hypoglycemia require reporting in the AE page and safety 
complementary e-CRFs and the hypoglycemia e-CRF. This applies for: 
 
• Hypoglycemia associated with coma or loss of consciousness, or 
• Hypoglycemic seizure, or 
• Hypoglycemia that meets other conditions for an SAE, as defined under “Serious Adverse 
Event” in Section 10.2.2 
The Investigator will adjudicate episodes of hypoglycemia reported in the e-Diary that appear to 
meet the criteria for SAEs. If the Investigator judges that the episode is not an SAE, it will be 
corrected on a data clarification form in the e-Diary and will not be recorded in an SAE e-CRF. 

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10.2.4.4 Guidelines for treating hypoglycemia 
A subject exhibiting signs of hypoglycemia will be treated as appropriate by the Investigator, 
parent, or other caregiver. 
 
 
10.2.5 Cough 
Cough as an isolated symptom will be reported as an AE in the e-CRF. For cough associated with 
a defined clinical entity (e.g., upper respiratory tract infection), the appropriate diagnosis 
associated with the cough will be recorded in the AE e-CRF. 
 
 
10.3 OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
 
10.3.1 General guidelines for reporting adverse events 
All AEs, regardless of seriousness or relationship to IMP/NIMP, occurring between consent/assent 
and the end of the study will be recorded. 
 
AEs are to be recorded as defined by the protocol on the corresponding e-CRF for subjects who 
are enrolled and for those who fail screening. 
 
For screen failed subjects, recording in the e-CRF is only performed in case of an SAE occurring 
during the screening period or in case of an AE when some study-specific screening procedures 
expose the subject to safety risks. Whenever possible, diagnosis or syndrome should be reported 
instead of individual associated symptoms (e.g., record “Influenza” not fever, chills, etc). The 
Investigator should specify the date of onset, intensity (see definitions in Section 10.2.1), action 
taken with respect to IMP/NIMP, corrective treatment/therapy given, additional investigations 
performed, outcome, and Investigator’s opinion as to whether there is a reasonable possibility that 
the AE was caused by the IMP/NIMP. 
 
In order to ensure the safety of the subjects, the Investigator should take appropriate measures to 
follow all AEs until clinical recovery is complete and laboratory results have returned to normal, 
or until no further improvement is expected, or until death. Follow-up of the AE resolution/status 
will end at the follow-up visit. If necessary, SAEs will be followed beyond the last planned visit 
per protocol until resolution, no further improvement is expected, or death. Additional 
investigations of the SAE may be requested by the Sponsor. 
 
When treatment is prematurely discontinued, an early termination (ET) visit should be conducted 
as soon as possible. Laboratory, vital sign, or electrocardiogram abnormalities are to be recorded 
as AEs only if: 
 
• Laboratory and/or vital signs not specifically addressed elsewhere in the protocol change 
≥ 10 × the upper or the lower limits of normal and are undesired, and are a change from 
the pre-enrollment assessment values, and/or 
 
• Are symptomatic, and/or 

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• Are clinically significant 
• Require either corrective treatment or additional assessments, or a specialist consultation, 
and/or 
 
• Lead to IMP/NIMP discontinuation or modification of dosing, and/or 
• Meet criterion for an SAE, and/or 
• Are an AESI. 
 
10.3.2 Guidelines for reporting SAEs 
In the case of an SAE, the Investigator must immediately: 
 
• ENTER (within 24 hours) the SAE information in the appropriate screens of the e-CRF. 
The electronic data capture system will automatically send the notification to the safety 
team after approval by the Investigator within the e-CRF or after a standard delay. 
 
• SEND (by fax) copies of all procedures, examinations, and medications administered and 
the dates on which these were administered or performed. Care should be taken to ensure 
that the subject’s identity is redacted and the subject’s identifiers in the clinical study are 
properly mentioned on any copy of source document provided to the Sponsor. For 
laboratory results, include the laboratory normal ranges. 
 
PPD 24 hour safety hotline fax number: +1-888-529-3580 
 
+1-919-654-3836 
 
• All further data updates of the subject’s SAE should be recorded in the e-CRF as it 
becomes available, along with further documentation of procedures, examinations, and 
medications administered. Laboratory data, concomitant medication, subject study status, 
etc. should be sent (by fax) to the safety team within 24 hours of knowledge. In addition, 
an effort should be made to further document SAE within the week (7 days) following 
initial notification. 
 
A back-up plan is used (using paper flow) when the e-CRF system does not work. 
 
Back-up plan 
 
• SEND (by fax) within 24 hours, the signed and dated page(s) corresponding to those in 
the CRF to PPD SAE report form collection along with all of the documentation 
requested above. Follow-up instruction (above) should be implemented either by back-up 
plan or e-CRF: 
 
PPD 24 hour safety hotline phone number: +1-888-483-7729 
PPD 24 hour safety hotline fax number: +1-888-529-3580 
+1-919-654-3836 

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Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
subject and considered by the Investigator to be caused by the IMP with a reasonable possibility 
should be reported to the safety team. 
 
10.3.3 Guidelines for reporting adverse events of special interest 
For AESIs, (see Section 10.2.3), the Sponsor is to be informed immediately (i.e., within 24 hours), 
as per the SAE notification guidelines described in Section 10.3.2, even if a seriousness criterion is 
not met. 
 
10.4 OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least possibly related to the IMP (suspected 
unexpected serious adverse reaction) to the Health Authorities and Institutional Review 
Boards as required and to the Investigators 
 
• All SAEs that are expected and at least possibly related to the IMPs to the Health 
Authorities, according to local regulations 
Any AE not listed as an expected event in the investigator’s brochure or in this protocol will be 
considered as unexpected. 
 
The Sponsor will report all safety observations made during the conduct of the study in the CSR. 

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11 
HANDLING OF SUBJECT WITHDRAWAL 
 
11.1 LIST OF TREATMENT WITHDRAWAL CRITERIA 
• The subject fails to comply with prescribed dosing of the study treatment or any 
study-related procedures after multiple attempts made to obtain compliance. 
 
• An AE or SAE occurs that could affect the subject’s safety or well-being if treatment is 
continued. 
 
• The subject begins using another investigational product, the Investigator and study 
monitors should discuss together whether the added agent requires AFREZZA 
discontinuation. 
 
• The subject becomes pregnant. 
• The subject begins smoking. 
• Major protocol violations that, upon consultation between the Investigator and the 
medical monitor, are deemed to affect subject safety or the integrity of the study data. 
 
11.2 REASONS FOR TREATMENT WITHDRAWAL 
The subject, parents, or legally authorized representatives can withdraw from the study at any 
time, without giving a reason. The Investigator can also decide if it is in the subject’s best 
interest to discontinue participation in the study. The Investigator should discuss the subject’s 
withdrawal with a medical monitor beforehand, if possible. If not possible, the Investigator 
should discuss the withdrawal with a medical monitor within 24 hours of being informed of the 
decision. 
 
 
11.3 TREATMENT WITHDRAWAL FOLLOW-UP PROCEDURE 
For subjects who withdraw from the study for any reason, the Investigator will advise them 
about other treatment alternatives. All study treatment withdrawals should be recorded by the 
Investigator on the appropriate e-CRF screens. 
 
Subjects are to be assessed using the procedure planned for the Early Termination visit. For a 
complete list of procedures scheduled for the ET visit please refer to the Flow Chart 1.1. 
 
For any subject who fails to return to the site, the Investigator should make every effort to 
re-contact the subject (e.g., contact the subject’s family or private physician, review available 
registries or health care database), and to determine their health status, including at least his/her 
vital status. Attempts to contact the subject must be documented in the subject’s study records 
(e.g., times and dates of attempted telephone contact, receipt for sending a registered letter, and 
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Subjects withdrawn from the study must not be re-included in the study. Their inclusion 
numbers must not be reused. 

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12 
STUDY PROCEDURES 
 
12.1 VISIT SCHEDULE 
MKC-TI-155 Part 1 consists of: 
 
• A 7 to 21-day screening period 
• A 1-day in-clinic PK assessment 
• A 28-day outpatient study of the safety and ability to titrate AFREZZA in children ages 4 
to 17 years with T1DM 
 
All visits to the clinical site should take place in the morning at approximately the same time. For 
telephone-call visits, the subject is called by the Investigator or qualified designee at a 
pre-scheduled time. 
 
A timeframe of ±1 days using the day of Visit 2 as reference is acceptable. The post-treatment 
follow-up Visit 16 should occur 1 week ± 3 days after the last treatment. 
 
If a visit date is changed, the next visit should take place according to the original schedule. 
 
If a subject withdraws consent to participate in the study, or his/her physician decides 
participation is no longer in the subject’s best interest, an end of treatment visit should be 
conducted to evaluate the subject’s health status as soon as possible if the subject is willing and 
in the physician’s opinion able to do so. 
 
For a complete list of procedures scheduled for each study visit, please refer to the Study Flow 
Charts (1.1 and 1.2). The following sections provide additional details about how some of the 
procedures will be performed. 
 
 
12.1.1 Screening period 
Screening procedures for subjects on MDIs will be carried out between 7 to 21 days prior to 
inclusion. The screening visit will include all the investigations listed in the Flow Chart 1.1 and 
detailed in Section 9.2. Subjects may have any screening parameter re-checked 2 times. 
 
The subjects and their parent or legally authorized representative will receive information on the 
study objective(s) and procedures from the Investigator. Prior to any action related to the study, 
the informed consent document will have to be signed by the subject’s parent or legally 
authorized representative, and the subject, if able, to understand the nature, scope, and possible 
consequences of the clinical study. 
 
On safety grounds, pregnant females must not participate in this clinical trial because the trial 
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only females who take appropriate contraceptive measures may participate in this clinical trial 
(See Inclusion Criteria #12). 
 
This study consists of 3 age-related subject cohorts. A blood or urine pregnancy test will be 
carried out for female participants in Cohort 1 (ages 13-17) and Cohort 2 (ages 8-12) at the 
beginning of the clinical trial and also several times during the course of the trial. However, 
early-stage pregnancies can only be reliably detected a few days after conception. Female 
participants in Cohort 3 (ages 4-7) will not have pregnancy tests performed. 
 
Subjects who meet all the inclusion criteria (Section 7.2) and none of the exclusion criteria 
(Section 7.3) will be eligible for the study. 
 
Subjects will receive a glucose meter, supplies and training for use during the study. Subjects 
will also receive an Electronic Diary (e-diary) and be trained in its use. Instructions will be given 
on how and when to take blood glucose readings during the screening period and how to enter 
those reading into the e-diary. 
 
The PK visit will be scheduled and the subject will be reminded to bring their e-Diary to the PK 
visit. Five of seven fasting SMBG values obtained during the week prior to the PK visit must be 
between 80 and 250 mg/dL. Only the week (7 days) before the Day 2 visit values qualifies the 
subject for the study. Subjects will also be asked to refrain from vigorous physical activity within 
24 hours of Visit 2 (Day 1), to fast overnight, to maintain their hydration (water only), to take any 
basal insulin the night before Visit 2, and to take no other medication in the morning of the PK 
visit. 
 
 
12.1.2 PK assessment period (Visit 2) 
Subjects who successfully completed screening will participate in Visit 2/PK visit. Study staff 
will confirm subject fasted overnight for at least 8 hours (only water is permitted), and the last 
dose of basal insulin was administered the night before Visit 2. Subjects should test their glucose 
by meter at home prior to coming into the clinic for Visit 2. If their glucose is less than 80 
mg/dL, they should call the clinic and reschedule their Visit 2 PK Visit. 
 
Upon arriving at the clinic on the morning of Visit 2, subjects will have the following 
assessments performed before they receive the first dose of AFREZZA: 
 
• Blood glucose determination: Fasting pre-breakfast SMBG on the day of Visit 2 must 
be ≥80 mg/dL for the subject to participate in the PK assessment. However, if the SMBG 
value is >250 mg/dL, a urine sample will be checked for the presence of ketones using 
dipstick. If more than trace ketones are detected, the subject will not be permitted to 
proceed. The subject may return up to 2 more times on separate days to attempt to satisfy 
the SMBG criteria. 
 
• Abbreviated physical exam and vital signs prior to Afrezza dosing. 
• Urine pregnancy testing 

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• Urine cotinine 
• FEV1 evaluation by spirometry: Successive spirometry tests will be performed 
approximately 25 minutes before and 18, 55, 125, and 245 minutes after administration 
of AFREZZA to evaluate for possible acute changes in FEV1 related to dosing. 
Inhalation maneuver training: the BluHale system consists of an AFREZZA inhaler, an empty 
cartridge, and a pressure-sensing jacket that slips onto the inhaler. The jacket is designed for 
repeated use on multiple inhalers and does not require sterilization between subjects. Therefore, 
subjects may use the same jacket during training. Empty cartridges will be provided for training 
and practice. Subjects must demonstrate the ability to adequately perform the inspiratory 
maneuver utilizing the empty cartridge to continue in the study. 
 
If, in the opinion of the Investigator, a subject cannot adequately perform the inspiratory 
maneuver after a second training, the subject will be withdrawn from the study. The Site 
Operations Manual (SOM) provides a more detailed description of the BluHale Inspiratory 
System. 
 
Breakfast and AFREZZA dosing: subjects will receive a breakfast that is based on their 
assigned cohort and their Insulin/Carbohydrate ratio. (See Section 8.1.3 Initial dose for PK 
assessment) The meal will be provided by the clinical site. At the beginning of the meal, 
immediately before the first mouthful of food, the subject will inhale a dose of AFREZZA. The 
AFREZZA dose will be calculated based on the dosage table (Figure 1). The starting and ending 
time of breakfast will be recorded. 
 
Post dosing assessment: the subject will then remain at the clinical study site for approximately 
6 hours. The following procedures will be performed: 
 
• 4-hour blood PK sample collection for insulin and FDKP. See Table 3 for number of 
samples and Flow Chart 1.2 for sampling times. 
 
• Subjects will be monitored for signs of hypoglycemia. Blood glucose measurements will 
be taken during the course of the PK assessment visit according to the period Flow 
Chart 1.2, preferably by table top glucose analyzers present in the Investigator’s facility 
(e.g., Beckman or YSI). If blood glucose measurement cannot be done in the 
Investigator’s facility, blood samples need to be sent for central laboratory measurement. 
A subject exhibiting signs of hypoglycemia will be treated as appropriate. A snack will 
be given (e.g., 6 oz of milk) if any glucose measured during the PK test is <75 mg/dL. 
 
• Following the 4-hour PK test, plasma glucose will be assessed, after which the subject 
will receive another dose of AFREZZA, followed by lunch. The lunch should 
correspond in size and composition to the subject’s usual lunch. The AFREZZA dose 
should correspond to the subject's usual dose of prandial insulin. Consideration should 
be given to adjusting the lunchtime AFREZZA dose based on plasma glucose readings 
during the PK test and the pre-lunch plasma glucose value. 
 
Instructions for dose titration period 

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• The initial dose of AFREZZA for each meal will be determined based on the subject’s 
usual RAA dose for those meals and the glucose profile during the PK test; the doses 
will be recorded on a subject reminder card that the subject will take with them. 
 
• The subjects/parents will be instructed to administer AFREZZA at the beginning of each 
meal and to perform and record (e-Diary) an SMBG assessment at 120 to 150 minutes 
after each mealtime dose. Subjects will also be instructed to record the start and ending 
times of each meal and the AFREZZA® dosing time. 
• Pre-breakfast SMBG values will be obtained (for basal insulin adjustments) and recorded 
for this visit as well as for the duration of the study. 
 
• Study site staff will explain to subjects/parents how to titrate the prandial dose for each 
meal based on the 120 to 150 minute post-dose SMBG values. 
 
• Study site staff will explain to subjects/parents how to determine the appropriate 
postprandial or follow-on dose based on the value of 120 to 150 minute post-dose 
SMBG. 
 
• Instructions will be provided on proper use and storage of AFREZZA® (inhaler and 
cartridges), and subjects/parents will be reminded to bring all cartridges back to the site 
with them at their next visit. 
 
• Nutritional information will be provided (e.g., including carbohydrate content of meals 
and its impact on insulin requirements). Subjects will receive information about the 
importance of maintaining stable carbohydrate content of meals throughout this study. 
 
• Glucose meter test strips and Afrezza cartridges will also be provided. 
Discharge 
Subjects will be discharged from the clinic after the completion of PK sampling (4 hours), lunch, 
an abbreviated physical examination and vital signs. 
 
 
12.1.3 Dose titration period 
AFREZZA® will be taken at the beginning of each meal. 
 
The 28-day dose titration period will consist of 13 visits (Visits 3 to 15), which includes 4 site 
visits (Visit 6, 9, 12, and 15) and 9 telephone contacts (Visits 3, 4, 5, 7, 8, 10, 11, 13, and 14) 
primarily to adjust dosage and assess safety and tolerability. 
 
A follow-up visit (Visit 16) will be performed approximately 1 week after the end of the 
AFREZZA® treatment period for safety assessments. 

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12.1.3.1 Telephone contact (Visits 3, 4, and 5) 
Subjects will be contacted by the site via telephone 24 hours after Visit 2, primarily to record 
any AEs and concomitant medications and to ensure dosing and SMBG procedures are 
understood and are not problematic. 
 
Subjects will be contacted by the site 3 times by telephone prior to the next clinic visit (Visit 6). 
The phone calls will be made 1 day after Visit 2, and 3 and 5 days after Visit 2 (within the 
protocol defined visit windows of ±1 day). Mealtime AFREZZA dose will be adjusted per the 
Investigator’s discretion and recommendations described in Section 8.1.4, Section 8.1.5, and 
Section 8.1.6). 
 
Basal insulin dose will also be adjusted as necessary by the Investigator based on the subject’s 
pre-breakfast SMBG value according to Section 8.1.7. 
 
At Visit 5, subjects will be instructed to obtain 7-point glucose data (pre-meal and 120-150 
minutes post-dose at breakfast, lunch, and dinner as well as pre-bedtime, during one 24-hour 
day) prior to Visit 6. Subjects will also be reminded to bring their remaining drug supply and 
used cartridges to the next clinical site visit. 
 
 
12.1.3.2 Clinical site visits (Visits 6, 9, and 12) 
Subjects will return to the clinical site 2 to 4 days after the previous telephone contact (Visits 5, 
8, and 11, respectively) for clinical assessment and further dose adjustment. The subjects’ 
prandial doses will be adjusted for each meal according to Table 2 and their basal doses 
according to section 8.1.7 The subject will bring their remaining drug supply and used 
cartridges. Site staff will review unused IMP to assess compliance and need for additional IMP 
supply. Subjects will receive IMP and glucose test strips sufficient for approximately another 8 
days. The Investigator will review the e-Diary with the subject to evaluate compliance with 
dosing and SMBG assessment requirements and to review hypoglycemic events. The 
Investigator will adjudicate episodes of hypoglycemia reported in the e-Diary that appear to 
meet the criteria for SAEs. If the investigator judges that the episode is not an SAE, it will be 
corrected on a data clarification form in the e-Diary and will not be recorded on an SAE e-CRF. 
Subjects will be assessed according to the Flow Chart 1.1. Assessments include but are not 
limited to the following: 
• Urine pregnancy test for females of childbearing potential 
• Review of concomitant medications and AEs 
• Vital sign measurements 
• Abbreviated physical examination (general appearance, mental status, respiratory and 
cardiovascular systems, and other evaluations deemed appropriate by the Investigator 
for safety reasons) 
• Body weight 
• Urine cotinine 
• Spirometry (Visit 9) 

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• Blood glucose via glucose meter reading 
• Glucose test strips and AFREZZA® cartridges/inhalers provided (if necessary) 
• Dose titration based on SMBG values 
• 7-point glucose data will be reviewed and may be utilized to adjust dosing 
 
12.1.3.3 Telephone contact (Visits 7, 8, 10, 11, 13, and 14) 
There will be a safety/dose titration telephone contact after site Visits 6, 9, and 12. Adverse 
events and concomitant medications will be reviewed, and the subjects’ prandial doses will be 
adjusted for each meal according to Table 2 and their basal doses according to Section 8.1.7. 
Subjects will also be instructed to obtain 7-point glucose data (pre-meal and 120-150 minutes 
post-dose at breakfast, lunch, and dinner as well as pre-bedtime during one 24-hour day) prior to 
the next visit. 
 
 
12.1.3.4 End of titration (Visit 15) 
Subjects will return to the site 3 ± 1 days after the last telephone contact at Visit 14. During this 
visit (Visit 15), FEV1 will be assessed, and post-dose SMBG values since the last visit and 
current AFREZZA® doses will be reviewed. Subjects will be discharged from the clinic after an 
abbreviated physical examination (evaluating general appearance, mental status, respiratory and 
cardiovascular systems, and any other evaluations deemed necessary by Investigator). 
 
Subjects will be assessed according to the Flow Chart 1.1. Assessments include but are not 
limited to the following: 
• Urine pregnancy test for females of childbearing potential 
• HbA1c 
• Urine cotinine 
• Anti-insulin antibody 
• Review of concomitant medications and AEs 
• Abbreviated physical examination (general appearance, mental status, respiratory 
and cardiovascular systems, and other evaluations deemed appropriate by the 
Investigator for safety reasons) 
• Body weight 
• Vital sign measurements 
• Blood glucose via glucose meter reading 
• Spirometry or another pulmonary function test for a subject who is unable to 
perform the spirometry test 
• 7-point glucose data will be reviewed 
• Subjects will return all study supplies and receive a prescription for usual prandial 
RAA and for basal insulin 

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12.1.3.5 Follow-up (Visit 16) 
The subjects will return to the site for a follow-up visit 1 week ± 3 days after being off IMP 
(Visit 15). At which time FEV1 will be assessed and AEs, glycemic status, and general health 
based on an abbreviated physical examination will be evaluated. Subjects will be assessed 
according to the Flow Chart 1.1. Assessments include but are not limited to the following: 
 
• Body weight 
• Urine cotinine 
• Review of concomitant medications and AEs 
• Abbreviated physical examination (general appearance, mental status, respiratory 
and cardiovascular systems, and other evaluations deemed appropriate by the 
Investigator for safety reasons) 
 
• Vital sign measurements 
• Blood glucose by glucose meter 
• Spirometry or another pulmonary function test for a subject who is unable to 
perform the spirometry test 
 
• Urine pregnancy test for females of childbearing potential 
 
12.1.4 Early termination 
Early termination is defined as withdrawal or discontinuation at any point between AFREZZA 
administration on Day 1 and end of 28-day titration. 
 
Regardless of the reason for early termination, every effort must be made to perform the 
following end of treatment procedures prior to discharge: 
• Body weight 
• Review of AEs and concomitant medications 
• Abbreviated physical examination 
• Vital sign measurements 
• Spirometry 
• Blood glucose via glucose meter reading 
• HbA1c 
• Urine pregnancy test for females of childbearing potential 
• Urine cotinine 
• Prescription for RAA 
• Anti-insulin antibodies 

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Subjects who cannot adequately perform the inhalation maneuver with an empty cartridge at 
Visit 2 will not be required to have an additional physical examination for early termination. 
Physical examinations will be performed for subjects who discontinue after receiving 1 or more 
AFREZZA doses. 
 
After early termination, the Investigator or designee will follow up by telephone within 3 days to 
determine whether the subject experienced any previously unreported AEs during or subsequent 
to study participation. If so, the event(s) will be reported (as outlined in Section 10.3) and 
followed. 
 
The reasons for early treatment termination will be collected in the e-CRF. 
 
 
12.2 STUDY RECORD KEEPING 
All data reported in the e-CRF must be consistent with identified source documents present at 
the site; any discrepancies must be explained. 
 
Source documents are the original records. To satisfy International Council for 
Harmonization/Good Clinical Practice (ICH/GCP) guidance, source documentation must meet 
the following criteria for quality: 
 
1) Attributable. Source documentation must be attributable to a study team member listed on the 
site delegation of authority log (initialed or signed and dated) 
 
2) Legible. Source documentation must be clearly and completely legible 
 
3) Contemporaneous. Source documentation should be recorded contemporaneously, that is, at 
the time of the event 
 
4) Original. The information was first captured on the source document 
 
5) Accurate. The source documentation should be accurate and completely describe the event or 
assessment 
 
In addition, the study source records should be sufficient to document the activities and course 
of the site’s subjects while on study, and all of the study-related events from the site’s start-up 
through close out. 
 
 
12.2.1 Site essential documents 
Site essential documents for the study must be kept by the site in an organized site Investigator’s 
File. These essential documents individually and collectively permit evaluation of the study 
conduct and the quality of the data produced. These documents serve to demonstrate the site’s 
compliance with the standards of GCP and all applicable regulatory requirements. 

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All documents should be filed in the Investigator’s Site Study File and will be collected by the 
monitor for filing in the Study Master File (Sponsor’s documentation). 
 
Both site and Sponsor files are to be current, complete, and accurately filed (i.e., regulatory 
authority inspection ready) at all times from study start up through study close out. 

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13 
STATISTICAL CONSIDERATIONS 
Statistical analyses described in the following subsections will be performed as outlined in the 
statistical analysis plan (SAP) for the study. The SAP will be issued prior to database lock and 
will be included in the CSR for this protocol. If there are any deviations from the original SAP, 
these will be reported in the CSR, and the SAP will be amended as appropriate. For all analyses, 
the age cohort of a subject will be determined by their age at inclusion to the study. Individual 
data will be listed and sorted by age cohort, subject, visit, and time point. 
 
 
13.1 DETERMINATION OF SAMPLE SIZE 
 
Historical data 
Sample size calculation is based on information from a previous study conducted by MannKind 
Corporation with AFREZZA in adults with T1DM (MKC-TI-177). 
 
The study was a randomized, 2 × 2 crossover study comparing insulin exposure and 
pharmacodynamic response following a single dose inhalation of AFREZZA versus an 
equivalent dose of SC RAA. 
 
Determination of sample size 
For the purpose of sample size calculation, total standard deviations (SDTotal) of 0.250 to 0.750 
for inhaled insulin were used, based on the SDTotal observed for AFREZZA® in adults. 
Table 6 shows the maximum imprecision (in terms of the 95% confidence interval) for 
AFREZZA that will be obtained within an age cohort with 80% assurance, for a total number of 
subjects varying from 6 to 18, and a true SDTotal of 0.250, 0.425, 0.450, 0.725, and 0.750 for 
log(CL/F). 

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Table 6 
Maximum imprecision for geometric mean estimates of Cl/F-Figures applicable for 
one cohort 
 
Confidence level: 95%; Assurance: 80% 
Total SD on log scale 
Total number of subjects 
Maximum imprecision (%) 
0.250 
6 
27.2 
8 
21.9 
10 
18.8 
14 
15.2 
18 
13.1 
0.425 
6 
41.6 
8 
34.3 
10 
29.9 
14 
24.5 
18 
21.2 
0.450 
6 
43.5 
8 
35.9 
10 
31.3 
14 
25.7 
18 
22.3 
0.725 
6 
60.1 
8 
51.2 
10 
45.4 
14 
38.0 
18 
33.4 
0.750 
6 
61.3 
8 
52.4 
10 
46.5 
14 
39.0 
18 
34.3 
Imprecision is in terms of the relative distance (%) of the lower 95% confidence limit from the observed geometric
mean. 
Study design: 1-treatment parallel groups. 
PGM=DEVOPS/CPPK_STAT/E0173032/SAMPLE_SIZE/EXPLO/PGM/est_cros_Afrezza_TDR14323.sas 
OUT=EXPLO/OUTPUT/est_one_TDR14323_i.rtf (29JAN2015 - 2:00) 
In order to control the maximum imprecision of 95% confidence interval for the geometric mean 
estimate of CL/F within 40%, a total of 14 subjects in the first cohort will be required to achieve 
at least 80% power, assuming an SDTotal of 0.725 as the most conservative approach. For Cohort 
2 and Cohort 3, the sample size may be adjusted to account for the PK variability in Cohort 1. 

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13.2 SUBJECT DESCRIPTION 
 
13.2.1 Disposition, demographics, and baseline characteristics of subjects 
Subject disposition, demographics, and baseline characteristics will be summarized using 
descriptive statistics. Number and percentage of subjects taking concomitant medications will be 
summarized in frequency tables by therapeutic classes and generic terms using the World Health 
Organization dictionary. The number of subjects with pre-existing medical conditions will be 
summarized. 
 
A listing of comments in the e-CRF and/or deviation log related to investigational product 
compliance and dosing, safety, or other comments will be provided. 
 
 
13.3 ANALYSIS POPULATION 
A summary table of count of subjects included in each study population will be provided by age 
cohort and start dose. All exclusions from any analysis populations will be fully documented in 
the CSR. 
 
 
13.3.1 Safety population 
All subjects in the clinical study who receive a dose of AFREZZA will be included in the safety 
population. 
 
 
13.3.2 Pharmacokinetics 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. 
 
 
13.4 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristics, including usual insulin doses, will be analyzed for all 
subjects from the safety population per age cohort and overall. 
 
 
13.4.1 Subject demographic characteristics, medical history, and diagnoses 
Continuous variables (age, height, weight and body mass index) daily basal insulin dose, daily 
prandial SC insulin dose, and qualitative variables (gender, race) will be summarized by 
descriptive statistics. 
 
Demographic data will also be listed, including history of diabetes. 

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13.4.2 Baseline pharmacodynamic parameters 
Not applicable. 
 
 
13.4.3 Baseline safety parameters 
Safety parameters will be summarized in a descriptive manner for the included subjects. 
 
Baseline for safety parameters will be defined as the last available and evaluable parameter 
value before and closest to the first IMP dosing for laboratory data, and for vital sign 
parameters, including body temperature and further safety parameters unless specified 
differently. 
 
 
13.5 EXTENT OF STUDY TREATMENT EXPOSURE AND COMPLIANCE 
The following listings will be provided and sorted by subject: 
 
• Details of drug dosing (actual treatment received, date and time of IMP 
administrations, route of administration, intended and actual dose received) 
 
• Subjects receiving IMP from specified batch 
The exposure to IMP (i.e., number of doses of IMP and duration of IMP in days, defined by: 
[end date of administration – start date of administration + 1]) will be summarized categorically 
(counts and percentages) by age cohort and overall, on the safety and PK population. If 
appropriate, exposure will also be summarized by start dose. 
 
In addition, dose changes from baseline at the end of treatment for IMP (units and units/kg) will 
be summarized by age cohort and starting doses group for the safety population. 
 
 
13.6 PRIOR/CONCOMITANT MEDICATION/THERAPY 
Concomitant treatments will be coded according to the World Health Organization-Drug 
Dictionary (WHO-DD, latest version in use at time of database lock). Subjects who took 
medications that were stopped before the first IMP dosing and/or subjects who received 
concomitant treatments with the IMP will be listed. 
 
Non-IMP insulin treatment will be presented separately and doses will be summarized. 
 
 
13.7 ANALYSIS OF PHARMACODYNAMIC VARIABLES 
Not applicable. 
 
 
13.8 ANALYSIS OF SAFETY DATA 

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The safety evaluation will be based upon the review of the individual values (clinically 
significant abnormalities), descriptive statistics (summary tables, graphics) and if needed on 
statistical analysis (appropriate estimations, hypothesis tests). All the safety analyses will be 
performed using the safety population. 
 
 
13.9 PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS 
Not applicable. 
 
 
13.10 INTERIM ANALYSIS 
An interim analyses will be conducted on a cohort by cohort basis upon the completion of each 
cohort’s PK and 4-week Titration Phase of this protocol. 
 
Pharmacokinetics and safety data will be reviewed on a rolling basis by the Sponsor and the 
DMC in order to allow enrollment in Cohorts 2 and 3 as described in Section 6.1. 

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14 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
14.1 ETHICAL AND REGULATORY STANDARDS 
This clinical study will be conducted by the Sponsor, the Investigators, delegated Investigator 
staff, and Sub-Investigators in an ethical and humane manner; in accordance with ICH/GCP and 
all other applicable regulatory requirements; and the protocol, amendments, and study manuals. 
This clinical study will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first subject enrollment, in compliance with applicable regulatory 
requirements and with MannKind public disclosure commitments. 

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15 
STUDY MONITORING AND QUALITY 
 
15.1 INVESTIGATOR QUALITY AND REGULATORY RESPONSIBILITIES 
The Investigator is required to supervise the conduct of the study at her/his site to ensure 
compliance with ICH/GCP and all other regulatory requirements; ensure the rights and welfare 
of subjects at this site are protected; and conduct the study in compliance with the protocol, 
amendments, and study manuals. 
 
 
15.1.1 Protocol deviations 
Investigators must not intentionally deviate from the protocol except to avert immediate risk of 
harm to a subject. If the Investigator deviates from the protocol in order to avoid immediate 
harm to a subject, the PI or delegate should inform MannKind Medical Monitor of the event 
(date, subject number, and circumstance) by phone or by email within 24 business hours. 
 
All deviations from the protocol, ICH/GCP, or other regulatory requirements will be recorded at 
the site on a study log or e-CRF; discussed by delegated site staff with the site monitor no later 
than by the end of the next interim monitoring visit; and will be reported per their local EC and 
other regulatory requirements. 
 
The investigator and institution must agree to provide direct access to all study-related materials, 
study staff, facilities, and source documents for study monitors, auditors, or regulatory 
inspectors. 
 
 
15.2 SPONSOR QUALITY ASSURANCE AND REGULATORY RESPONSIBILITIES 
This study will be performed in compliance with MKC’s standard operating procedures (SOPs) 
for quality for tasks not transferred by contract to a CRO. For tasks contracted to CROs or 
Vendors, the CRO or Vendors’ SOPs will be followed. MKC will provide oversight of all 
activities contracted through a CRO (e.g., clinical monitoring, data management, project 
management) through review of clinical monitoring reports; study metrics review; data listings 
review; tracking study progress against the study timeline); and an audit program conducted at 
clinical study sites by a third party contracted to MKC. 

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15.3 DATA MONITORING COMMITTEE 
A DMC will be seated for this study. The DMC will remain independent of the clinical 
investigators and MannKind Corporation in order to avoid potential conflicts of interest. Other 
than being members of the DMC, members will have no relationship to the study, the design of 
the protocol, the conduct of the study, or the PIs. The DMC will review safety data on an 
ongoing basis. The frequency of meetings and the format and content of the data will be 
specified in the DMC Charter. The DMC will make recommendations to make pertinent changes 
to the protocol, and/or stop the study at any time if significant concerns regarding safety of the 
IMP or study procedures should arise. 
 
 
15.4 PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT 
OF A SITE 
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following: 
• The information on the product leads to doubt as to the benefit/risk ratio; 
• Patient enrollment is unsatisfactory; 
• The Investigator has received from the Sponsor all IMP, means, and information 
necessary to perform the clinical trial and has not included any patient after a reasonable 
period of time mutually agreed upon; 
• Non-compliance of the Investigator or Sub-Investigator, delegated staff with any 
provision of the clinical trial protocol, and breach of the applicable laws and regulations 
or breach of the ICH GCP; 
• The total number of patient are included earlier than expected 
 
15.5 CLINICAL STUDY RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary 
of the study results to the Investigator. 

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16 
BIBLIOGRAPHIC REFERENCES 
1. Silverstein J, Klingensmith G, Copeland K, Plotnick L, Kaufman F, Laffel L, et al. 
Care of children and adolescents with type 1 diabetes: a statement of the American 
Diabetes Association. Diabetes Care. 2005;28(1):186-212. 
 
2. American Diabetes Association. Standards of medical care in diabetes--2014. 
Diabetes Care. 2014;37 Suppl 1:S14-80. 
 
3. Bangstad HJ, Danne T, Deeb L, Jarosz-Chobot P, Urakami T, Hanas R. Insulin 
treatment in children and adolescents with diabetes. Pediatr Diabetes. 2009;10 Suppl 
12:82-99. 
 
4. Rao R, Hershey T. The impact of hypoglycemia on the developing brain. Transl 
Endocrinol Metabol. 2012;3(4):137-159. 
 
5. Wiegand S, Raile K, Reinehr T, Hofer S, Näke A, Rabl W, et al. Daily insulin 
requirement of children and adolescents with type 1 diabetes: effect of age, gender, 
body mass index and mode of therapy. Eur J Endocrinol. 2008;158(4):543-9. 
 
6. Type 2 diabetes in children and adolescents. American Diabetes Association. 
Diabetes Care. 2000;23(3):381-9. 
 
7. Investigator’s Brochure: Technosphere Insulin Inhalation System. MannKind 
Corporation Version 10.0. 31 Jul 2012. 
 
8. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a 
sample of the general U.S. population. Am J Respir Crit Care Med. 1999;159(1):179- 
87. 
 
9. Wang X, Dockery DW, Wypij D, Gold DR, Speizer FE, Ware JH, et al. Pulmonary 
function growth velocity in children 6 to 18 years of age. Am Rev Respir Dis. 
1993;148(6 Pt 1):1502-8. 
 
10. Ly TT, Maahs DM, Rewers A, Dunger D, Oduwole A, Jones TW. ISPAD Clinical 
Practice Consensus Guidelines 2014: Assessment and management of hypoglycemia 
in children and adolescents with diabetes. Pediatr Diabetes. 2014:15 Suppl 20:180- 
92. 

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17 
INVESTIGATOR’S SIGNATURE 
 
 
 
Study Title: 
Open-label, single-arm, multiple-dose safety, titration, and 
pharmacokinetic study of AFREZZA in pediatric subjects ages 
4 to 17 years with type 1 diabetes mellitus 
Study Number: 
MKC-TI-155 Part 1 – Amendment 3 
Final Date: 
14 February 2018 
 
I have read the protocol of Study MKC-TI-155 Part 1 Amendment 3 as described above. I agree 
to comply with all applicable regulations and to conduct the study as described in the protocol. 
 
Signed: 
 
Print name:  
  
Date:  
 

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18 
APPENDICES 
 
18.1 
APPENDIX A 
N/A 
 
18.2 APPENDIX B 
N/A 
 
18.3 APPENDIX C - PHASE 3 STUDY (PART 2 OF THE AFREZZA PEDIATRIC 
DEVELOPMENT PROGRAM)