DOS [Dosing Optimization Study]: Open-label, Single-arm, Proof-of-Concept Dosing Study of Afrezza® in Adult Subjects 18 Years and Older With Type 1 or Type 2 Diabetes Mellitus
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2
Sponsor: Mannkind Corporation

 
 
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Clinical Study Protocol 
 
Protocol Title: 
DOS [Dosing Optimization Study]: Open-label, 
Single-arm, Proof-of-Concept Dosing Study of 
Afrezza® in Adult Subjects 18 Years and Older with 
Type 1 or Type 2 Diabetes Mellitus 
Protocol Number: 
MKC-TI-191 
Clinical Phase: 
Phase 4 
Protocol Version and Date: 
Original, 15 March 2021 
NCT 
04849845 
Sponsor: 
MannKind Corporation 
30930 Russell Ranch Road, Suite 300 
Westlake Village, CA 91362 
 
 
This study will be performed in compliance with Good Clinical Practice, the Declaration of 
Helsinki (with amendments), and local legal and regulatory requirements. 
 
CONFIDENTIAL 
This document and its contents are the property of and confidential to MannKind Corporation. 
Any unauthorized copying or use of this document is prohibited. 
 
 

 
 
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SIGNATURE PAGE 
 
Protocol Title: DOS [Dosing Optimization Study]: Open-label, Single-arm, Proof-of-Concept 
Dosing Study of Afrezza® in Adult Subjects 18 Years and Older with Type 1 or Type 2 Diabetes 
Mellitus 
The undersigned have reviewed the format and content of this protocol and have approved the 
clinical study protocol. The undersigned agree that the trial will be carried out in accordance with 
the clinical study protocol, Good Clinical Practice, with the Declaration of Helsinki (with 
amendments), and with the laws and regulations of the countries in which the study takes place. 
Any modifications of the clinical study protocol must be agreed upon by the Sponsor and the 
Investigator and must be documented in writing. 
Sponsor Approval: 
Signature: 
Date: 
Name: 
Kevin Kaiserman, MD 
Title: 
Vice President, Medical Affairs and Safety 
MannKind Corporation 
 
Investigator Agreement: 
I have read the clinical study protocol and agree the trial will be carried out in accordance with 
Good Clinical Practice, with the Declaration of Helsinki (with amendments), and with the laws 
and regulations of the countries in which the study takes place. 
Signature: 
Date: 
Name (print): 
Site Name: 
Site Address: 
  

 
 
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SYNOPSIS 
Protocol Title: 
DOS [Dosing Optimization Study]: Open-label, Single-arm, 
Proof-of-Concept Dosing Study of Afrezza® in Adult Subjects 
18 Years and Older with Type 1 or Type 2 Diabetes Mellitus 
Protocol Number: 
MKC-TI-191 
Sponsor: 
MannKind Corporation 
Investigator(s)/Study 
Center(s):  
This study will be conducted by Investigators at 2 or more study 
centers located in the United States. 
Phase of 
Development: 
Phase 4 
Objectives: 
Primary Objective: 
 To evaluate the efficacy of Afrezza administered at 2 different 
doses, combined with basal insulin, in adults 18 years and older 
with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus 
(T2DM) as measured by: 
o Mean change from baseline postprandial glucose based 
on self-monitored blood glucose (SMBG) from 
immediately before administering Afrezza (t=0; baseline) 
to 15, 30, 45, 60, 90 and 120 minutes after Afrezza 
dosing in conjunction with a standardized meal challenge 
Secondary Objective: 
 To evaluate the safety of Afrezza administered at 2 different 
doses, combined with basal insulin, in adults 18 years and older 
with T1DM or T2DM, as measured by: 
o Event rates and incidence of Level 1 (<70 mg/dL) and 
Level 2 (<54 mg/dL) hypoglycemic events within the 
120 minutes after Afrezza dosing  
o Event rates and incidence of severe hypoglycemic events, 
defined as events requiring assistance of another person 
to actively administer carbohydrate, glucagon, or other 
resuscitative actions within the 120 minutes after Afrezza 
dosing 
o Change in percent predicted forced expiratory volume in 
1 second (FEV1) before Afrezza dosing to 120 minutes 
after Afrezza dosing  
o Incidence and severity of adverse events (AEs): 
treatment-emergent adverse events (TEAEs), serious AEs 
(SAEs), and AEs of special interest (AESIs) 
Study Design: 
MKC-TI-191 is a Phase 4, single-arm, multicenter, proof-of-concept 
clinical trial evaluating the efficacy and safety of Afrezza, 
administered according to the current Afrezza prescribing 

 
 
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information (PI) compared to a titrated dose, in combination with a 
basal insulin in adult subjects (≥18 years of age) with T1DM or 
T2DM.  
Eligible subjects will be on a stable regimen consisting of a 
basal-bolus insulin therapy prior to screening. 
The study is composed of up to 4 clinic visits (screening, 2 treatment 
visits, and a follow-up visit): 
 Screening (Visit 1): Informed consent will be obtained and 
eligibility confirmed. Eligible subjects will be enrolled at Visit 1. 
 Visit 2: The first dose of Afrezza will be based on the dose of 
subcutaneous rapid-acting insulin analog (RAA) that the subject 
would normally take, converted according to the guidelines 
provided in the current Afrezza PI. If the subject’s normal RAA 
dose is <4 units, the subject will be asked to consume enough 
nutritional shake, per their normal insulin:carbohydrate ratio, to 
cover an RAA dose of ≥4 units such that their Afrezza dose at 
Visit 3 is higher than the dose taken at Visit 2. After completing 
the standardized meal challenge, the Investigator will decide, 
based on the subject’s glucose excursion at Visit 2, if the subject 
should proceed to Visit 3 where a second dose of Afrezza will be 
administered. 
 Visit 3: The second dose of Afrezza will be based on the dose of 
subcutaneous RAA that the subject would normally take, 
converted by multiplying their RAA dose by 2 and rounding 
down to the nearest Afrezza cartridge size.  
 Follow-up (Visit 4): Subjects will return for safety assessments 
24 to 72 hours after their last dose of Afrezza. 
Treatment Period 
Subjects will come into the clinic in a fasting state for Visits 2 and 3, 
with exception of treating hypoglycemia. Fasting will be defined as 
no intake of drink or food, with exception of water, for ≥6 hours 
before the clinic visit. At the beginning of each visit, before their 
dose of Afrezza, subjects will have FEV1 measurements taken in the 
clinic. 
Before each dose of Afrezza, subjects will be trained on proper 
inhalation technique with BluHale® PRO.  
Each meal challenge will consist of 1 to 2 bottles of nutritional shake 
to be fully consumed within 15 minutes. The nutritional shake will 
contain approximately 240 calories, 41 g carbohydrate, 10 g protein, 
and 4 g fat per bottle. Each Afrezza dose will be administered at the 
start of the meal challenge. 
The subject’s SMBG value must be between 100 and 200 mg/dL 
without requiring a correction dose of bolus insulin in order to 
receive the Afrezza dose and complete the meal challenge. Subjects 

 
 
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using an insulin pump will be instructed to make sure their insulin 
pump is not in automated insulin delivery mode for the 3 hours 
before and during Visits 2 and 3. Subjects will also be instructed not 
to inject correction doses of bolus insulin during the 6 hours 
immediately preceding each Afrezza dose. If the subject requires a 
bolus insulin injection to correct hyperglycemia within the 6 hours 
prior to the scheduled visit, the meal challenge will need to be 
rescheduled. An SMBG measurement will be taken 15 minutes 
before the expected dose of Afrezza so the Investigator can assess if 
the subject is within the required SMBG range (100 to 200 mg/dL). 
If the subject’s SMBG value is <100 mg/dL at the start of the visit, 
the Investigator can provide 15 g of fast-acting carbohydrates and 
remeasure SMBG after 30 minutes to determine if the subject should 
proceed to the meal challenge. The SMBG value obtained 
immediately before each dose of Afrezza (t=0) will be used to 
determine if the subject can proceed to the meal challenge and will 
serve as the baseline value for that visit. 
Subjects will be monitored by the Investigator for at least 2 hours 
after administering each dose of Afrezza. The subject will be 
instructed not to ingest additional food for the 2 hours they are in the 
clinic for observation, with exception of treating hypoglycemia; any 
treatment for hypoglycemia (e.g., snack or glucose) will be 
documented.  
Subjects will take SMBG measurements 15 minutes before their 
Afrezza dose and at t=0 (baseline), 15, 30, 45, 60, 90, and 
120 minutes with respect to their Afrezza dose, where t=0 
corresponds to the time immediately before administering their dose 
of Afrezza. Additional SMBG measurements may be taken per 
Investigator discretion. 
Subjects will have an FEV1 measurement after completion of each 
standardized meal challenge (120 minutes after the Afrezza dose) at 
Visits 2 and 3. 
Follow-up Visit 
Subjects will be asked to return to the clinic within 24 to 72 hours 
after their last dose of Afrezza for safety assessments, including a 
final FEV1 measurement. 
Planned Sample Size: 
20 subjects (number of subjects to complete the study) 
Medical Condition or 
Disease Under 
Investigation: 
T1DM and T2DM, with no more than 50% of subjects having T2DM 

 
 
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Subject Selection 
Criteria: 
Inclusion Criteria 
At screening: 
1. Subjects ≥18 years of age at the time of signing the informed 
consent form 
2. Clinical diagnosis of T1DM or T2DM (per the Investigator) and 
on a stable basal-bolus insulin regimen 
Exclusion Criteria 
At screening: 
1. History of asthma, chronic obstructive pulmonary disease, or any 
other clinically important pulmonary disease (e.g., cystic fibrosis, 
bronchopulmonary dysplasia), use of any medications to treat 
such conditions within the last year, or significant congenital or 
acquired cardiopulmonary disease 
2. History of serious complications of diabetes (e.g., active 
proliferative retinopathy or symptomatic autonomic neuropathy)  
3. On dialysis 
4. Respiratory tract infection within 14 days before screening 
(subject may return 14 days after resolution of symptoms for 
rescreening) 
5. Treatment with any investigational drug in the past 30 days or an 
investigational device in the past 2 weeks 
6. Any disease other than diabetes or initiation of any new 
medication that, in the judgment of the Investigator, could have a 
direct impact on glycemic control during the study  
7. Use of antiadrenergic drugs (e.g., beta blockers and clonidine) 
8. Any concurrent illness (other than diabetes mellitus) not 
controlled by a stable therapeutic regimen 
9. History of a significant eating disorder (e.g., anorexia or bulimia 
nervosa) 
10. Current drug or alcohol abuse or a history of drug or alcohol 
abuse that, in the opinion of the Investigator or the Sponsor, 
would make the subject an unsuitable candidate for participation 
in the study 
11. History of smoking (includes cigarettes, cigars, pipes, vaping 
devices, and marijuana) in the 6 months before screening 
12. Female subject who is pregnant, breastfeeding, intends to 
become pregnant, or is of child-bearing potential and not using 
adequate contraceptive methods as required by local regulation 
or practice (may include sexual abstinence) 
13. An event of severe hypoglycemia, as judged by the Investigator, 
within the 90 days before screening 

 
 
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14. An episode of diabetic ketoacidosis requiring hospitalization 
within the 90 days before screening 
15. Exposure to Afrezza in the 30 days before screening 
Study Treatment(s): 
All subjects will receive Afrezza in this study. 
Test Product, Dose, 
and Mode of 
Administration: 
Test product: Afrezza® [insulin human] inhalation powder 
Active ingredient: Human insulin, recombinant DNA origin 
Dose regimen: Individualized  
Mode of Administration: Oral inhalation 
Basal Insulin Therapy 
Dose, and Mode of 
Administration: 
Basal insulin analog: The subject’s personal basal insulin. The dose 
and type of basal insulin should not be changed between Visits 1 and 
3. 
Dose regimen: Individualized  
Mode of Administration: Subcutaneous injection or via pump. 
Note: Pumps cannot be in automated insulin delivery mode for the 
3 hours before or during Visits 2 and 3. 
Duration of 
Treatment: 
Two individual doses of Afrezza will be administered during this 
study, during Visits 2 and 3, with a standardized meal challenge.  
Criteria for 
Evaluation: 
This study will evaluate the efficacy and safety of Afrezza 
administered according to new dosing guidelines, combined with 
basal insulin, based on the endpoints outlined below: 
Efficacy Endpoint 
 Change in SMBG from immediately before administering the 
dose of Afrezza (t=0; baseline) to 15, 30, 45, 60, 90 and 
120 minutes after Afrezza dosing 
Safety Endpoints 
 Event rates and incidence Level 1 (<70 mg/dL) and Level 2 
(<54 mg/dL) hypoglycemic events 
 Event rates and incidence of severe hypoglycemic events, 
defined as events requiring assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative 
actions  
 Incidence and severity of AEs: TEAEs, SAEs, and AESIs 
 Change in FEV1 from t=0 to 120 minutes after Afrezza dosing 
Statistical Methods: 
Sample Size Determination 
Twenty subjects are planned to complete the study. Subjects who do 
not complete the study may be replaced. The sample size of 
20 subjects was not determined using statistical methods, but rather 
was chosen based on clinical considerations. 
Analysis Populations 

 
 
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All subjects in the clinical study who receive a dose of Afrezza will 
be included in analyses. 
Analysis of Efficacy Endpoints 
SMBG values will be summarized by visit. A summary table with 
descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum) by time point relative to Afrezza dosing will be 
provided. SMBG data will also be presented graphically. 
Analysis of Safety Endpoints 
The incidence of hypoglycemia (total, nocturnal, and severe) and 
number of hypoglycemic episodes will be summarized. Summary 
tables providing frequency counts and the percentage of subjects 
within each category will be provided for Level 1 hypoglycemia 
(SMBG <70 mg/dL) and Level 2 hypoglycemia 
(SMBG <54 mg/dL). Exposure-adjusted incidence rates and 
exposure-adjusted event rates will be calculated and summarized. 
The number and percentage of subjects with TEAEs will be 
tabulated by system organ class and preferred term by relationship to 
treatment and by severity.  
A summary table by study visit with descriptive statistics for FEV1 at 
all time points will be provided. The FEV1 data will also be 
presented graphically.  

 
 
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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2 
SYNOPSIS ...................................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 9 
TABLES ....................................................................................................................................... 11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................... 12 
1 
INTRODUCTION ................................................................................................................ 14 
1.1 Background ....................................................................................................................... 14 
1.2 Study Rationale ................................................................................................................. 14 
1.3 Risks and Benefits............................................................................................................. 15 
2 
STUDY OBJECTIVES ......................................................................................................... 16 
2.1 Primary Objective ............................................................................................................. 16 
2.2 Secondary Objective ......................................................................................................... 16 
3 
INVESTIGATIONAL PLAN ............................................................................................... 17 
3.1 Overall Study Design and Plan ......................................................................................... 17 
3.2 Study Duration .................................................................................................................. 17 
3.3 Selection of Study Population ........................................................................................... 17 
3.3.1 Inclusion Criteria ...................................................................................................... 18 
3.3.2 Exclusion Criteria ..................................................................................................... 18 
3.3.3 Removal of Subjects from Therapy or Assessment .................................................. 19 
3.3.4 Replacement of Subjects ........................................................................................... 20 
3.4 Treatments......................................................................................................................... 20 
3.4.1 Details of Study Treatments and Storage Conditions ............................................... 20 
3.4.2 Dosage Schedule ....................................................................................................... 21 
3.4.3 Treatment Assignment .............................................................................................. 21 
3.4.4 Drug Packaging and Blinding ................................................................................... 22 
3.4.5 Drug Inventory and Accountability .......................................................................... 22 
3.4.6 Treatment Compliance .............................................................................................. 22 
3.4.7 Prior and Concomitant Illnesses and Treatments...................................................... 22 
3.5 Assessments ...................................................................................................................... 23 
3.5.1 Schedule of Assessments .......................................................................................... 23 

 
 
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3.5.2 Study Procedures ...................................................................................................... 25 
3.5.3 Procedures for Subjects Who Prematurely Withdraw from the Study ..................... 30 
3.5.4 Efficacy Assessment ................................................................................................. 30 
3.5.5 Safety Assessments ................................................................................................... 30 
3.5.6 Appropriateness of Measurements ............................................................................ 32 
4 
ADVERSE EVENT REPORTING....................................................................................... 33 
4.1 Definitions and Criteria..................................................................................................... 33 
4.1.1 Adverse Events ......................................................................................................... 33 
4.1.2 Serious Adverse Events ............................................................................................ 33 
4.1.3 Adverse Events of Special Interest ........................................................................... 34 
4.1.4 Abnormal Laboratory Values ................................................................................... 34 
4.1.5 Assessing Relationship ............................................................................................. 35 
4.2 Reporting Procedures and Requirements .......................................................................... 36 
4.2.1 Adverse Events ......................................................................................................... 36 
4.2.2 Adverse Events of Special Interest and Severe Hypoglycemia ................................ 36 
4.2.3 Serious Adverse Events ............................................................................................ 36 
4.3 Procedures for Documenting Pregnancy During Study .................................................... 37 
5 
DATA MANAGEMENT AND STATISTICAL ANALYSIS ............................................. 38 
5.1 Data Management Considerations .................................................................................... 38 
5.2 Statistical Considerations .................................................................................................. 38 
5.2.1 General Considerations ............................................................................................. 38 
5.2.2 Randomization .......................................................................................................... 38 
5.2.3 Sample Size Justification .......................................................................................... 38 
5.2.4 Analysis Populations ................................................................................................. 38 
5.2.5 Protocol Deviations ................................................................................................... 38 
5.2.6 Subject Disposition ................................................................................................... 39 
5.2.7 Demographic and Baseline Characteristics .............................................................. 39 
5.2.8 Medical History ........................................................................................................ 39 
5.2.9 Concomitant Medications ......................................................................................... 39 
5.2.10 
Treatment Exposure and Compliance .................................................................... 39 
5.2.11 
Efficacy Analyses .................................................................................................. 39 

 
 
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5.2.12 
Safety Analyses ..................................................................................................... 39 
6 
STUDY MANAGEMENT ................................................................................................... 41 
6.1 Ethics and Consent ............................................................................................................ 41 
6.1.1 Regulations and Guidelines ...................................................................................... 41 
6.1.2 Institutional Review Board ....................................................................................... 41 
6.1.3 Informed Consent...................................................................................................... 41 
6.1.4 Data Protection.......................................................................................................... 41 
6.2 Discontinuation of the Study by the Sponsor ................................................................... 41 
6.3 Study Documentation........................................................................................................ 41 
6.4 Data Management and Quality Control ............................................................................ 42 
6.4.1 Case Report Forms .................................................................................................... 42 
6.4.2 Study Monitoring and Quality Assurance................................................................. 42 
6.5 Retention of Records......................................................................................................... 42 
6.6 Use of Study Findings ....................................................................................................... 43 
6.7 Financial Disclosure.......................................................................................................... 43 
6.8 Publications and Disclosure Policy ................................................................................... 43 
7 
REFERENCES ..................................................................................................................... 44 
 
 
TABLES 
Table 1:  
Test Product (Afrezza) .............................................................................................. 21 
Table 2:  
Schedule of Assessments .......................................................................................... 24 
Table 3:  
Dose of Afrezza at Visit 2 ......................................................................................... 27 
Table 4:  
Dose of Afrezza at Visit 3 ......................................................................................... 29 
 
 
 

 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
BMI 
body mass index 
CGM 
continuous glucose monitor 
COVID-19 
coronavirus 2019 
CRF 
case report form 
DKA 
diabetic ketoacidosis 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ITT 
intent to treat 
IRB 
institutional review board 
PI 
prescribing information 
RAA 
rapid-acting insulin analog 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2  
SC 
subcutaneous(ly) 
SMBG 
self-monitored blood glucose 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
TI  
Technosphere Insulin 
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
 

 
 
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DEFINITIONS OF TERMS 
Enrollment: The date when the subject has consented to participate in the study and eligibility 
criteria are met. 
Start of the study: The study starts on the date that the informed consent form is signed for the 
first subject. 
End of the study: The study ends with the last visit of the last subject participating in the study. 

 
 
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1 
 INTRODUCTION 
1.1 Background 
Diabetes constitutes one of the fasting growing global health emergencies. The prevalence of 
type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are rising, with nearly half 
a billion people living with diabetes worldwide (IDF 2019). Among adults aged 20-79 years, an 
estimated 463.0 million adults worldwide have diabetes (~9.3% of all adults in this age group). 
In both T1DM and T2DM, the therapeutic objective is to optimally control blood glucose levels 
and this objective is fundamentally the same in all subjects with diabetes, with individual 
circumstances and needs dictating what those optimal levels should be. In order to delay or 
prevent complications associated with diabetes, it is critical that patients adhere to their diabetes 
treatment regimen. Among patients treated with a multiple daily injection regimen of insulin, 1 
in 5 (~20%) mealtime injections are intentionally missed, leading to challenges in achieving 
effective glycemic control (Peyrot et al. 2010). Reasons for omitting insulin injections include 
interference with daily activities, injection pain, and embarrassment.  
Technosphere® Insulin inhalation powder (TI inhalation powder) provides an alternative to 
injectable insulin. TI inhalation powder and the Gen2 Inhaler were approved as Afrezza® (insulin 
human) inhalation powder and Afrezza Inhaler by the United States Food and Drug 
Administration (FDA) on 27 June 2014 to improve glycemic control in adult patients ≥ 18 years 
of age with diabetes mellitus and has been registered by the Brazilian Health Regulatory Agency 
(ANVISA) as of 03 June 2019. Afrezza is an ultra-rapid-acting insulin that 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 is absorbed 
systemically. After administration of Afrezza in adults, the maximum serum insulin 
concentration occurs in approximately 12 to 15 minutes (versus 45 to 60 minutes for a 
rapid-acting insulin analog [RAA] via subcutaneous [SC] route) and returns to near baseline 
levels in approximately 180 minutes (versus about 5 hours for RAA) (Afrezza IB 2021).  
This unique ultra-rapid time-action profile allows for simpler and more flexible mealtime dosing, 
lessens the potential for interprandial hypoglycemia, and enables additional postprandial dosing 
to decrease mealtime glycemic excursions, when needed, based on the patient’s self-measured 
glucose levels.  
1.2 Study Rationale 
The current study aims to evaluate 2 different doses of Afrezza in adults ≥ 18 years of age. 
Subjects will administer an Afrezza dose based on the current prescribing information (PI) with a 
meal challenge, and then proceed to a second meal challenge where a second Afrezza dose will 
be administered based on the subject’s RAA dose multiplied by 2 and rounded down to the 
nearest Afrezza cartridge size, subject to Investigator discretion.  

 
 
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Pooled Afrezza trial data suggests that subjects achieve similar glycemic control with a dose 
ratio of 1.5- to 2-fold the equivalent unit value of a SC insulin analog in head-to-head 
comparisons (Kendall et al. 2020, Grant et al. 2019). Thus, the Sponsor has chosen to evaluate 
2 different doses of Afrezza to assess whether a higher dose results in improved postprandial 
glucose control. 
1.3 Risks and Benefits 
A clear benefit of Afrezza is fewer injections compared to subjects using RAAs injected 
subcutaneously. 
The following safety risks have been identified through evaluation of all currently available data 
with Afrezza: 
Important identified risks 
 Bronchospasm in subjects with underlying chronic obstructive lung disease 
 Severe hypoglycemia 
 Hyperglycemia during initiation of treatment due to inadequate conversion of RAA dose 
Important potential risks 
 Diabetic ketoacidosis (DKA) 
 Hyperglycemia during acute illness or change of treatment 
 Lung cancer: Data are insufficient to determine whether Afrezza has an effect on lung or 
respiratory tract tumors. In subjects with active lung cancer, a prior history of lung 
cancer, or in subjects at risk for lung cancer, the Investigator considers whether the 
benefits of Afrezza use outweigh this potential risk. 
Further information on the benefits and risks of Afrezza are provided in the Investigator’s 
Brochure (IB) (Afrezza IB 2021). 

 
 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is: 
 To evaluate the efficacy of Afrezza administered at 2 different doses, combined with 
basal insulin, in adults 18 years and older with T1DM or T2DM as measured by: 
o 
Mean change from baseline in postprandial glucose based on self-monitored blood 
glucose (SMBG) from immediately before administering the dose of Afrezza (t=0; 
baseline) to 15, 30, 45, 60, 90 and 120 minutes after Afrezza dosing in conjunction 
with a standardized meal challenge 
2.2 Secondary Objective 
The secondary objective of this study is:  
 To evaluate the safety of Afrezza administered at 2 different doses, combined with basal 
insulin, in adults 18 years and older with T1DM or T2DM, as measured by: 
o 
Event rates and incidence of Level 1 (<70 mg/dL) and Level 2 (<54 mg/dL) 
hypoglycemic events within the 120 minutes after Afrezza dosing 
o 
Event rates and incidence of severe hypoglycemic events, defined as events 
requiring assistance of another person to actively administer carbohydrate, 
glucagon, or other resuscitative actions within the 120 minutes after Afrezza dosing 
o 
Change in percent predicted forced expiratory volume in 1 second (FEV1) from 
before Afrezza dosing to 120 minutes after Afrezza dosing 
o 
Incidence and severity of adverse events (AEs): treatment-emergent adverse events 
(TEAEs), serious AEs (SAEs), and AEs of special interest (AESIs) 

 
 
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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
MKC-TI-191 is a Phase 4, single-arm, multicenter clinical trial evaluating the efficacy and safety 
of Afrezza, administered according to the current Afrezza PI compared to a titrated dose, in 
combination with a basal insulin in adult subjects (≥18 years of age) with T1DM or T2DM.  
Eligible subjects will be on a stable regimen consisting of a basal-bolus insulin therapy prior to 
screening. 
The study is composed of up to 4 clinic visits (screening, 2 treatment visits, and a follow-up 
visit): 
 Screening (Visit 1): Informed consent will be obtained and eligibility confirmed. 
Eligible subjects will be enrolled at Visit 1. 
 Visit 2: The first dose of Afrezza will be based on the dose of SC RAA that the subject 
would normally take, converted according to the guidelines provided in the current 
Afrezza PI. If the subject’s normal RAA dose is <4 units, the subject will be asked to 
consume enough nutritional shake, per their normal insulin:carbohydrate ratio, to cover 
an RAA dose of ≥4 units such that their Afrezza dose at Visit 3 is higher than the dose 
taken at Visit 2. After completing the standardized meal challenge, the Investigator will 
decide, based on the subject’s glucose excursion at Visit 2, if the subject should proceed 
to Visit 3 where a second dose of Afrezza will be administered. 
 Visit 3: The second dose of Afrezza will be based on the dose of SC RAA that the 
subject would normally take, converted by multiplying their RAA dose by 2 and 
rounding down to the nearest Afrezza cartridge size.  
 Follow-up Visit (Visit 4): Subjects will return for safety assessments, including a final 
FEV1 measurement, 24 to 72 hours after their last dose of Afrezza. 
See Section 3.5 for information on the assessments to be performed at these visits. 
3.2 
Study Duration 
Two individual doses of Afrezza will be administered during the study, during Visits 2 and 3. 
The duration of each subject’s participation in the trial is expected to be approximately 2 weeks.  
The end of the clinical study is defined as the day the last subject completes his/her last visit. The 
length of the entire study (from the first subject enrolled to the last subject last visit) is expected 
to be approximately 3 months. 
3.3 
Selection of Study Population 
The population sought for this study is adult subjects ≥18 years of age with T1DM or T2DM. No 
more than 50% of subjects enrolled will have T2DM. Twenty subjects are planned to complete 
the study. Subjects who do not complete the study may be replaced. 
Specific inclusion and exclusion criteria are detailed in Section 3.3.1 and Section 3.3.2. 

 
 
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3.3.1 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible to participate in the study: 
At screening: 
1. Subjects ≥18 years of age at the time of signing the informed consent form 
2. Clinical diagnosis of T1DM or T2DM (per the Investigator) and on a stable basal-bolus 
insulin regimen 
3.3.2 Exclusion Criteria 
Subjects meeting any of the following exclusion criteria at screening will not be enrolled in the 
study. 
1. History of asthma, chronic obstructive pulmonary disease, or any other clinically 
important pulmonary disease (e.g., cystic fibrosis, bronchopulmonary dysplasia), use of 
any medications to treat such conditions within the last year, or significant congenital or 
acquired cardiopulmonary disease 
2. History of serious complications of diabetes (e.g., active proliferative retinopathy or 
symptomatic autonomic neuropathy)  
3. On dialysis 
4. Respiratory tract infection within 14 days before screening (subject may return 14 days 
after resolution of symptoms for rescreening) 
5. Treatment with any investigational drug in the past 30 days or an investigational device 
in the past 2 weeks 
6. Any disease other than diabetes or initiation of any new medication that, in the judgment 
of the Investigator, could have a direct impact on glycemic control during the study  
7. Use of antiadrenergic drugs (e.g., beta blockers and clonidine)  
8. Any concurrent illness (other than diabetes mellitus) not controlled by a stable 
therapeutic regimen 
9. History of a significant eating disorder (e.g., anorexia or bulimia nervosa) 
10. Current drug or alcohol abuse or a history of drug or alcohol abuse that, in the opinion of 
the Investigator or the Sponsor, would make the subject an unsuitable candidate for 
participation in the study 
11. History of smoking (includes cigarettes, cigars, pipes, vaping devices, and marijuana) in 
the 6 months before screening 
12. Female subject who is pregnant, breastfeeding, intends to become pregnant, or is of child-
bearing potential and not using adequate contraceptive methods as required by local 
regulation or practice (may include sexual abstinence) 
13. An event of severe hypoglycemia, as judged by the Investigator, within the 90 days 
before screening 
14. An episode of DKA requiring hospitalization within the 90 days before screening 

 
 
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15. Exposure to Afrezza in the 30 days before screening 
Subjects who are unable to comply with the requirements of the study or who, in the opinion of 
the Investigator, should not participate in the study are not eligible. In addition, any subjects for 
whom Afrezza is contraindicated, based on the Afrezza PI (Afrezza 2020), should not be 
enrolled in the study.  
3.3.3 Removal of Subjects from Therapy or Assessment 
A subject will be considered to have completed the study when the subject completes the 
treatment visits and the follow-up visit assessments.  
If a subject discontinues from the study before completing all protocol-specified visits, an 
early-termination visit should be conducted as soon as possible to have the assessments shown in 
the Schedule of Assessments (Table 2).  
Participation in the study is strictly voluntary. A subject or legally authorized representative has 
the right to withdraw from the study at any time and for any reason. If he/she chooses to 
withdraw, the Investigator must be informed immediately. The Investigator has the right to 
terminate participation of any subject at any time if the Investigator deems it in the subject’s best 
interest. The Investigator should discuss the subject’s withdrawal with the medical monitor 
beforehand, if possible. If not possible, the Investigator should discuss the withdrawal with the 
medical monitor within 24 hours of being informed of the decision.  
For any subject who fails to return to the site, the Investigator should make every effort to 
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. 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 a copy of the letter). 
Subjects withdrawn from the study must not be re-enrolled in the study. Their identification 
numbers must not be reused. 
3.3.3.1 Reasons for Discontinuation 
The reason and circumstances for early termination will be documented in the subject’s case 
report form (CRF). The reason for any early discontinuation should be indicated on this form. The 
primary reason for a subject’s early study termination should be selected from the following 
standard categories of early termination: 
 Adverse Event: Clinical or laboratory events occur that, in the medical judgment of the 
Investigator could affect the subject’s safety or well-being if treatment is continued. This 
includes serious (Section 4.1.2) and nonserious AEs regardless of relation to the study 
drug. 
 Withdrawal of Consent: The subject desires to withdraw from further participation in the 
study in the absence of an Investigator-determined medical need to withdraw. If the 
subject gives a reason for withdrawing, it should be recorded in the CRF. 

 
 
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 Major Protocol Violation: The subject’s findings or conduct fails to meet the protocol 
entry criteria or fails to adhere to the protocol requirements that are deemed to affect 
subject safety or the integrity of the study data.  
 Pregnancy: The subject becomes pregnant. 
 Smoking: The subject begins smoking or vaping, including smoking marijuana. 
 Lost to Follow-up: The subject stops coming for visits and study personnel are unable to 
contact the subject. 
 Other: The subject discontinues from the study for a reason other than those listed above, 
such as termination of study by Sponsor. 
If a subject discontinues from the study due to the ongoing severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) global pandemic, information should be captured on the CRF so 
this information can be summarized in the clinical study report at the end of the study, in line 
with the FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency (FDA 2021). The reason for discontinuation should be recorded on the 
CRF as SARS-CoV-2/coronavirus 2019 (COVID-19), if applicable, and include as many details 
as possible.  
For example, specific reasons may include, but are not limited to: 
 The subject exhibits symptoms consistent with COVID-19 within the last 10 days 
(yes/no). 
 The subject has a positive test result for SARS-CoV-2 (yes/no). 
 The subject has neither symptoms nor a positive test but has chosen to discontinue 
treatment due to COVID-19 concerns. 
3.3.4 Replacement of Subjects 
Subjects who discontinue from the study will not be replaced. 
3.4 
Treatments 
3.4.1 Details of Study Treatments and Storage Conditions 
The test product is defined as Afrezza [insulin human] inhalation powder administered using the 
inhaler (Table 1). 

 
 
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Table 1:  
Test Product (Afrezza) 
Test Product 
Trade Name 
Afrezza® 
Nonproprietary Name 
Technosphere® Insulin inhalation powder and Gen2C inhalation 
system 
Manufacturer 
MannKind Corporation 
Active Ingredient 
Human insulin, recombinant DNA origin 
Formulation 
Inhalation powder 
Each milligram of formulation contains 3.0 units of human 
insulin. 
Route 
Oral inhalation 
The inhaler is breath-powered by the subject. When the subject 
inhales through the device, the powder is aerolized and delivered 
to the lung.  
Dose(s) 
Individualized; See Section 3.5.2.2.1.1 (Visit 2) and 
Section 3.5.2.2.2.1 (Visit 3) for guidelines. 
Storage (Not in Use) 
Refrigerated at 2°C to 8°C (36°F to 46°F) 
Note: The inhaler should be at room temperature for 10 minutes 
before use. 
Storage (In Use) 
 Room temperature storage 25°C (77°F) 
 Excursions permitted to 15 to 30°C (59°F to 86°F) 
 Sealed (unopened) blister card: Must be used within 10 days 
 Opened strip: Must be used within 3 days 
Packaging 
Blister card containing 15 cartridges. Two blister cards are 
overwrapped in a foil pouch. 
Strength(s) 
Pre-metered single-dose 4-, 8-, and 12-unit cartridges will be 
provided. 
Lot and Batch Numbers 
Will be recorded in the study master file and provided in the final 
clinical study report 
In addition, subjects will take their personal basal insulin while enrolled in the study. The dose 
and type of basal insulin should not be changed between Visits 1 and 3. 
Basal insulin therapy administered via either SC injection or pump will be permitted, but pumps 
cannot be in automated insulin delivery mode for the 3 hours before or during Visits 2 or 3.  
3.4.2 Dosage Schedule 
Subjects will administer Afrezza at Visits 2 and 3, at the start of a meal challenge, according to 
the dosing guidelines provided in Section 3.5.2.2.1.1 (Visit 2) and Section 3.5.2.2.2.1 (Visit 3). 
3.4.3 Treatment Assignment 
All subjects in this study will receive Afrezza at Visits 2 and 3.  

 
 
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Subjects in this study will be assigned a unique subject identification number. Once screening 
procedures are complete, eligible subjects will be enrolled. 
3.4.4 Drug Packaging and Blinding 
This is an open-label clinical study. Neither clinical site personnel nor subjects will be blinded to 
treatment. 
3.4.5 Drug Inventory and Accountability 
The Investigator or designee is responsible for maintaining Afrezza and inhaler accountability 
records to ensure appropriate distribution throughout the clinical study. Investigators should 
maintain records that document adequately that the subjects were provided the doses specified by 
the protocol and reconcile all Afrezza and inhalers received at the site before final disposition. At 
the end of the study, or as directed, all Afrezza and inhalers, including unused, partially used, 
and empty containers will be discarded. 
3.4.6 Treatment Compliance 
It is expected that subjects will be compliant with all dosing instructions and subjects will 
administer both doses of Afrezza under clinical supervision at the study site.  
3.4.7 Prior and Concomitant Illnesses and Treatments 
3.4.7.1 Prior and Concomitant Illnesses 
Illnesses present at screening will be considered to be prior illnesses (medical history). The 
subject’s history of diabetes should be recorded at screening on the CRF. Subjects will also be 
questioned about drug and environmental allergies, family pulmonary disease history, and their 
smoking status/exposure to pulmonary toxins. Investigators (or their designee) should document 
all other significant illnesses that the subject has experienced within 6 months of screening as 
medical history on the CRF.  
After enrollment, any new or worsening illnesses should be documented as AEs in the CRF. 
3.4.7.2 Concomitant Treatments 
Any medication or therapy that is taken by or administered to the subject during the course of the 
study must be recorded in the CRF. The entry must include the dose, regimen, route, indication, 
and dates of use. 
Concomitant treatments, defined as treatments taken after enrollment, include all nonstudy 
treatments that are taken by subjects at any time during the clinical study, including prescription 
drugs, herbal supplements, or over-the-counter medications, should be recorded as concomitant 
medications.  
Antiadrenergic drugs (e.g., beta blockers and clonidine) are prohibited during the study. Subjects 
should continue their prestudy antihyperglycemic medications but no changes to their 
medications should be made between Visits 1 and 3. The initiation of drugs or herbal 

 
 
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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 medical monitor.  
3.5 
Assessments 
Unless otherwise indicated, all assessments will be performed by the Investigator or a qualified 
designee.  
3.5.1 Schedule of Assessments 
The procedures to be performed throughout the study are outlined in the Schedule of 
Assessments (Table 2).  

 
 
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Table 2:  
Schedule of Assessments 
Clinic Visit 
Screening 
Treatment Period 
Follow-up 
Early 
Termination 
Visit 1 a 
Visit 2 
Visit 3 
Visit 4 
Day 
Up to 
7 days 
before 
Visit 2 
1 
Day 4 
 Day 7 
Visit Window 
NA 
+/- 2 days 
+/- 2 days 
Informed consent 
X 
 
 
 
 
COVID-19 screening 
assessment b 
X 
 
 
 
 
Demographics and medical 
history 
X 
 
 
 
 
Eligibility criteria confirmed 
and subject registration 
X 
 
 
 
 
Vital signs measurement 
X 
 
 
 
 
Complete physical 
examination and record height 
and weight 
X 
 
 
 
 
Record concomitant 
medications 
X 
X 
X 
X 
X 
Smoking status and evaluation 
of pulmonary toxin exposure 
X 
 
 
 
 
Laboratory assessments 
HbA1c 
X 
 
 
 
 
Urine pregnancy test c 
X 
 
 
 
 
Education, treatment, and clinic assessments 
Training on the use of Afrezza 
with BluHale PRO 
 
X 
X 
 
 
Dose of Afrezza with 
standardized meal d 
 
X 
X 
 
 
SMBG measurements e 
 
X 
X 
 
 
CGM readings, if applicable f 
 
X 
X 
 
 
FEV1 measurement  
X 
X g 
X g 
X 
X 
Collect and review glucose 
meter data 
 
X 
X 
 
 
Record AEs 
X h 
X 
X 
X 
X 
Record any hypoglycemic 
episodes i 
 
X 
X 
 
 
Provide discharge instructions 
to the subject 
 
X 
X 
 
 
AE=adverse event, BMI=body mass index, CGM=continuous glucose monitor, COVID-19=coronavirus 2019, CRF=case report 
form, FEV1=forced expiratory volume in 1 second, HbA1c=glycated hemoglobin A1c, SMBG=self-monitored blood glucose. 
Note: Subjects should arrive to the clinic in a fasting state for Visits 2 and 3, with exception of treating hypoglycemia. Fasting is 
defined as no intake of drink or food, with exception of water, for ≥6 hours before the clinic visit.  
a. 
Visits 1 and 2 may be consolidated into a single clinic visit, provided the subject is in a fasting state and able to complete all 
assessments required for both visits. 
b. 
Subjects will be asked to provide a recent negative COVID-19 test (if available), confirm they have no symptoms of 
COVID-19, or provide evidence of COVID-19 vaccination. 
c. 
A negative urine pregnancy test is required for enrollment, from all female subjects of child-bearing potential. After 
enrollment, additional pregnancy tests may be conducted as needed at the discretion of the Investigator. 

 
 
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d. 
The subject’s SMBG value must be between 100 and 200 mg/dL without requiring a correction dose of bolus insulin in 
order to receive the Afrezza dose and complete the meal challenge. 
e. 
Subjects should use their Sponsor-provided blood glucose meter to take SMBG values: 15 minutes before their Afrezza 
dose, immediately before administering their dose of Afrezza (t=0; baseline) and at 15, 30, 45, 60, 90 and 120 minutes after 
Afrezza dosing. Additional SMBG measurements may be taken per Investigator discretion. 
f. 
If the subject is wearing a CGM, they will be asked to write down their CGM value every time they take an SMBG 
measurement in the clinic. These CGM values will be entered in the CRF completed at Visit 2 and Visit 3. 
g. 
At the beginning of Visits 2 and 3, before their dose of Afrezza, subjects will have FEV1 measurements taken in the clinic. 
After completion of the standardized meal challenge (120 minutes after Afrezza dose), subjects will have another FEV1 
measurement before leaving the clinic. 
h. 
Any AE that occurs after the subject enrolls in the study (consent date) will be recorded. 
i. 
Hypoglycemic episodes will be defined as all SMBG measurements <70 mg/dL. See Section 3.5.5.6. 
 
3.5.2 Study Procedures 
Subject consent will be obtained at screening before any clinical study procedures are performed. 
Procedures will be performed at the visits indicated in the Schedule of Assessments (Table 2). A 
detailed description of each assessment can be found in Sections 3.5.4 (efficacy) and 3.5.5 
(safety).  
3.5.2.1 Screening (Visit 1) 
Subject consent will be obtained upon screening before any study procedures are performed. 
The following will be performed at Visit 1: 
 Record demographics and medical history (see Section 3.5.5.1) 
 Record vital signs (see Section 3.5.5.4) 
 Perform complete physical examination (see Section 3.5.5.2) 
 Record height and weight (see Section 3.5.5.3) 
 Record concomitant medications (see Section 3.4.7.2) 
 Record smoking status and pulmonary toxin exposure 
 Measure and record FEV1 
 Collect blood and urine for laboratory tests (see Section 3.5.5.7) 
 Perform COVID-19 screening assessment 
 Enrollment (if eligibility criteria are met) 
Visits 1 and 2 may be consolidated into a single clinic visit, provided the subject is in a fasting 
state and able to complete all assessments required for both visits. 
3.5.2.2 Treatment Period 
Subjects will come into the clinic in a fasting state for Visits 2 and 3, with exception of treating 
hypoglycemia. Fasting will be defined as no intake of drink or food, with exception of water, for 
≥6 hours before the clinic visit.  
Subjects must have an SMBG value between 100 and 200 mg/dL without requiring a correction 
dose of bolus insulin in order to receive each Afrezza dose and complete the meal challenges. 

 
 
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Subjects using an insulin pump will be instructed to make sure their insulin pump is not in the 
automated insulin delivery mode for the 3 hours before and during treatment visits. Subjects will 
also be instructed not to inject correction doses of bolus insulin during the 6 hours immediately 
preceding each Afrezza dose. If the subject requires a bolus insulin injection to correct 
hyperglycemia within the 6 hours prior to the scheduled visit, the meal challenge will need to be 
rescheduled. An SMBG measurement will be taken 15 minutes before the expected dose of 
Afrezza so the Investigator can assess if the subject is within the required SMBG range (100 to 
200 mg/dL). If the subject’s SMBG value is <100 mg/dL, the Investigator can provide 15 g of 
fast-acting carbohydrates and remeasure SMBG after 30 minutes to determine if the subject 
should proceed to the meal challenge. The SMBG value obtained immediately before each dose 
of Afrezza (t=0) will be used to determine if the subject can proceed to the meal challenge and 
will serve as the baseline value for that visit. 
Each meal challenge will consist of 1 to 2 bottles of nutritional shake to be fully consumed 
within 15 minutes. The nutritional shake will contain approximately 240 calories, 41 g 
carbohydrate, 10 g protein, and 4 g fat per bottle. Each Afrezza dose will be administered at the 
start of the meal challenge. 
3.5.2.2.1 Visit 2  
The following procedures will be performed at Visit 2: 
 Record concomitant medications (see Section 3.4.7.2) 
 Complete training on the Afrezza inhaler using BluHale® PRO 
 Measure and record FEV1 before Afrezza dose  
 Take first dose of Afrezza with standardized meal challenge according to 
Section 3.5.2.2.1.1 
 Measure and record FEV1 after completion of the meal challenge 
 Record AEs 
 Collect and review glucose meter data 
 Record any hypoglycemic episodes (see Section 3.5.5.6)  
 Provide discharge instructions to the subject 
3.5.2.2.1.1 Standardized Meal Challenge and Afrezza Dosing at Visit 2  
The Afrezza dose to be taken at Visit 2 will be based on the dose of RAA that the subject would 
normally take, converted according to the guidelines provided in the current Afrezza PI as shown 
in Table 3.  
For Afrezza doses exceeding 12 units, inhalations from multiple cartridges are necessary. To 
achieve the required total mealtime dose, subjects should use a combination of 4-unit, 8-unit, and 
12-unit cartridges.    

 
 
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Table 3:  
Dose of Afrezza at Visit 2 
RAA Dose (Units) 
Afrezza Dose (Units) 
Up to 4 
4 
5 
8 
6 
7 
8 
9 
12 
10 
11 
12 
13 
16 
14 
15 
16 
17 
20 
18 
19 
20 
21 
24 
22 
23 
24 
RAA=rapid-acting insulin analog (e.g., insulin aspart or insulin lispro) 
Note: There is no maximum dose of Afrezza and the required total mealtime dose may differ from the examples provided in this 
table.  
The dose of Afrezza will be administered at the start of the meal challenge. The subject must 
consume 1 to 2 bottles of nutritional shake within 15 minutes for the meal challenge and take 
SMBG measurements 15 minutes before their Afrezza dose, immediately before administering 
the Afrezza dose (t=0; baseline) and at 15, 30, 45, 60, 90, and 120 minutes after Afrezza dosing. 
The subject will remain under clinical supervision for the 2 hours after their dose of Afrezza. 
If the subject is wearing a continuous glucose monitor (CGM), they will be asked to write down 
their CGM value every time they take an SMBG measurement in the clinic. These CGM values 
will be entered in the CRF completed at Visit 2. 
After completing the standardized meal challenge, the Investigator will decide, based on the 
subject’s glucose excursion at Visit 2 if the subject should proceed to Visit 3 where a titrated 
dose of Afrezza will be administered according to Table 4. 

 
 
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3.5.2.2.2 Visit 3 
The following procedures will be performed at Visit 3: 
 Record concomitant medications (see Section 3.4.7.2) 
 Complete refresher training on the Afrezza inhaler using BluHale PRO 
 Measure and record FEV1 before Afrezza dose  
 Take the dose of Afrezza with standardized meal challenge according to 
Section 3.5.2.2.1.1 
 Measure and record FEV1 after completion of the meal challenge 
 Record AEs 
 Collect and review glucose meter data 
 Record any hypoglycemic episodes (see Section 3.5.5.6) 
 Provide discharge instructions to the subject 
3.5.2.2.2.1 Standardized Meal Challenge and Afrezza Dosing at Visit 3 
The Afrezza dose to be taken at Visit 3 will be based on the dose of RAA that the subject would 
normally take, converted by multiplying their RAA dose by 2 and rounding down to the nearest 
Afrezza cartridge size as shown in Table 4. If the subject’s normal RAA dose is <4 units, the 
subject will be asked to consume enough nutritional shake, per their normal insulin:carbohydrate 
ratio, to cover an RAA dose of ≥4 units such that their Afrezza dose at Visit 3 is higher than the 
dose taken at Visit 2. 
For Afrezza doses exceeding 12 units, inhalations from multiple cartridges are necessary. To 
achieve the required total mealtime dose, subjects should use a combination of 4-unit, 8-unit, and 
12-unit cartridges. 

 
 
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Table 4:  
Dose of Afrezza at Visit 3 
RAA Dose (Units) 
Afrezza Dose (Units) 
<4 
4 
4 
8 
5 
6 
12 
7 
8 
16 
9 
10 
20 
11 
12 
24 
13 
14 
28 
15 
16 
32 
17 
18 
36 
19 
20 
40 
21 
22 
44 
23 
24 
48 
RAA=rapid-acting insulin analog (e.g., insulin aspart or insulin lispro) 
Note: There is no maximum dose of Afrezza and the required total mealtime dose may differ from the examples provided in this 
table.  
The dose of Afrezza will be administered at the start of the meal challenge. The subject must 
consume 1 to 2 bottles of nutritional shake within 15 minutes for the meal challenge and take 
SMBG measurements 15 minutes before their Afrezza dose, immediately before administering 
the Afrezza dose (t=0; baseline) and at 15, 30, 45, 60, 90, and 120 minutes after Afrezza dosing. 
The subject will remain under clinical supervision for the 2 hours after their dose of Afrezza.  
If the subject is wearing a CGM, they will be asked to write down their CGM value every time 
they take an SMBG measurement in the clinic. These CGM values will be entered in the CRF 
completed at Visit 3. 

 
 
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3.5.2.3 Follow-up (Visit 4) / Early-Termination Visit 
The following procedures will be performed at Visit 4, or if the subject discontinues early, at the 
early-termination visit: 
 Record concomitant medications (see Section 3.4.7.2) 
 Measure and record FEV1  
 Record AEs 
3.5.3 Procedures for Subjects Who Prematurely Withdraw from the Study 
Any subject who discontinues treatment prematurely should have an early-termination visit 
conducted as soon as possible to complete the assessments indicated in Table 2 and 
Section 3.5.2.3.  
3.5.4 Efficacy Assessment 
3.5.4.1 Self-Monitored Blood Glucose 
Subjects will measure their blood glucose using the Sponsor-provided blood glucose meter and 
corresponding supplies (lancets, control solutions, test strips, etc.). Subjects will be instructed at 
both Visits 2 and 3 to take SMBG values 15 minutes before their Afrezza dose, immediately 
before administering their dose of Afrezza (t=0; baseline), and at 30, 45, 60, 90 and 120 minutes 
after Afrezza dosing. Additional SMBG measurements may be taken per Investigator discretion. 
3.5.5 Safety Assessments 
3.5.5.1 Medical History and Demographics 
A detailed medical history should be taken to assess whether or not subjects meet the 
inclusion/exclusion criteria, 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 or T2DM). In addition, subjects will be queried 
about drug and environmental allergies, family pulmonary disease history, and any change in 
their smoking status.  
Demographic data, including age (years), race, ethnicity, and gender (male, female, other, or 
“decline to state”) will also be collected. 
3.5.5.2 Physical Examinations 
A complete physical examination, including general appearance, ear, nose, throat, lung, and 
cardiac auscultation will be performed at Visit 1.  
Abbreviated physical examinations will be performed as deemed appropriate by the Investigator 
for safety reasons; these abbreviated physical examinations will include, but are not limited to, 
general appearance, respiratory and cardiovascular systems, and other evaluations, as needed. 
All changes identified as clinically noteworthy must be recorded in an AE page of the CRF.  

 
 
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3.5.5.3 Height and Weight 
Height, in centimeters, 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. 
Body weight, in kilograms, 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. 
The body mass index (BMI) value will be calculated based on the height and weight. 
3.5.5.4 Vital Signs 
Vital signs will include body temperature, respiratory rate, pulse, and sitting systolic and 
diastolic blood pressures. Vital sign measurements will be recorded with the subject in a sitting 
position for 5 minutes before the measurement is taken. 
3.5.5.5 Pulmonary Function Tests 
Subjects will undergo pulmonary function tests (spirometry) according to American Thoracic 
Society and European Respiratory Society recommendations in the clinic.  
The FEV1 values will be recorded in the CRF. 
3.5.5.6 Hypoglycemic Events 
A hypoglycemic episode is defined as any event with SMBG <70 mg/dL (i.e., Level 1 
hypoglycemia) or SMBG <54 mg/dL (i.e., Level 2 hypoglycemia). Severe hypoglycemic events 
are defined as events requiring assistance of another person to actively administer carbohydrate, 
glucagon, or other resuscitative actions. Severe hypoglycemic events will be documented as 
SAEs in the CRF. Nonsevere hypoglycemic events will not be documented as AEs but will be 
recorded in the hypoglycemia page of the CRF.  
After the standardized meal challenges at Visit 2 and Visit 3, subjects will be monitored for signs 
of hypoglycemia. Subjects exhibiting signs of hypoglycemia will be treated as appropriate (e.g., 
provided with a snack or glucose) and the type of treatment given and time will be recorded. If a 
subject experiences hypoglycemia, SMBG measurements should be performed every 15 minutes 
until hypoglycemia is resolved. 
3.5.5.7 Clinical Laboratory Tests 
The clinical site will collect blood samples for HbA1c from subjects at Visit 1 and samples will 
be forwarded to the central laboratory for analysis. Urine pregnancy tests (for β-human chorionic 
gonadotropin) will be performed locally for women of child-bearing potential only. 

 
 
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3.5.5.8 Adverse Events 
All AEs occurring after enrollment and through the duration of the study will be recorded. See 
Section 4 for additional information. 
3.5.6 Appropriateness of Measurements 
All assessments to be used in this study are commonly used and generally recognized as relevant 
in diabetes studies.  

 
 
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4 
ADVERSE EVENT REPORTING 
Throughout the course of the study, all AEs will be monitored and recorded in an AE page of the 
CRF, including the AE’s description, start and end date, seriousness, severity, action taken, and 
relationship to the study drug. If AEs occur, the first concern will be the safety of the study 
subjects. All AEs will be followed until resolved or stable and the outcome documented in the 
CRF. 
4.1 
Definitions and Criteria 
4.1.1 Adverse Events 
Per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) E2A, an AE is any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. 
The intensity of each AE will be determined according to the following criteria: 
 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. 
Medical interventions such as surgeries, diagnostic procedures, and therapeutic procedures are 
not AEs but the action taken to treat a particular medical condition. They should be recorded as 
treatment of the AEs. 
4.1.2 Serious Adverse Events 
An SAE or reaction is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event (e.g., intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias, or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse; malignancy tumors 
[histologically different from primary tumor]) 

 
 
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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 subject or may require 
intervention to prevent one of the other outcomes listed in the definition above.  
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. An 
SAE is not necessarily severe (e.g., an overnight hospitalization for a diagnostic procedure must 
be reported as an SAE even though the occurrence is not medically serious). Furthermore, a 
severe AE is not necessarily serious (e.g., nausea of several hours’ duration may be rated as 
severe but may not be considered serious). 
4.1.3 Adverse Events of Special Interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern, specific to the 
investigational medicinal product 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 the SAE 
notification guidelines described in Section 4.2.2.  
The following AEs are considered AESIs: 
 Acute bronchospasm 
 Clinically relevant decline in pulmonary function (>20% decline from baseline percent 
predicted FEV1 accompanied by respiratory symptoms) 
 Hypersensitivity reactions, including anaphylaxis, which can occur with insulin products, 
including Afrezza 
 DKA 
The following diagnostic criteria must be met to be considered a DKA event (ADA 2004): 
 Arterial blood pH <7.30 or serum bicarbonate <15 mEq/L 
 Blood glucose >250 mg/dL (or >13.9 mmol/L) 
 Serum ketones or large/moderate urine ketones 
 Symptoms such as polyuria, polydipsia, nausea, or vomiting 
 Treatment provided in a health care facility 
4.1.4 Abnormal Laboratory Values 
Any abnormality in a laboratory value that is new in onset or that has worsened in severity or 
frequency from the baseline condition and meets one of the following criteria will be recorded in 
the AE pages of the CRF: 
 Requires therapeutic intervention or diagnostic tests 
 Leads to discontinuation of study drug 
 Has accompanying or inducing symptoms or signs 

 
 
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 Is judged by the Investigator as clinically significant 
4.1.5 Assessing Relationship 
The Investigator will classify every AE according to its relationship to study drug, study device, 
or study-related procedure. The AE relationship categories that will be used are listed below: 
Related:  
 An AE that occurs at a reasonable time interval after administration of the investigational 
product, use of the device, or procedure 
 An AE that follows a known response pattern to the investigational product, use of the 
device, or procedure 
 An AE that improves after stopping the investigational product, use of the device, or 
procedure and reappears after repeated exposure to the investigational product, device, or 
procedure. Depending on the nature of the AE, rechallenge may not be possible. 
Probably related:  
 An AE that occurs at a reasonable time interval after administration of the investigational 
product, use of the device, or procedure 
 An AE that follows a known response pattern to the investigational product, use of the 
device, or procedure, where an alternative explanation (e.g., a concomitant drug or 
concurrent disease) is less likely 
Possibly related:  
 An AE that occurs at a reasonable time interval after administration of the investigational 
product, use of the device, or procedure 
 An AE that follows a known response pattern to the investigational product, use of the 
device, or procedure, but could have been produced by the subject’s clinical status or by 
other therapies 
Unlikely related:  
 An AE for which sufficient information exists to indicate that the etiology is unrelated to 
the investigational product, use of the device, or procedure 
 An AE for which another etiology is specified 
Not related:  
 An AE without a temporal relationship to the investigational product (e.g., an AE 
occurring in a subject who has not received investigational product), use of the device, or 
procedure 
 An AE for which another cause is known 

 
 
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4.2 
Reporting Procedures and Requirements 
4.2.1 Adverse Events 
Any AEs occurring from when the subject enrolls in the study (consent date) until they exit the 
study will be recorded.  
The Investigator should document all AEs in the subjects’ source documentation, on the AE page 
of the CRF, and the SAE report (if the AE is serious). AEs of hypoglycemia that meet SAE 
criteria should be documented in the AE page of the CRF and SAE report.  
The Investigator should specify the date of the onset of the AE, the intensity (see definitions in 
Section 4.1), action taken with respect to the study drug, corrective treatment/therapy given, 
additional investigations performed, outcome, and the relationship to study drug (Section 4.1.5). 
Whenever possible, the diagnosis or syndrome should be reported instead of individual 
associated symptoms (e.g., record “influenza” if this is the diagnosis instead of “fever” and 
“chills”).  
Every AE and SAE should be followed until resolved, or resolved with sequelae, or considered 
stable in the opinion of the Investigator. To the extent possible, event resolution information will 
be obtained by means of due diligence (see the site operations manual). 
If the severity of an AE increases, a new AE page in the CRF must be completed for that AE. 
The date of change would be included as the end date for the original AE and the start date for 
the new AE of greater severity. 
4.2.2 Adverse Events of Special Interest and Severe Hypoglycemia 
As soon as possible (desired within 24 hours of Investigator or study coordinator awareness), the 
investigational center staff must report all events of severe hypoglycemia and AESIs (including 
DKA) to the Sponsor. For these events, the AE page of the CRF will be completed with all 
known details as soon as possible, this will serve as notification to the Sponsor. If the study 
database cannot be accessed due to technical problems, contact the Sponsor and provide the 
known details of the event. Once the access issue has been corrected, the event should be entered 
onto an AE page in the CRF.  
Source documents that support the event (e.g., clinic notes, hospital admission and discharge 
records, lab reports, emergency medical technician reports, emergency room/urgent care) should 
be provided to the Sponsor. All source documents/medical records should be redacted. Each 
source page should be identified with the subject identification number. 
4.2.3 Serious Adverse Events 
Prompt notification by the Investigator to the Sponsor of an SAE (within 24 hours) is essential so 
that legal obligations and ethical responsibilities toward the safety of participants and the safety 
of a study intervention under clinical investigation are met.  

 
 
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The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with all applicable regulatory requirements relating to safety reporting to 
the regulatory authority, institutional review board (IRB), and investigators. 
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 investigational product with a 
reasonable possibility should also be reported. 
4.3 
Procedures for Documenting Pregnancy During Study 
If a female subject becomes pregnant during the study, the Investigator will notify the medical 
monitor immediately following pregnancy confirmation. A subject who becomes pregnant over 
the course of this study will be discontinued from study drug and followed for safety outcomes 
until 30 days beyond resolution of the pregnancy. Pregnancy is not in and of itself an AE. 
However, if any adverse findings in a child or fetus of a subject exposed to the study drug before 
conception or during pregnancy should be reported as AEs.  

 
 
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5 
DATA MANAGEMENT AND STATISTICAL ANALYSIS 
5.1 
Data Management Considerations 
Paper CRFs will be employed for this study. Completed CRFs for this study will be forwarded to 
the Sponsor or its representative where editing and construction of a validated database will 
occur. Data will be quality checked, double-entered, and verified before entry into the database. 
Queries will be issued for any inconsistencies, omissions, and discrepancies and will be resolved 
by the appropriate parties. The statistical analysis of these data will be performed by the Sponsor 
or its representative. All AEs will be coded using the latest version of the Medical Dictionary for 
Regulated Activities (MedDRA). Concomitant medications will be coded using the latest version 
of WHODrug Global. Data management details will be outlined in a separate data management 
plan. 
5.2 
Statistical Considerations 
Any deviations from the analyses described below will be documented prior to database lock, 
which will be described in the clinical study report. 
5.2.1 General Considerations 
All statistical processing will be performed using the most current version of SAS® software 
(SAS Institute Inc, Cary, NC) at the time of the analysis. Summary tables (descriptive statistics 
and/or frequency tables) will be provided for screening and/or baseline variables, efficacy 
variables, and safety variables. Continuous variables will be described by descriptive statistics 
(n, mean, median, standard deviation, minimum, and maximum). Frequency counts and 
percentage of subjects within each category will be provided for categorical data.  
Individual data will be listed and sorted by treatment, subject identification number, visit, and 
time point. 
Database lock will occur upon the completion of the study. 
5.2.2 Randomization 
This study is an open-label, single-arm study (not randomized). 
5.2.3 Sample Size Justification 
The sample size (20 subjects completing the study) was not determined using statistical methods, 
but rather was chosen based on clinical considerations.  
5.2.4 Analysis Populations 
All subjects in the clinical study who receive a dose of Afrezza will be included in the analyses 
reported at the end of the study. 
5.2.5 Protocol Deviations 
Major protocol deviations (number and percentage of subjects) will be summarized. All protocol 
deviations will be reviewed by clinical and statistical personnel to identify important deviations 

 
 
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(those anticipated to have an impact on efficacy or safety findings) before the primary database 
lock. 
5.2.6 Subject Disposition 
Disposition (the number and percentage of subjects completed or discontinued from the study) 
will be summarized by visit and/or study period. Reasons for discontinuation will also be 
summarized. 
5.2.7 Demographic and Baseline Characteristics 
Demographic and baseline characteristics, including usual basal and bolus insulin doses, at 
screening will be summarized descriptively. Summary statistics will include frequency and 
percentage, means, standard deviation, minimum, and maximum as appropriate. 
5.2.8 Medical History 
Medical history data will be collected at the screening visit. The number and percentage of 
subjects with each medical history preferred term and system organ class will be summarized. 
5.2.9 Concomitant Medications 
All nonstudy medications will be coded with the current version of WHODrug Global. 
Concomitant medications refer to nonstudy medications that have been used on or after 
administering the first dose of study drug. Among the concomitant medications, new 
concomitant medications refer to medications that are started after administering the first dose of 
study drug.  
The number and percentage of subjects administering concomitant medications and new 
concomitant medications will be summarized by Anatomic Therapeutic Chemical Classification 
System Level 4 category and preferred term.  
5.2.10 Treatment Exposure and Compliance 
Descriptive statistics will be used to summarize subject dosing information including the basal, 
bolus, and total insulin doses by visit. 
A by-subject listing of study drug administration will also be provided.  
5.2.11 Efficacy Analyses 
SMBG values will be summarized by visit. A summary table with descriptive statistics (n, mean, 
median, standard deviation, minimum, and maximum) by time point relative to Afrezza dosing 
will be provided. SMBG data will also be presented graphically. 
5.2.12 Safety Analyses 
The incidence of hypoglycemia (total, nocturnal, and severe) and number of hypoglycemic 
episodes will be summarized. Summary tables providing frequency counts and the percentage of 
subjects within each category will be provided for Level 1 hypoglycemia (SMBG <70 mg/dL) 

 
 
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and Level 2 hypoglycemia (SMBG <54 mg/dL). Exposure-adjusted incidence rates and 
exposure-adjusted event rates will be calculated and summarized. 
The number and percentage of subjects with TEAEs will be tabulated by system organ class and 
preferred term by relationship to treatment and by severity.  
A summary table by study visit with descriptive statistics for FEV1 at all time points will be 
provided. The FEV1 data will also be presented graphically. 

 
 
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6 
STUDY MANAGEMENT 
6.1 
Ethics and Consent 
6.1.1 Regulations and Guidelines 
The study will be performed in accordance with this protocol state and federal laws, and ICH 
guidelines for Good Clinical Practice.  
6.1.2 Institutional Review Board 
The clinical trial documents, including this protocol, will be reviewed by the relevant IRB before 
the start of the study.  
Conduct of the trial must be approved by an appropriately constituted IRB. Approval is required 
for the study protocol, protocol amendment(s), informed consent forms(s), subject information 
sheets, and any advertising materials. No investigational product will be shipped to a site until 
written IRB authorization has been received by the Sponsor or its representative. 
6.1.3 Informed Consent 
For each trial subject, written consent will be obtained before any protocol-related activities are 
performed. As part of this procedure, the Investigator or a designated representative must explain 
orally and in writing the nature, duration, and purpose of the study, and the action of the study 
drug in such a manner that the subject is aware of the potential risks, inconveniences, or adverse 
effects that may occur. Subjects should be informed that they may withdraw from the study at 
any time without any resulting disadvantage. They will receive all information that is required by 
local regulations and ICH guidelines. 
6.1.4 Data Protection 
The Sponsor will ensure the confidentiality of a subject’s medical information in accordance 
with all applicable laws and regulations. 
Personal data generated within the scope of this study must be available for inspection upon 
request by representatives of the Sponsors’ monitors, representatives, and collaborators. 
6.2 
Discontinuation of the Study by the Sponsor 
The Sponsor reserves the right to discontinue the study at this site or at all sites for safety or 
administrative reasons at any time. In particular, a site that does not recruit at a reasonable rate 
may be discontinued. Should the study be terminated and/or the site closed for whatever reason, 
all documentation pertaining to the study and study drug must be returned to the Sponsor or its 
representative. 
6.3 
Study Documentation 
The Investigator will acknowledge that he/she has received a copy of the Afrezza IB and assures 
the Sponsor that he/she will comply with the protocol. No changes in this protocol can be made 
without the Sponsor’s written approval. 

 
 
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6.4 
Data Management and Quality Control 
6.4.1 Case Report Forms 
The Investigator should maintain adequate and accurate source documents and trial records that 
include all pertinent observations on each of the site’s trial subjects. Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete. 
All clinical data will be captured in a validated database.  
The Investigator site staff will enter and edit the data via a secure network, with secure access 
features (username and password). A complete audit trail will be maintained. The Investigator 
will approve the data using an electronic signature, and this approval will be used to confirm the 
accuracy of the data recorded. Data for all subjects will be recorded in CRFs. The subject data 
will be accessible from the Investigator’s site throughout the trial. The CRF must be kept current 
to reflect subject status at each phase during the course of the trial. The CRF will not capture 
personalized data. The Investigator must make a separate confidential record of personalized 
details (name and initials) on the subject identification and enrollment log.  
It is the responsibility of the Investigator of the respective site to ensure that all subject 
discontinuations or changes in study or other medications entered in the subject’s CRF are also 
made on the subject’s medical records. The CRFs for any subject leaving the study should be 
completed at the time of the final visit or shortly thereafter. 
6.4.2 Study Monitoring and Quality Assurance 
This study will be performed in compliance with the Sponsor’s standard operating procedures 
(SOPs) or with the contract research organization’s SOPs, if applicable, and with regulations set 
forth by the FDA, ICH, and other significant regulatory authorities. Compliance will be achieved 
through study-specific audits of clinical sites and review of data. The Investigator or their 
qualified designee will enter the information required by the protocol on CRFs provided by the 
Sponsor. Site monitors should visit each clinical site at a frequency documented in the 
monitoring plan to review CRFs for completeness and accuracy. Any discrepancies found 
between source documents and completed CRFs should be queried and appropriate clinical site 
personnel should address and or correct those discrepancies.  
Computerized and manual procedures should be used to review and check data from CRFs and 
data from external sources for omissions, apparent errors, and values that may require further 
clarification from the clinical site. Data queries will be addressed by appropriate clinical 
personnel in the CRF. Only authorized personnel can make corrections to CRF in the clinical 
database and all corrections are documented in the CRF audit trail. 
6.5 
Retention of Records 
The Investigator must arrange for retention of study records at the site. The Investigator should 
take measures to prevent accidental or premature destruction of these documents for the duration 
of the retention period. 

 
 
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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. 
6.6 
Use of Study Findings 
By signing the study protocol, the Investigator agrees to the use of results of the study for the 
purposes of national and international registration. If necessary, the authorities will be notified of 
the Investigator’s name, address, qualifications, and extent of involvement. Reports covering 
clinical and biometric aspects of the study will be prepared by the Sponsor or its representative. 
6.7 
Financial Disclosure 
Investigators will be required to disclose any financial equity interests in the Sponsor and any 
conflicts of interest. 
6.8 
Publications and Disclosure Policy 
This clinical study will be registered on ClinicalTrials.gov no later than 21 days after the first 
subject is enrolled, in compliance with applicable regulatory requirements. 
As a multicenter trial, the Sponsor intends to publish clinical data from all centers participating 
in the investigation. Authorship and manuscript composition will reflect joint cooperation 
between multiple investigators, sites, and the Sponsor’s personnel. Authorship will be 
established before writing of the manuscript. 
In conformity with International Committee of Medical Journal Editors (ICMJE 2019) 
recommendations, investigators whose contribution consists solely in the collection of data will 
not be named individually as authors. Rather, those investigators may be included in a collective 
authorship (e.g., “Clinical Investigators”) or acknowledged individually with their 
contribution(s) specified. 
Individual investigators and/or their associates subsequently may publish additional findings of 
this study in scientific journals or present them at scientific meetings, provided that the Sponsor 
is given ample opportunity to review and authorize the disclosure of data for any proposed 
abstract, manuscript, or slide presentation before its submission. This review is required to 
ensure that the Sponsor authorizes the presentation of the data prior to disclosure. 

 
 
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7 
REFERENCES 
American Diabetes Association (ADA). Hyperglycemic crises in diabetes. Diabetes Care. 
2004;27(Suppl 1):94-102. 
Afrezza (insulin human) inhalation powder prescribing information. MannKind Corporation. 
Danbury, CT 06810; February 2020. 
Food and Drug Administration [FDA]. FDA guidance on conduct of clinical trials of medical 
products during COVID-19 public health emergency. [cited 07 Feb 2021]. Available from: 
https://www.fda.gov/media/136238/download 
Grant ML, Pompilio F, Sharma G, Krueger JA, Kendall DM, Zaveri N. 151-OR: Technosphere 
Insulin Provides Better Early Postprandial Glucose Control than Subcutaneous Rapid-Acting 
Analog. Diabetes. 2019;68(Suppl 1). 
International Diabetes Federation. IDF Diabetes Atlas, 9th edition. Brussels, Belgium: 
International Diabetes Federation, 2019. 
International Committee of Medical Journal Editors [ICMJE]. Recommendations for the 
conduct, reporting, editing, and publication of scholarly work in medical journals. Updated 
December 2019 [cited 08 Mar 2021]. Available from: http://icmje.org/icmje-
recommendations.pdf  
Investigator’s Brochure: Technosphere Insulin Inhalation System. MannKind Corporation 
Version 16.0. 03 Jan 2021. 
Kendall DM, Krueger JA, Abaniel R, Morey PM, Jones MC, Grant M, et al. Inhaled 
Technosphere® Insulin dosing vs subcutaneous analog insulin dosing for comparable efficacy 
in type 1 diabetes. Poster 1023-P. American Diabetes Association’s 80th Scientific Sessions; 
12-16 June 2020; Virtual format. 
Peyrot M, Rubin R, Kruger DF, Travis LB: Correlates of insulin injection omission. Diabetes 
Care. 2010;33(2):240-245.