ABC [Afrezza With Basal Combination]: A Phase 4 Study of Mealtime Control With Afrezza in Adult Subjects With Type 1 Diabetes Mellitus in Combination With an Automated Insulin Pump or Insulin Degludec
Phase: PHASE4
Conditions: Type 1 Diabetes
Sponsor: Mannkind Corporation

Protocol Title: ABC [Afrezza with Basal Combination]: A Phase 4 Study of Mealtime Control with Afrezza 
in Adult Subjects with Type 1 Diabetes Mellitus in Combination with an Automated Insulin Pump or 
Insulin Degludec 
Brief Title: Afrezza With Basal Combination (ABC) 
Protocol Number: MKC-TI-192 
Clinical Phase: Phase 4 
Protocol Version and Date: Version 2.0, 20 June 2022 
Sponsor: MannKind Corporation, 30930 Russell Ranch Road, Suite 300, Westlake Village, CA 91362 
NCT Number: NCT05243628 

Clinical Study Protocol
Protocol Title:
ABC [Afrezza with Basal Combination]: A Phase 4 
Study of Mealtime Control with Afrezza in Adult 
Subjects with Type 1 Diabetes Mellitus in 
Combination with an Automated Insulin Pump or 
Insulin Degludec 
Protocol Number:
MKC-TI-192
Clinical Phase:
Phase 4
Protocol Version and Date:
Version 2.0, 20 June 2022
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: ABC [Afrezza with Basal Combination]: A Phase 4 Study of Mealtime Control 
with Afrezza in Adult Subjects with Type 1 Diabetes Mellitus in Combination with an 
Automated Insulin Pump or Insulin Degludec
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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REVISION HISTORY
VERSION
NUMBER
AUTHOR
APPROVER
EFFECTIVE 
DATE
REVISION DESCRIPTION
1.0
MannKind
Kevin 
Kaiserman
01Feb2022
Original version
1.1
Johanna Ulloa
Kevin 
Kaiserman
04Mar2022
(1) Updated CGM language to clarify that reports will be 
downloaded for Medtronic CGM and pumps and reports/data will 
be downloaded for Dexcom CGM and Tandem pump. (2) Updated 
meter language to clarify that all subjects will receive a study-
provided glucose meter (minimally) for collection of 
hypoglycemia events. (3) Updated Table 3 to review/download 
unblinded CGM at V2, collect glucose meter data at V14 and EOT, 
and clarified that insulin degludec injection supplies are only for 
Afrezza + Insulin Degludec group. (4) Removed placement of 
Dexcom G6 PRO from Section 3.7.2. (5) Clarified in section 
3.8.1.1 that blinded CGM at baseline can be worn for up to 20 days 
during a 28-day screening window. (6) Clarified in section 3.7.2.1 
that confirmation of glucose being ≥70mg/dl will happen 15 
minutes before start of the meal. (7) Updated history of diabetes 
definition in section 3.8.2.1 to only include date of clinical 
diagnosis of T1DM, start date of current insulin treatments, and 
treatment name. (8) Incorporated vital signs as an optional 
procedure during the physical examination. (9) Updated statistical 
processing tools in section 5.3.
2.0
Jennifer Pleitez
Kevin 
Kaiserman
20June2022
(1) Inclusion criteria 4 revised to ensure that subjects are using the 
AID automated mode function (2) Added Table 4 to identify visits 
that require CGM/pump report/data; added one additional report to 
retrieve (10d prior to V9) (3) Clarified that post-meal insulin 
correction doses and the insulin to use for correction dose of each 
Afrezza treatment group. (4) Added requirement to train 
participants on CGM use (5) Inserted instruction to take carbs or 
glucagon should a subject accidentally take Afrezza with a meal 
announcement. (6) Inserted instruction to train subject on 
appropriate use of glucagon for emergency situations; language 
added to ensure subject has glucagon available in the event of 
hypoglycemia. (7) Inserted text to ensure that participants are 
trained to identify and manage any events of hypo and 
hyperglycemia. Provided specific instruction to manage DKA if 
glucose is >250 mg/dL (8) Added that subjects who experience 
respiratory symptoms that are not associated with an upper 
respiratory infection (URI) should undergo additional pulmonary 
function test to monitor clinically relevant decline. (9) Inserted text 
to define the clinically relevant decline in pulmonary function. (10) 
Inserted criteria or discontinuing the study (11) Added details of 
post study interview
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SYNOPSIS
Protocol Title:
ABC [Afrezza with Basal Combination]: A Phase 4 Study of 
Mealtime Control with Afrezza in Adult Subjects with Type 1 
Diabetes Mellitus in Combination with an Automated Insulin Pump 
or Insulin Degludec
Protocol Number:
MKC-TI-192
Sponsor:
MannKind Corporation
Investigator(s)/Study 
Center(s): 
This study will be conducted by Investigators at two or more study 
centers located in the United States.
Phase of 
Development:
Phase 4
Objectives:
Primary Objective:

To evaluate the change in glycated hemoglobin (HbA1c) from 
baseline to end of study in adults 18 years of age with type 1 
diabetes mellitus (T1DM) for each of the three following groups:
o Afrezza + AID: Afrezza for bolus (mealtime) in combination 
with use of a continuous subcutaneous insulin infusion (CSII) 
pump with an automated insulin delivery (AID) algorithm 
using a rapid-acting insulin analog (RAA) for basal and 
correction insulin coverage
o Afrezza + Insulin Degludec: Afrezza for bolus (mealtime and 
correction) in combination with insulin degludec for basal 
insulin coverage
o AID Control: CSII pump with an AID algorithm using an 
RAA for all bolus (mealtime and correction) and basal insulin 
coverage
Secondary Objectives:

To evaluate the safety of study treatment based on hypoglycemia 
event rate and severe hypoglycemia incidence rate in adults 
18 years of age with T1DM for each of the three following 
groups:
o Afrezza + AID
o Afrezza + Insulin Degludec 
o AID Control

To evaluate the impact of study treatment on overall glycemic 
control when comparing baseline versus end of treatment period 
as measured by core continuous glucose monitoring (CGM) 
metrics:
o Change in percent time in range (TIR), defined as time spent 
with glucose in the range of 70 to 180 mg/dL
o Change in percent time below range (TBR), defined as time 
spent with glucose <70 mg/dL
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o Change in percent time spent with glucose <54 mg/dL
o Change in percent time above range (TAR), defined as time 
spent with glucose >180 mg/dL
o Change in percent time spent with glucose >250 mg/dL
o Change in glycemic variability as measured by coefficient of 
variation (CV)
The above metrics will be evaluated in adults 18 years of age 
with T1DM for each of the three following groups:
o
Afrezza + AID
o
Afrezza + Insulin Degludec 
o
AID Control
Study Design:
MKC-TI-192 is a Phase 4, 90-day, randomized, three-arm, 
multicenter clinical trial evaluating the treatment paradigm and 
efficacy of Afrezza in controlling postprandial glucose in adult 
subjects (≥18 years of age) with T1DM. Subjects will be randomized 
to one of three treatment groups (two Afrezza groups and one control 
group): 

Afrezza + AID: Subjects in this group will use Afrezza for their 
bolus (mealtime) insulin and a CSII pump with an AID 
algorithm using RAA for their basal and correction insulin 
coverage.

Afrezza + Insulin Degludec: Subjects in this group will use 
Afrezza for their bolus (mealtime and correction) insulin and 
insulin degludec for basal insulin coverage. 

AID Control: Subjects in this group will use a CSII pump with 
an AID algorithm using RAA for all bolus (mealtime and 
correction) and basal insulin coverage (control group).
The study is composed of up to 5 clinic visits (screening, 3 treatment 
visits, and an end-of-treatment visit) and 9 telephone visits:

Visit 1 (Screening): Informed consent will be obtained and 
screening procedures performed. Laboratory values will be 
collected for HbA1c, creatinine and thyroid-stimulating hormone 
(TSH); a documented normal TSH or creatinine level within 
6 months of screening can be used in lieu of testing. A baseline 
forced expiratory volume in one second (FEV1) measurement 
will be obtained. A Dexcom G6 Professional (G6 Pro) blinded 
CGM device will be placed on each subject. Subjects will 
continue to use their own CGM device in addition to the blinded 
CGM.

Visit 2 (Randomization & Meal Challenge): At least 10 days 
(+ 4 days) after Visit 1, subjects will return for Visit 2. At this 
visit, the Investigator will evaluate for appropriate use of the 
blinded sensor and will download the blinded CGM data (CSV 
file). If sensor wear time is inadequate, sensor wear can be 
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repeated once and this becomes an unscheduled visit. The subject 
will return to the clinic 10 days (+ 4 days) later, and if the sensor 
wear is adequate and all eligibility criteria are met, be 
randomized to study treatment and proceed to the meal challenge 
and other Visit 2 assessments. 
Subjects will be randomized in a 2:2:1 ratio to the following 
treatment groups, with the goal of 25 subjects enrolled:

Afrezza + AID (N=10)

Afrezza + Insulin Degludec (N=10)

AID Control (N=5)
In order to achieve balanced representation of Medtronic 670G/ 
770G and Tandem Control IQ AID users for each group, the 
randomization will target for a minimum number of subjects who 
use each AID system as follows: 

Within each Afrezza group (Afrezza + AID, Afrezza + 
Insulin Degludec):
o
3 subjects using Medtronic 670G/770G
o
3 subjects using Tandem Control IQ AID

Within the AID Control group:
o
2 subjects using Medtronic 670G/770G
o
2 subjects using Tandem Control IQ AID
Subjects will come to the clinic fasting with no manual insulin bolus 
administered within the prior 4 hours. CGM reports and pump 
reports will be downloaded from V1 to V2 using Carelink for 
Medtronic CGM and pumps, CGM reports/data and pump 
reports/data will be downloaded from V1 to V2 using Clarity for 
Dexcom CGM and t:connect for Tandem pumps. The site will de-
identify all reports and data. Subjects will undergo a 2-hour meal 
tolerance test in the clinic. The Afrezza + Insulin Degludec and the 
Afrezza + AID groups will receive an Afrezza initial dose that is 2 
times the calculated RAA dose (based on their insulin-to-
carbohydrate ratio [I:CHO] calculated prandial dose) rounded down 
to the nearest 4-unit dose of Afrezza, but not exceeding 24 units of 
Afrezza. The Afrezza dose will be administered at the start of the 
meal challenge. The AID Control group will administer bolus insulin 
10 ± 5 minutes (per label) prior to the meal, per Investigator 
discretion. The start of the meal will define t=0. Subjects in the 
Afrezza + Insulin Degludec group will continue on AID throughout 
the meal tolerance test and then transition to insulin degludec at the 
discretion of the Investigator. Basal insulin doses and time of 
administration in all study subjects will be documented. Subjects 
should have glucagon available for use in the event of hypoglycemia 
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and should not be discharged until hypoglycemia is resolved.

Visits T3, T4, T5, T6, T7, T8 (Telephone): Between Visits 2 
and 9 in the clinic, several telephone visits will be conducted. 
During these visits, the Investigator will titrate insulin dosages, 
ask about changes to concomitant medications, record any 
adverse events (AE) and hypoglycemic events, and answer any 
questions/concerns raised by the subject. 

Visit 9 (Clinic): This visit will be conducted at least 30 days 
(+ 7 days) after Visit 2. CGM reports and pump reports will be 
downloaded from V2 to V9 using Carelink for Medtronic CGM 
and pumps, CGM reports/data and pump reports/data will be 
downloaded from V2 to V9 using Clarity for Dexcom CGM and 
t:connect for Tandem pumps.  The site will de-identify all reports 
and data. The Investigator will titrate insulin dosages. Basal 
insulin dosages will be documented.

Visits T10, T11, T12 (Telephone): Between Visits 9 and 13 in 
the clinic, three telephone visits will be conducted. During these 
visits, the Investigator will titrate dosages and answer any 
questions/concerns raised by subjects. 

Visit 13 (Clinic): This visit will occur 8 to 10 days prior to 
Visit 14. CGM reports and pump reports will be downloaded 
from V9 to 30 days after V9 using Carelink for Medtronic CGM 
and pumps, CGM reports/data and pump reports/data will be 
downloaded from V9 to 30 days after V9 using Clarity for 
Dexcom CGM and t:connect for Tandem pumps. The site will 
de-identify all reports/data. The Investigator will place a Dexcom 
G6 Pro blinded sensor on subjects in all groups. The Investigator 
will titrate insulin dosages. Additionally, Afrezza + AID and 
Afrezza + Degludec groups will be asked to log meal 
announcements and Afrezza doses in the final 10 days. 

Visit 14 (Clinic): At least 90 days following Visit 2 (+ 7 days), 
subjects will return for HbA1c measurement and safety 
assessments, including a final FEV1 measurement. The 
Investigator will download the blinded CGM data (CSV file) 
from the prior sensor wear. Additionally, CGM reports and pump 
reports will be downloaded from 30 days before V14 to V14 and 
from V13 to V14 using Carelink for Medtronic CGM and pumps, 
CGM reports/data and pump reports/data will be downloaded 
from 30 days before V14 to V14 and from V13 to V14 using 
Clarity for Dexcom CGM and t:connect for Tandem pumps. The 
site will de-identify all reports and data. Basal insulin dosages 
will be documented.
Planned Sample Size:
25 subjects (10 in each Afrezza group, 5 in AID Control group)
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Medical Condition or 
Disease Under 
Investigation:
T1DM 
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 
3. 7.0% and <11.0% HbA1c
4.
Treatment with a CSII pump with an AID algorithm 
(Medtronic 670G/770G or Tandem Control IQ) for at least 3 
months, including use of the AID automated mode function.
5. Ability to pay for their own RAA used in the insulin pump or 
injections, either through co-pay or self-pay, for the duration of 
the study (see acceptable insulin analogs below) 
6. Willingness to follow study procedures including discontinuing 
their insulin pump and transitioning to insulin degludec 
injections plus Afrezza
Exclusion Criteria
At screening:
1. A recent history of asthma (defined as using any medications to 
treat within the last year), chronic obstructive pulmonary disease 
(COPD), or any other clinically important pulmonary disease 
(e.g., cystic fibrosis, bronchopulmonary dysplasia), or significant 
congenital or acquired cardiopulmonary disease
2. History of serious complications of diabetes (e.g., active 
proliferative retinopathy or symptomatic autonomic neuropathy) 
3. History of hypersensitivity to insulin or any of the Afrezza 
excipients
4. On dialysis
5. Respiratory tract infection within 14 days before screening 
(subject may return 14 days after resolution of symptoms for 
rescreening)
6. Exposure to any investigational drug in the past 30 days or an 
investigational device in the past 2 weeks
7. Adrenal insufficiency, active use of steroids or planned steroid 
use
8. Hypothyroidism not controlled, as defined by TSH outside the 
upper limit of the reference range by >1.5 × in the last 6 months, 
according to the local laboratory reference range 
9. Hyperthyroidism not controlled, as defined by TSH below the 
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normal reference range, according to the local laboratory
10. Use of antiadrenergic drugs (e.g., beta blockers and clonidine)
11. Any concurrent illness (other than diabetes mellitus) not 
controlled by a stable therapeutic regimen
12. History of a significant eating disorder (e.g., anorexia or bulimia 
nervosa)
13. 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
14. History of smoking (includes cigarettes, cigars, pipes, vaping 
devices, and marijuana) in the 6 months before screening
15. Female subject who is pregnant, breast-feeding, 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)
16. An event of severe hypoglycemia, as reported by the patient, 
within the last 180 days before screening
17. An episode of diabetic ketoacidosis requiring hospitalization 
within the last 180 days before screening
18. Exposure to Afrezza in the 30 days before screening
19. Abnormal TSH, or creatinine levels above 2.0 mg/dL
Study Treatment(s):
Subjects randomized to the Afrezza + AID group (N=10) or the 
Afrezza + Insulin Degludec group (N=10) will receive Afrezza in 
this study. The AID Control group (N=5) will continue AID with 
their currently prescribed RAA. 
AID Systems:
Acceptable AID systems in this study are Medtronic 670G/770G and 
Tandem Control IQ AID. 
The randomization will target for a minimum of 3 subjects each who 
use Medtronic 670G/770G and Tandem Control IQ AID in each of 
the Afrezza groups, and a minimum of 2 subjects each who use 
Medtronic 670G/770G and Tandem Control IQ AID in the AID 
Control group. 
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 and RAA 
Insulin Therapy Dose, 
and Mode of 
Administration:
Basal insulin analog: Insulin degludec
Infused rapid-acting: Insulin aspart (Novolog® or Fiasp®) or 
insulin lispro (Humalog®, Admelog®, or Lyumjev®) for basal insulin 
coverage (insulin pump/AID users)
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Dose regimen: Individualized 
Mode of Administration: Subcutaneous injection or infusion
Duration of 
Treatment:
90 days
Criteria for 
Evaluation:
This study will evaluate the efficacy and safety of Afrezza combined 
with basal insulin or AID with insulin pump therapy, based on the 
endpoints outlined below:
Efficacy Endpoints

Change in HbA1c from baseline to end of study
Safety Endpoints

Event rates and incidence of Level 1 (<70 mg/dL) and Level 2 
(<54 mg/dL) hypoglycemic events as confirmed by self-
monitored blood glucose (SMBG)

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: treatment-emergent AEs, serious 
adverse events (SAEs), adverse events of special interest 
(AESIs), and device complaints

Change in FEV1 from screening to end of study
Statistical Methods:
Sample Size Determination
Twenty-five subjects are planned to complete this proof-of-concept 
study. Subjects who discontinue from the study within the first 
4 weeks will be replaced. Subjects who discontinue from the study 
after 4 weeks will not be replaced. If possible, HbA1c measurements 
will be obtained for subjects who discontinue after 4 weeks of 
participation. The sample size of 25 subjects was not determined 
using statistical methods.
Analysis Populations
All randomized subjects in the clinical study will be included in the 
Intent-To-Treat (ITT) Population. ITT subjects who have no major 
protocol deviations that would have an impact on the primary 
endpoint assessment will be included in the Per-Protocol (PP) 
Population.
Descriptive Summary of Efficacy
HbA1c values will be summarized at baseline and end of study for 
the ITT Population. CGM values and metrics will be summarized by 
visit. A summary table with descriptive statistics (n, mean, median, 
standard deviation, minimum, and maximum) will be provided. 
CGM data will also be presented graphically.
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Descriptive Summary of Safety
The incidence of hypoglycemia confirmed by SMBG (total and 
severe) and the percentage time (by CGM) with glucose below 
70 mg/dL and below 54 mg/dL will be reported. Nocturnal is defined 
as midnight to 0600 and severe hypoglycemia is defined as an event 
requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions.
The number and percentage of subjects with treatment-emergent AEs 
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 
screening and end of study will be provided. The FEV1 data will also 
be presented graphically.
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TABLE OF CONTENTS
SIGNATURE PAGE .......................................................................................................................2
REVISION HISTORY ....................................................................................................................3
SYNOPSIS ......................................................................................................................................4
1
INTRODUCTION .................................................................................................................17
1.1 Background........................................................................................................................17
1.2 Study Rationale..................................................................................................................18
1.3 Risks and Benefits .............................................................................................................18
1.3.1
Afrezza.......................................................................................................................18
1.3.2
Insulin Degludec........................................................................................................19
1.3.3
Continuous Glucose Monitoring ...............................................................................19
2
STUDY OBJECTIVES .........................................................................................................21
2.1 Primary Objective..............................................................................................................21
2.2 Secondary Objectives ........................................................................................................21
3
INVESTIGATIONAL PLAN................................................................................................22
3.1 Overall Study Design and Plan..........................................................................................22
3.2 Study Duration...................................................................................................................26
3.3 Selection of Study Population ...........................................................................................26
3.4 STUDY TREATMENT.....................................................................................................29
3.4.1
Test Product, Dose, and Mode of Administration.....................................................29
3.4.2
Basal and Rapid-Acting Insulin Therapy Dose and Mode of Administration...........30
3.4.3
Afrezza Training........................................................................................................30
3.4.4
Dosage Schedule........................................................................................................30
3.4.5
Treatment Assignment...............................................................................................31
3.4.6
Drug Packaging and Blinding....................................................................................31
3.4.7
Drug Inventory and Accountability...........................................................................32
3.4.8
Treatment Compliance...............................................................................................32
3.4.9
Prior and Concomitant Illnesses and Treatments ......................................................32
3.5 Assessments.......................................................................................................................32
3.6 Schedule of Assessments...................................................................................................33
3.7 Study Procedures ...............................................................................................................41
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3.7.1
Screening (V1)...........................................................................................................41
3.7.2
Randomization (V2) ..................................................................................................41
3.7.3
Telephone Visits (T3-T8) ..........................................................................................43
3.7.4
Clinic Visit (V9) ........................................................................................................43
3.7.5
Telephone Visits (T10-T12) ......................................................................................44
3.7.6
Clinic Visit (V13) ......................................................................................................44
3.7.7
Visit 14 / Early-Termination Visit.............................................................................44
3.8 Post Study Interview..........................................................................................................45
3.9 Procedures for Subjects Who Prematurely Withdraw from the Study..............................45
3.9.1
Efficacy Assessments ................................................................................................45
3.9.2
Safety Assessments....................................................................................................46
3.9.3
Appropriateness of Measurements ............................................................................48
4
ADVERSE EVENT REPORTING .......................................................................................49
4.1 Definitions and Criteria .....................................................................................................49
4.1.1
Adverse Events..........................................................................................................49
4.1.2
Serious Adverse Events.............................................................................................49
4.1.3
Adverse Events of Special Interest............................................................................50
4.1.4
Abnormal Laboratory Values ....................................................................................50
4.1.5
Assessing Relationship..............................................................................................50
4.2 Reporting Procedures and Requirements...........................................................................51
4.2.1
Adverse Events..........................................................................................................51
4.2.2
Adverse Events of Special Interest............................................................................52
4.2.3
Serious Adverse Events.............................................................................................52
4.2.4
Procedures for Documenting Pregnancy During Study.............................................52
5
DATA MANAGEMENT AND STATISTICAL ANALYSIS..............................................54
5.1 Data Management Considerations.....................................................................................54
5.2 Statistical Considerations ..................................................................................................54
5.3 General Considerations......................................................................................................54
5.4 Primary Endpoint...............................................................................................................54
5.4.1
Safety Endpoints........................................................................................................54
5.5 Randomization...................................................................................................................55
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5.6 Sample Size Justification...................................................................................................55
5.7 Analysis Populations .........................................................................................................55
5.8 Protocol Deviations ...........................................................................................................55
5.9 Subject Disposition............................................................................................................55
5.10 Demographic and Baseline Characteristics .......................................................................55
5.11 Medical History .................................................................................................................55
5.12 Concomitant Medications..................................................................................................56
5.13 Treatment Exposure and Compliance................................................................................56
5.14 Descriptive Summary of Efficacy .....................................................................................56
5.15 Descriptive Summary of Safety.........................................................................................56
6
STUDY MANAGEMENT ....................................................................................................57
6.1 Ethics and Consent ............................................................................................................57
6.1.1
Regulations and Guidelines.......................................................................................57
6.1.2
Institutional Review Board........................................................................................57
6.1.3
Informed Consent ......................................................................................................57
6.1.4
Data Protection ..........................................................................................................57
6.1.5
Discontinuation of the Study by the Sponsor ............................................................57
6.1.6
Study Documentation ................................................................................................58
6.2 Data Management and Quality Control.............................................................................58
6.2.1
Case Report Forms ....................................................................................................58
6.3 Study Monitoring and Quality Assurance .........................................................................58
6.4 Retention of Records .........................................................................................................59
6.5 Use of Study Findings .......................................................................................................59
6.6 Financial Disclosure ..........................................................................................................59
6.7 Publications and Disclosure Policy ...................................................................................59
7
REFERENCES ......................................................................................................................61
TABLES
Table 1: 
Test Product (Afrezza)...............................................................................................29
Table 2: 
Starting Dose of Afrezza for Subjects in the Afrezza Groups...................................31
Table 3: 
Schedule of Assessments...........................................................................................34
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Table 4: CGM/Pump Reports and Data to be Downloaded ..........................................................40
FIGURES
Figure 1: 
MKC-TI-192 Study Schematic
23
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
adverse event
AESI
AID
adverse event of special interest
automated insulin delivery
BMI
body mass index
CGM
continuous glucose monitor
CI
confidence interval
COVID-19
coronavirus 2019
CRF
CSII
CV
case report form
continuous subcutaneous insulin infusion
coefficient of variation
DKA
diabetic ketoacidosis
FDA
Food and Drug Administration
FEV1
HbA1c
forced expiratory volume in 1 second
glycated hemoglobin
IB
Investigator’s Brochure
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
I:CHO
Insulin to Carb Ratio
ITT
intent to treat
IRB
institutional review board
MDI
PPG
PPGE
multiple daily injection(s)
postprandial glucose
postprandial glucose excursion
RAA
rapid-acting insulin analog
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
SD
severe acute respiratory syndrome coronavirus 2 
standard deviation
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Abbreviation
Definition
SC
subcutaneous
SMBG
self-monitored blood glucose
SOP
TAR
TBR
standard operating procedure
time above range
time below range
TEAE
treatment-emergent adverse event
TI
TIR 
TSH
Technosphere Insulin
time in range
thyroid-stimulating hormone
T1DM
type 1 diabetes mellitus
URI
Upper Respiratory Infection
DEFINITIONS OF TERMS
Enrollment: The date when the subject has consented to participate in the study and eligibility 
criteria are met.
ITT: Intent to Treat
PP: Per Protocol
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
According to the latest estimates, >1.6 million Americans have type 1 diabetes mellitus (T1DM) 
(CDC 2020). Importantly, the incidence of T1DM is increasing at an annual rate of 
approximately 1.9% (Divers et al. 2020).
T1DM is a chronic autoimmune disorder characterized by a destruction of the insulin-producing 
β-cells of the pancreatic islets, leading to insulin deficiency, subsequent hyperglycemia and the 
need for exogenous insulin therapy. T1DM is associated with increased microvascular and 
macrovascular disease, reduced life span and significant healthcare-related costs (Foster et al. 
2019, Rawshani et al. 2018, Livingstone et al. 2015, Tao et al. 2010).
In order to delay or prevent complications associated with diabetes, it is critical that patients 
adhere to their diabetes treatment regimen. The therapeutic objective for diabetes management is 
to match the endogenous pattern of insulin secretion as closely as possible without causing 
hypoglycemia (Pettus et al. 2016). Use of intensified, basal-bolus insulin therapy is considered 
standard of care for treatment of patients with T1DM (ADA 2021b).
Despite advances in glucose monitoring and insulin delivery technologies, a significant 
proportion of individuals with type 1 diabetes are not achieving their glycemic targets (Foster et 
al. 2019). Nonadherence to prescribed insulin regimens is high and remains a major driver of 
poor glucose control (Riaz et al. 2014). Among patients treated with a multiple daily insulin 
injection (MDI) regimen, 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. 
However, nonadherence to mealtime and correction dosing is also problematic among insulin 
pump users (Burdick et al. 2004).
Technosphere® Insulin inhalation powder (TI inhalation powder) provides an alternative to 
injectable insulin for prandial glucose control. TI inhalation powder and the Gen2 Inhaler were 
approved as Afrezza® (insulin human) inhalation powder and Afrezza Inhaler by the United 
States 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 route) and returns to near baseline levels in approximately 180 minutes (versus 
about 5 hours for RAA) (Afrezza IB). 
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This unique ultra-rapid time-action profile allows for simpler and more flexible mealtime dosing, 
lessens the potential for inter-prandial 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
Approximately 40% to 60% of patients with T1DM use continuous subcutaneous insulin 
infusion (CSII) devices, commonly referred to as insulin pumps (Umpierrez et al. 2018, Miller et 
al. 2015). CSII devices are computerized devices programmed to deliver an RAA under the skin 
continuously throughout the day via a catheter attached to a person’s abdomen. When used in 
tandem with continuous glucose monitoring (CGM) this is a closed-loop system. Hybrid closed-
loop systems are characterized by the coexistence of algorithm-driven automated insulin delivery 
(AID) for basal insulin coverage combined with manual mealtime bolus insulin doses. 
The current study aims to evaluate mealtime use of Afrezza in adults ≥18 years of age with 
T1DM who currently use AID. In this study, Afrezza-treated subjects will use two different 
methods for basal insulin delivery (subcutaneous [SC] injection of long-acting insulin or an AID 
system with RAA) compared to a control group (without Afrezza) of patients on an AID system 
with RAA. 
Subjects will administer their initial Afrezza dose based on the subject’s current insulin-to-
carbohydrate (I:CHO) ratio multiplied by 2 and rounded down to the nearest Afrezza dose size, 
subject to Investigator discretion, but not exceeding 24 units of Afrezza. 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 subcutaneous insulin analog in head-to-head comparisons (Kendall et 
al. 2020, Grant et al. 2019), which is significantly higher than the dose conversion in the label. 
Additionally, a proof-of-concept study was done with 20 patients demonstrating improved 
postprandial glucose excursions (PPGE) with the higher dose of Afrezza compared to the current 
label (Afrezza 2020). This higher initial conversion dose of Afrezza will be used for the first 
dose under medical supervision in the clinic.
1.3
Risks and Benefits 
1.3.1
Afrezza
Clear benefits of Afrezza include faster onset of insulin response, ability to administer insulin at 
mealtimes, lower risk of hypoglycemia and fewer injections compared to subjects using RAAs 
injected subcutaneously for post-prandial control.
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
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
Hyperglycemia during initiation of treatment due to inadequate conversion of RAA dose
Important potential risks

Diabetic ketoacidosis

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) and the Afrezza prescribing information (Afrezza 2020).
1.3.2
Insulin Degludec
Subjects who are randomized to treatment with Afrezza in combination with a basal insulin will 
discontinue using their insulin pump and inject insulin degludec for basal insulin coverage. 
During the transition period, there is a risk of increased hyperglycemia and/or hypoglycemia 
while the basal insulin dose is optimized. To mitigate the risk to subjects in this study, subjects 
will be provided training in the clinic and frequent telephone visits will occur in the first 21 days 
after randomization.
See the prescribing information for Tresiba for a complete list of risks (Tresiba 2019).
1.3.3
Continuous Glucose Monitoring
CGM will be used in this study to enable real-time display of glucose values. Subjects will wear 
a blinded Dexcom G6 Professional (Dexcom G6 Pro) between screening and randomization and 
during the last 10 days of the study, in addition to their own personal CGM. Subjects will be 
provided training in the clinic for how to operate the Dexcom G6 Pro. Additionally, subjects will 
measure their glucose throughout the study using an unblinded CGM system (sensors, 
transmitter) and glucose meters, if required. 
Subjects will also be instructed to measure glucose values using a blood glucose meter (self-
monitored blood glucose [SMBG] value), as required by their personal CGM system, and to 
confirm glucose levels when their CGM is <70mg/dL and anytime their CGM reading does not 
match their symptoms or expectations.
Use of CGM is associated with a low risk for developing a local skin infection at the site of the 
CGM sensor placement. Itchiness, redness, bleeding, and bruising at the insertion site may occur 
as well as local tape allergies. CGM sensors may fracture in situ on rare occasions. In the rare 
instances when this has occurred in the past, consulting physicians and surgeons have 
recommended not to remove the wire fragment from beneath the skin as long as there are no 
symptoms of infection or inflammation. In the event that signs and/or symptoms of infection or 
inflammation arise such as redness, swelling, and pain subjects should consult with the 
Investigator or prescribing physician for the best course of action. If there is no portion of the 
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broken sensor wire fragment visible above the skin, attempts to remove it without medical 
guidance are not advised.
For a complete list of risks for Dexcom G6, refer to the Dexcom G6 Pro User Guide 
(Dexcom 2020). For a complete list of risks for the subject’s personal CGM that they will 
continue to use during the study, refer to the corresponding user guide.
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2
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective of this study is:

To evaluate the change in HbA1c from baseline to end of study in adults 18 years of age 
with T1DM for each of the three following groups:
o
Afrezza + AID: Afrezza for bolus (mealtime) in combination with use of a CSII pump 
with an AID algorithm using a RAA for basal and correction insulin coverage
o
Afrezza + Insulin Degludec: Afrezza for bolus (mealtime and correction) in combination 
with insulin degludec for basal insulin coverage
o
AID Control: CSII pump with an AID algorithm using an RAA for all bolus (mealtime 
and correction) and basal insulin coverage
2.2
Secondary Objectives
The secondary objectives of this study are: 

To evaluate the safety of study treatment based on hypoglycemia event rate and severe 
hypoglycemia incidence rate in adults ≥18 years of age with T1DM for each of the three 
following groups:
o
Afrezza + AID
o
Afrezza + Insulin Degludec 
o
AID Control

To evaluate the impact of study treatment on overall glycemic control when comparing 
baseline versus end of treatment period as measured by core CGM metrics:
o
Change in percent time in range (TIR), defined as time spent with glucose in the range of 
70 to 180 mg/dL
o
Change in percent time below range (TBR), defined as time spent with glucose 
<70 mg/dL
o
Change in percent time spent with glucose <54 mg/dL
o
Change in percent time above range (TAR), defined as time spent with glucose 
>180 mg/dL
o
Change in percent time spent with glucose >250 mg/dL
o
Change in glycemic variability as measured by coefficient of variation (CV)

The above metrics to be evaluated on each of the three following groups in adults 18 years 
of age with T1DM for each of the three following groups:
o
Afrezza + AID
o
Afrezza + Insulin Degludec 
o
AID Control
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3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
MKC-TI-192 is a Phase 4, 90-day, randomized, three-arm, multicenter clinical trial evaluating 
the treatment paradigm and efficacy of Afrezza in controlling postprandial glucose in adult 
subjects (≥18 years of age) with T1DM. Subjects will be randomized to one of three treatment 
groups (two Afrezza groups and one control group): 

Afrezza + AID: Subjects in this group will use Afrezza for their bolus (mealtime) insulin and 
a CSII pump with an AID algorithm using RAA for their basal and correction insulin 
coverage.

Afrezza + Insulin Degludec: Subjects in this group will use Afrezza for their bolus (mealtime 
and correction) insulin and insulin degludec for basal insulin coverage.

AID Control: Subjects in this group will use a CSII pump with an AID algorithm using RAA 
for all bolus (mealtime and correction) and basal insulin coverage (control group).
See Figure 1 for a schematic of the study design.
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Figure 1: 
MKC-TI-192 Study Schematic
AID=automated insulin delivery, CGM=continuous glucose monitor, CSII=continuous subcutaneous insulin infusion, FEV1= forced expiratory volume in 1 second, 
HbA1c=glycated hemoglobin A1c, T1DM=type 1 diabetes mellitus
a.
The Screening Visit should be scheduled 10 days (+ 4 days) before the subject’s expected date of randomization. Subjects will be provided with a blinded Dexcom G6 
Professional CGM device at the Screening Visit, which they will use in addition to their own CGM device during the Screening Period. At Visit 2, blinded CGM data 
will be downloaded and CGM sensor wear evaluated. If CGM sensor wear time is inadequate, per the discretion of the Investigator, the Screening Period can be extended 
and sensor wear can be repeated once. The subject will return to the clinic 10 days (+ 4 days) later and, if sensor wear is adequate and all eligibility criteria met, be 
randomized to study treatment and proceed with the meal challenge.
b.
Only applies to subjects in the Afrezza + Insulin Degludec group who use a Medtronic 670G/770G system.
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The study is composed of up to 5 clinic visits (screening, 3 treatment visits, and an end-of-
treatment visit) and 9 telephone visits:

Visit 1 (Screening): At the Screening Visit, informed consent will be obtained and screening 
procedures performed. Laboratory values will be collected for HbA1c, creatinine and 
thyroid-stimulating hormone (TSH); a documented normal TSH or creatinine level within 
6 months of screening can be used in lieu of testing. A baseline forced expiratory volume in 
one second (FEV1) measurement will be obtained. A Dexcom G6 Pro blinded CGM device 
will be placed on each subject. Subjects will continue to use their own CGM device in 
addition to the blinded CGM.

Visit 2 (Randomization & Meal Challenge): At least 10 days (+ 4 days) after Visit 1, 
subjects will return for Visit 2. At this visit, the Investigator will evaluate for appropriate use 
of the blinded sensor and will download the blinded CGM data (CSV file). If sensor wear 
time is inadequate, sensor wear can be repeated once and this becomes an unscheduled visit. 
The subject will return to the clinic 10 days (+ 4 days) later, and if the sensor wear is 
adequate and all eligibility criteria are met, be randomized to study treatment and proceed to 
the meal challenge and other Visit 2 assessments. 
Subjects will be randomized in a 2:2:1 ratio to the following treatment groups, with the goal 
of 25 subjects enrolled:
o
Afrezza + AID (N=10)
o
Afrezza + Insulin Degludec (N=10)
o
AID Control (N=5)
In order to achieve balanced representation of Medtronic 670G or 770G and Tandem Control 
IQ AID users for each group, the minimum subject numbers will be as follows:
o
At least 5 subjects using Medtronic 670G or 770G
o
At least 5 subjects using Tandem Control IQ
Subjects will come to the clinic fasting with no manual insulin bolus administered within the 
prior 4 hours. CGM reports and pump reports will be downloaded from V1 to V2 using Carelink 
for Medtronic CGM and pumps, CGM reports/data and pump reports/data will be downloaded 
from V1 to V2 using Clarity for Dexcom CGM and t:connect for Tandem pumps (
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). The site will de-identify all reports and data. Subjects will undergo a 2-hour meal 
tolerance test in the clinic. The Afrezza + Insulin Degludec and the Afrezza + AID 
groups will be administered an Afrezza initial dose that is 2 times the calculated RAA 
dose (based on their insulin-to-carbohydrate ratio [I:CHO] calculated prandial dose) 
rounded down to the nearest 4-unit dose of Afrezza, but not exceeding 24 units of 
Afrezza. The Afrezza dose will be administered at the start of the meal challenge. The 
AID Control group will administer bolus insulin 10 ± 5 minutes (per label) prior to the 
meal, per Investigator discretion. The start of the meal will define t=0. Subjects in the 
Afrezza + Insulin Degludec will continue on AID throughout the meal tolerance test and 
then transition to insulin degludec at the discretion of the Investigator. Basal insulin doses 
and time of administration in all study subjects will be documented. Subjects should have 
glucagon available for use in the event of hypoglycemia and should not be discharged 
until hypoglycemia is resolved.

Visits T3, T4, T5, T6, T7, T8 (Telephone): Between Visits 2 and 9 in the clinic, several 
telephone visits will be conducted. During these visits, the Investigator will titrate insulin 
dosages, ask about changes to concomitant medications, record any AEs and hypoglycemic 
events, and answer any questions/concerns raised by the subject. 

Visit 9 (Clinic): This visit will be conducted at least 30 days (+7 days) after Visit 2. CGM 
reports and pump reports will be downloaded from V2 to V9 and from 10 days prior to V9 to 
V9 using Carelink for Medtronic CGM and pumps, CGM reports/data and pump reports/data 
will be downloaded from V2 to V9 and from 10 days prior to V9 to V9 using Clarity for 
Dexcom CGM and t:connect for Tandem pump).  The site will de-identify all reports and 
data.  The Investigator will titrate insulin dosages. Basal insulin dosages will be documented.

Visits T10, T11, T12 (Telephone): Between Visits 9 and 13 in the clinic, three telephone 
visits will be conducted. During these visits, the Investigator will titrate dosages and answer 
any questions/concerns raised by subjects. 
Visit 13 (Clinic): This visit will occur 8 to 10 days prior to Visit 14. CGM reports and pump 
reports will be downloaded from V9 to 30 days after V9 using Carelink for Medtronic CGM and 
pumps, CGM reports/data and pump reports/data will be downloaded from V9 to 30 days after 
V9 using Clarity for Dexcom CGM and t:connect for Tandem pumps (
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). The site will de-identify all reports/data.  The Investigator will place a Dexcom G6 Pro blinded 
sensor on subjects in all groups. The Investigator will titrate insulin dosages. Additionally, 
Afrezza + AID and Afrezza + Degludec groups will be asked to log meal announcements and 
Afrezza doses in the final 10 days. 
Visit 14 (Clinic): At least 90 days following Visit 2 (+ 7 days), subjects will return for HbA1c 
measurement and safety assessments, including a final FEV1 measurement. The Investigator will 
download the blinded CGM data (CSV file) from the prior sensor wear. Additionally, CGM 
reports and pump reports will be downloaded from 30 days before V14 to V14 and from V13 to 
V14 using Carelink for Medtronic CGM and pumps, CGM reports/data and pump reports/data 
will be downloaded from 30 days before V14 to V14 and from V13 to V14 using Clarity for 
Dexcom CGM and t:connect for Tandem pumps (
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). The site will de-identify all reports and data. Basal insulin dosages will be documented. See 
Section 3.7 for information on the assessments to be performed at these visits.
3.2
Study Duration
The length of the entire study (from first subject enrolled to the last subject last visit) is expected 
to be 180 days. The end of the clinical study is defined as the day the last subject completes 
his/her last visit. 
3.3
Selection of Study Population
The population sought for this study is adult subjects ≥18 years of age with T1DM. Twenty-five 
subjects are planned to complete the study. Subjects who discontinue from the study within the 
first 4 weeks will be replaced. Subjects who discontinue from the study after 4 weeks will not be 
replaced. If possible, HbA1c measurements will be obtained for subjects who discontinue after 
4 weeks of participation. 
3.3.1.1
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 
3. 7.0% and <11.0% HbA1c
4.
Treatment with a CSII pump with an AID algorithm (Medtronic 670G/770G or Tandem 
Control IQ) for at least 3 months, including use of the AID automated mode function
5. Ability to pay for their own RAA used in the insulin pump or injections, either through co-
pay or self-pay, for the duration of the study (See acceptable insulin analogs in Section 3.4.2)
6. Willingness to follow study procedures including discontinuing their insulin pump and 
transitioning to insulin degludec injections plus Afrezza
3.3.1.2
Exclusion Criteria
Subjects meeting any of the following exclusion criteria at screening will not be enrolled in the 
study.
At screening:
1. A recent history of asthma (defined as using any medications to treat within the last year), 
chronic obstructive pulmonary disease (COPD), or any other clinically important pulmonary 
disease (e.g., cystic fibrosis, bronchopulmonary dysplasia), or significant congenital or 
acquired cardiopulmonary disease
2. History of serious complications of diabetes (e.g., active proliferative retinopathy or 
symptomatic autonomic neuropathy) 
3. History of hypersensitivity to insulin or any of the Afrezza excipients
4. On dialysis
5. Respiratory tract infection within 14 days before screening (subject may return 14 days after 
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resolution of symptoms for rescreening)
6. Exposure to any investigational drug in the past 30 days or an investigational device in the 
past 2 weeks
7. Adrenal insufficiency, active use of steroids or planned steroid use
8. Hypothyroidism not controlled, as defined by TSH outside the upper limit of the reference 
range by >1.5 × in the last 6 months, according to the local laboratory reference range
9. Hyperthyroidism not controlled, as defined by TSH below the normal reference range, 
according to the local laboratory
10. Use of antiadrenergic drugs (e.g., beta blockers and clonidine)
11. Any concurrent illness (other than diabetes mellitus) not controlled by a stable therapeutic 
regimen
12. History of a significant eating disorder (e.g., anorexia or bulimia nervosa)
13. 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
14. History of smoking (includes cigarettes, cigars, pipes, vaping devices, and marijuana) in the 
6 months before screening
15. Female subject who is pregnant, breast-feeding, 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)
16. An event of severe hypoglycemia, as reported by the patient, within the last 180 days before 
screening
17. An episode of diabetic ketoacidosis (DKA), as determined by the Investigator, requiring 
hospitalization within the last 180 days before screening
18. Exposure to Afrezza in the 30 days before screening
19. Abnormal TSH or creatinine levels above 2.0 mg/dL 
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 prescribing information (Afrezza 2020), 
should not be enrolled in the study. 
3.3.1.3
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 end-of-treatment 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 3). 
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 
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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-included in the study. Their inclusion numbers 
must not be reused. Subjects withdrawn within the first 4 weeks will be replaced. However, 
subjects withdrawn from the study after 4 weeks will not be replaced. If possible, HbA1c 
measurements will be obtained for subjects who are withdrawn after 4 weeks of participation.
3.3.1.3.1 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 (AE): 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.

Treatment Noncompliance: The subject fails to comply with the prescribed dosing of the 
study treatment after multiple attempts have been made to obtain compliance.

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: If a subject becomes pregnant, she will be discontinued from the study.

Smoking: The subject begins smoking or vaping, including smoking marijuana.

DKA: The subject has 2 events of DKA.

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 
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Public Health Emergency (FDA 2021). The reason for discontinuation should be recorded on the 
CRF as SARS-CoV-2/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.
3.3.1.3.2 Replacement of Subjects
Subjects who discontinue from the study within the first 4 weeks will be replaced. However, 
subjects who discontinue from the study after 4 weeks will not be replaced. If possible, HbA1c 
measurements will be obtained for subjects who discontinue after 4 weeks of participation.
3.4
STUDY TREATMENT
3.4.1
Test Product, Dose, and Mode of Administration
The test product is defined as Afrezza administered using the inhaler (Table 1). 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.
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 aerosolized and 
delivered to the lung. 
Dose(s)
Individualized
Storage (Not in Use)
Refrigerated at 2°C to 8°C (36°F to 46°F): Until expiration date
Note: The inhaler should be at room temperature for 10 minutes 
before use.
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Test Product
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
3.4.2
Basal and Rapid-Acting Insulin Therapy Dose and Mode of Administration
Subjects in the Afrezza + Insulin Degludec group will be treated with insulin degludec 
administered subcutaneously for basal insulin coverage. 
Subjects in the Afrezza + AID Control group will be treated with infused rapid-acting: insulin 
aspart (Novolog® or Fiasp®) or insulin lispro (Humalog®, Admelog®, or Lyumjev®) for basal 
insulin coverage (insulin pump/AID users). The dose regimen will be individualized.
Subjects in the AID Control group will be treated with infused rapid-acting: insulin aspart 
(Novolog or Fiasp) or insulin lispro (Humalog, Admelog, or Lyumjev) for basal insulin and 
prandial/correction insulin coverage (insulin pump/AID users). The dose regimen will be 
individualized.
3.4.3
Afrezza Training
At Visit 2, subjects in Afrezza groups (Afrezza + Insulin Degludec and Afrezza + AID) 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 the second repeated training, the subject will be withdrawn from the study.
3.4.4
Dosage Schedule
Subjects in the Afrezza groups (Afrezza + Insulin Degludec and Afrezza + AID) will administer 
their first dose of Afrezza at Visit 2, at the start of the meal challenge. Afrezza will be dosed at 2 
× the calculated RAA dose rounded down to the nearest 4-unit dose (based on their I:CHO dose 
calculated for mealtime), but not exceeding 24 units of Afrezza. The Afrezza dose will be 
administered at the start of the meal challenge. The start of the meal will define t=0. After the 
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meal challenge and at subsequent visits, Afrezza will be titrated to glycemic effect per 
Investigator discretion.
 
Table 2: Starting Dose of Afrezza for Subjects in the Afrezza Groups
RAA Dose (Units)
Afrezza Dose (Units)
<4
4
4
5
8
6
7
12
8
9
16
10
11
20
≥12
24*
RAA=rapid-acting insulin analog (e.g., insulin aspart or insulin lispro)
*The initial mealtime dose (taken at Visit 2 in the Afrezza + AID and Afrezza + Insulin Degludec groups) should not exceed 24 
units of Afrezza.
Note: Aside from the initial mealtime dose cap mentioned (24 units of Afrezza), there is no maximum dose of Afrezza and the 
required total mealtime dose for the subject during the study may differ from the examples provided in this table.
Following the initial dose of Afrezza and throughout the study, post-meal insulin correction 
doses can be taken no sooner than 60 to 90 minutes after a previous dose of Afrezza if the 
subject’s glucose value is >160mg/dL, or per investigator discretion. Subjects in the 
Afrezza+AID group will correction dose with RAA while subjects in the Afrezza+Tresiba group 
will correction dose with Afrezza.
3.4.5
Treatment Assignment
Subjects in this study will be assigned a unique subject ID. Once screening procedures are 
complete and eligibility is confirmed, eligible subjects will be enrolled and randomized to 
treatment at Visit 2.
All subjects in the Afrezza groups will receive Afrezza at Visit 2 and continue this treatment 
through Visit 14. Subjects in the AID Control group will not receive Afrezza and will continue 
using their CSII pump with AID algorithm and RAA throughout the study.
3.4.6
Drug Packaging and Blinding
This is an open-label clinical study. Neither clinical site personnel nor subjects will be blinded to 
treatment.
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3.4.7
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. The Investigator 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.
3.4.8
Treatment Compliance
It is expected that subjects will be compliant with all dosing instructions and subjects will 
administer the initial dose of Afrezza under clinical supervision at the study site. 
3.4.9
Prior and Concomitant Illnesses and Treatments
3.4.9.1
Prior and Concomitant Illnesses
All 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. The Investigator (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 on the CRF.
3.4.9.2
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 2. The initiation of 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 medical monitor. 
3.5
Assessments
Unless otherwise indicated, all assessments will be performed by the Investigator or a qualified 
designee. 
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3.6
Schedule of Assessments
The procedures to be performed throughout the study are outlined in the Schedule of 
Assessments (Table 3).
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Table 3: Schedule of Assessments
Study Period
Screen
Treatment Period
In-clinic Visit (V)
Telehealth Visit (T)
V1
V2
T3
T4
T5
T6
T7
T8
V9
T10
T11
T12
V13
V14
Day
0
1
2
4
7
14
21
30
37 b
44 b
51 b
80
90
(EOT)
Visit Window (Days)
Up to 
28 Days 
Before 
Random. a
--
--
--
--
±2
±2
±2
+7
±2
±2
±2
+2
+7
ET c
Informed consent 
X
Eligibility criteria 
confirmed
X
X
Demographics and 
medical history
X
Randomization
X
Physical examination, 
including weight and 
height
X
X
X
Prior/concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Smoking status and 
evaluation of 
pulmonary toxin 
exposure
X
X
X
Adverse events d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
COVID-19 screening e  
X
Hypoglycemic events f   
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c (central 
laboratory) 
X
X
X c
Pregnancy test g     
X
TSH test h
X
Serum creatinine h
X
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Study Period
Screen
Treatment Period
In-clinic Visit (V)
Telehealth Visit (T)
V1
V2
T3
T4
T5
T6
T7
T8
V9
T10
T11
T12
V13
V14
Day
0
1
2
4
7
14
21
30
37 b
44 b
51 b
80
90
(EOT)
Visit Window (Days)
Up to 
28 Days 
Before 
Random. a
--
--
--
--
±2
±2
±2
+7
±2
±2
±2
+2
+7
ET c
FEV1 measurement
X
X
X
Dispensing and 
placement of blinded 
CGM sensors
X
X
Instruction of subject 
on blinded CGM 
procedures
X
X
Review of blinded 
CGM readings and 
compliance
X
Removal and 
download of blinded 
CGM
X
X
Review/download 
unblinded CGM data i 
X
X
X
X
X
Review/download 
pump data i
X
X
X
X
X
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Study Period
Screen
Treatment Period
In-clinic Visit (V)
Telehealth Visit (T)
V1
V2
T3
T4
T5
T6
T7
T8
V9
T10
T11
T12
V13
V14
Day
0
1
2
4
7
14
21
30
37 b
44 b
51 b
80
90
(EOT)
Visit Window (Days)
Up to 
28 Days 
Before 
Random. a
--
--
--
--
±2
±2
±2
+7
±2
±2
±2
+2
+7
ET c
Remind subjects in the 
Afrezza + AID group 
to NOT enter carb 
intake/meal 
announcements into 
their insulin pump j
X
X
X
X
X
X
X
X
X
X
X
Training on use of the 
study-provided 
glucose meter 
X
Dispense glucose 
meter and supplies 
X
Provide additional 
glucose test strips and 
lancets, as necessary
X
X
X
Collect and review 
glucose meter data
X
X
X
X
X
Instruct subject on 
logging of meal 
announcements and 
Afrezza doses, as 
applicable
Xj
X
Collect information on 
meal announcements 
and Afrezza doses, as 
applicable
X
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Study Period
Screen
Treatment Period
In-clinic Visit (V)
Telehealth Visit (T)
V1
V2
T3
T4
T5
T6
T7
T8
V9
T10
T11
T12
V13
V14
Day
0
1
2
4
7
14
21
30
37 b
44 b
51 b
80
90
(EOT)
Visit Window (Days)
Up to 
28 Days 
Before 
Random. a
--
--
--
--
±2
±2
±2
+7
±2
±2
±2
+2
+7
ET c
First dose of Afrezza 
(Afrezza groups) or 
dose of RAA (AID 
Control group) with 
standardized meal
X
Titration of all insulins 
to glycemic effect
X
X
X
X
X
X
X
X
X
X
X
Afrezza Groups Only
Training for use and 
storage of Afrezza 
X
Training, as needed, 
on CGM use including 
but not limited to the 
use of alerts, 
interpretation of 
trends, interfering 
substances, 
contraindications, etc
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Afrezza 
inhalers and 
cartridges, as 
necessary
X
X
X
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Study Period
Screen
Treatment Period
In-clinic Visit (V)
Telehealth Visit (T)
V1
V2
T3
T4
T5
T6
T7
T8
V9
T10
T11
T12
V13
V14
Day
0
1
2
4
7
14
21
30
37 b
44 b
51 b
80
90
(EOT)
Visit Window (Days)
Up to 
28 Days 
Before 
Random. a
--
--
--
--
±2
±2
±2
+7
±2
±2
±2
+2
+7
ET c
Disbursement/
placement of 
unblinded CGM 
sensors k
X
X
Training on use of 
unblinded CGM k
X
Assess the need for 
Afrezza correction 
dosing based on CGM 
profile
X
X
X
X
X
X
X
Dispense insulin 
degludec and injection 
supplies, as necessary 
(Afrezza + Insulin 
Degludec group only)
X
X
Record basal insulin 
dosages (Afrezza + 
Insulin Degludec 
group only)
X
X
X
X
Collect Afrezza 
unused inhalers and 
cartridges as well as 
any unopened bottles 
of insulin degludec
X
X
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AID=automated insulin delivery, CGM=continuous glucose monitoring, COVID-19=coronavirus 2019, EOT=end of treatment, ET=early termination, FEV1=forced expiratory 
volume in 1 second, HbA1c=glycated hemoglobin A1c, RAA=rapid-acting insulin analog, Random=randomization, Screen=screening, SMBG=self-monitored blood glucose, 
TSH=thyroid-stimulating hormone.
a. 
The Screening Visit should be scheduled 10 days (+ 4 days) before the subject’s expected date of randomization. When subjects return for Visit 2, blinded CGM data 
will be downloaded and CGM sensor wear evaluated. If CGM sensor wear time is inadequate, per the discretion of the Investigator, the Screening Period can be extended 
(this becomes an unscheduled visit) and sensor wear can be repeated once. The subject will return to the clinic 10 days (+ 4 days) later and, if sensor wear is adequate 
and all eligibility criteria met, be randomized to study treatment and proceed with the meal challenge and Visit 2 assessments. Visit 2 should be within 4 days of the end 
of the final sensor wear data (i.e., the CGM sensor with adequate wear time).
b.
The timing of telephone visits T10, T11, and T12 is relative to Visit 9 (T10 should occur 7 days [±2 days] from Visit 9, T11 is 14 days [±2 days] from Visit 9, and T12 is 
31 days [±2 days] from Visit 9).
c.
A sample should be collected for HbA1c at the ET visit if the subject discontinues the study after 4 weeks of participation.
d.
Any adverse event that occurs after the subject enrolls in the study (consent date) will be recorded.
e.
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.
f. 
Subjects should use their study provided blood glucose meter to take an SMBG value if their CGM reading is <70 mg/dL or if their CGM reading does not match their 
symptoms or expectations. Hypoglycemic episodes will be defined as all SMBG measurements <70 mg/dL. See Section 3.9.2.6.
g. 
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.
h.
A documented normal level within 6 months of screening can be used in lieu of testing.
i.
CGM reports and pump reports will be downloaded from V1 to V2 at V2, V2 to V9 and 10 days before V9 to V9 at V9, V9 to 30 days after V9 at V13, and 30 days 
before V14 to V14 and V13 to V14 at V14 using Carelink for Medtronic CGM and pumps. CGM reports/data and pump reports/data will be downloaded from V1 to V2 
at V2, V2 to V9 and 10 days before V9 to V9 at V9, V9 to 30 days after V9 at V13, and 30 days before V14 to V14 and V13 to V14 at V14 using Clarity for Dexcom 
CGM and t:connect for Tandem pumps. The site will de-identify all reports and data.
j.
Subjects in the Afrezza + AID group will be instructed not to enter carb intake/meal announcements in the pump system. In the event that they accidentally enter carb 
intake/meal announcement for a certain meal, they should NOT dose Afrezza for that same meal. If they accidentally take Afrezza with a meal announcement, carbs or 
glucagon should be administered.  For subjects in the Afrezza + AID group, the site will confirm at every visit (phone or in person) to make sure they are not entering 
carb intake/meal announcements in the pump system.
k.
Only applies to subjects in the Afrezza + Insulin Degludec group who use a Medtronic 670G/770G system.
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Table 4: CGM/Pump Reports and Data to be Downloaded
Reports/Data to be Downloaded
V2
V9
V13
V14
Blinded G6 PRO Data
X
X
V1 to V2 CGM/pump report/data
X
V2 to V9 CGM/pump report/data
X
V9 minus 10 Days to V9 CGM/pump report/data
X
V9 to V9 plus 30 Days CGM/pump report/data
X
V14 minus 30 Days to V14 CGM/pump report/data
X
V13 to V14 CGM/pump report
X
Study Meter Download
X
X
X
X
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3.7
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 3). A 
detailed description of each assessment can be found in Sections 3.9.1 (efficacy) and 3.9.2 
(safety). 
3.7.1
Screening (V1)
Subject consent will be obtained upon screening before any study procedures are performed.
The following will also be performed at Visit 1:

Record demographics and medical history (see Section 3.9.2.1)

Perform physical examination (see Section 3.9.2.2)

Record height and weight (see Section 3.9.2.3)

Record vital signs (see Section 3.9.2.4), as deemed appropriate by investigator

Record concomitant medications 

Record smoking status and pulmonary toxin exposure

Measure and record FEV1

Collect blood and urine for laboratory tests (see Section 3.9.2.8) 

Perform COVID-19 screening assessment

Place Dexcom G6 Pro CGM device in blinded mode
3.7.2
Randomization (V2)
When subjects return for Visit 2, blinded CGM data will be downloaded and CGM sensor wear 
evaluated. If CGM sensor wear time is inadequate, per the discretion of the Investigator, the 
Screening Period can be extended and sensor wear can be repeated once (this becomes an 
unscheduled visit). The subject will return to the clinic 10 days (+4 days) later and, if sensor 
wear is adequate and all eligibility criteria met, be randomized to study treatment and proceed 
with the meal challenge and Visit 2 assessments. Visit 2 should be within 4 days of the end of the 
final sensor wear data (i.e., the CGM sensor with adequate wear time).
The following procedures will be performed at Visit 2:

Enrollment (if eligibility criteria are met)

Record concomitant medications

Record current basal insulin dosages 

Remove blinded Dexcom G6 Pro CGM
Download and de-identify data from Dexcom G6 Pro device (
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
)
Download and de-identify of unblinded CGM reports and pump reports for Medtronic CGM and 
pumps (
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
) 
Download and de-identify of unblinded CGM reports/data and pump reports/data for Dexcom 
CGM and t:connect for Tandem pumps (
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
)

Subjects randomized to study treatment (Afrezza + Insulin Degludec, Afrezza + AID, or AID 
Control)

Disbursement/placement of unblinded CGM sensor (only applies to subjects in the Afrezza + 
Insulin Degludec group who use a Medtronic 670G/770G system)

Conduct 2-hour, in-clinic meal tolerance test

Subjects will take their first dose of Afrezza or their dose of RAA with standardized meal 
challenge as described in Section 3.7.2.1.

Record AEs

Record any hypoglycemic episodes (see Section 3.9.2.6)

Provide additional subject training, as needed, on CGM use, including but not limited to the 
use of alerts, interpretation of trends, interfering substances, and contraindications. 

Provide study treatment instructions to the subject. Subjects in the Afrezza + AID group 
should be instructed NOT to enter carb intake/meal announcements into their insulin pump 
during the study, to avoid the risk of an automated insulin bolus (i.e., to avoid stacking 
insulin). In the event that they accidentally enter carb intake/meal announcement for a certain 
meal, they should NOT dose Afrezza for that same meal. In the event they accidentally enter 
carb intake/meal announcement for a certain meal and take a dose of Afrezza for that same 
meal, they should ingest carbohydrates or administer glucagon and contact the study team as 
soon as possible.

Provided adequate training on the appropriate use of glucagon emergency kits to all subjects. 
3.7.2.1
Meal Challenge
Subjects will come into the clinic in a fasting state for Visit 2, 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 will also be instructed not to administer manual bolus 
doses of insulin during the 4 hours immediately preceding the meal challenge. If the subject 
requires a manual bolus insulin dose to correct hyperglycemia within the 4 hours prior to the 
scheduled visit, the meal challenge will need to be rescheduled. 
The CGM glucose value will be confirmed 15 minutes before the start of the meal. If the 
subject’s CGM value is ≥70 mg/dL, the subject can start the meal challenge 15 minutes later. If 
the subject’s CGM value is <70 mg/dL, the Investigator can provide 15 g of fast-acting 
carbohydrates and reassess the CGM glucose value after 30 minutes and if the subject’s new 
CGM value is ≥70 mg/dL, the subject can start the meal challenge 15 minutes later. The CGM 
value obtained immediately before the start of the meal (defined as t=0) will serve as the baseline 
glucose value for that visit.
Subjects in the Afrezza groups will receive training on how to use the Afrezza Inhaler using 
BluHale technology, as well as how to identify and manage any events of hypo and 
hyperglycemia.
In addition to CGM, subjects will be instructed to take SMBG measurements 15 minutes before 
the start of the meal, immediately before the start of the meal (t=0), and at 15, 30, 45, 60, 90, and 
120 minutes after the start of the meal challenge.
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The meal challenge will consist of 1-2 bottles of Boost nutritional shake (1 bottle is 
approximately 240 calories, 41 g carbohydrate, 10 g protein, and 4 g fat). The meal is to be fully 
consumed within 15 minutes. Each Afrezza dose will be administered at the start of the meal 
challenge. The RAA dose will be administered 10 ± 5 minutes (per label) before the start of the 
meal challenge, per Investigator discretion.
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. 
The blood glucose monitoring values and CGM values (if available) will be entered in the CRF 
completed at Visit 2. Afrezza subjects will remain under clinical supervision for the 2 hours after 
their dose of Afrezza.  Subjects should have glucagon available for use in the event of 
hypoglycemia and should not be discharged until hypoglycemia is resolved. 
3.7.3
Telephone Visits (T3-T8)

Telephone Visits 3 to 8 will be conducted as summarized below:
o
T3 phone call on Day 1 (the day after randomization on Day 0)
o
T4 phone call on Day 2
o
T5 phone call on Day 4 
o
T6 phone call on Day 7 (± 2 days)  
o
T7 phone call on Day 14 (± 2 days)  
o
T8 phone call on Day 21 (± 2 days)  
At these visits:

Record changes to concomitant medications

Record any AEs

Record hypoglycemic events

Titrate mealtime, correction and basal insulin dosages 

Answer subjects’ questions/concerns

Remind subjects in the Afrezza + AID group to NOT enter carb intake/meal announcements 
into their insulin pump during the study, to avoid the risk of an automated insulin bolus (i.e., 
to avoid stacking insulin).
3.7.4
Clinic Visit (V9)

Record changes to concomitant medications

Record any AEs

Record hypoglycemic events

Collect and review glucose meter data
Download and de-identify of unblinded CGM reports and pump reports for Medtronic CGM and 
pumps (
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
)
Download and de-identify of unblinded CGM reports/data and pump reports/data for Dexcom 
CGM and t:connect for Tandem pumps (
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
)

Remind subjects in the Afrezza + AID group to NOT enter carb intake/meal announcements 
into their insulin pump during the study, to avoid the risk of an automated insulin bolus (i.e., 
to avoid stacking insulin). 

Titrate mealtime, correction and basal insulin dosages 

Record current basal insulin dosages 

Assess the need for Afrezza correction dosing based on CGM profile (Afrezza groups only)

Provide subject with any needed supplies (e.g., glucose test strips, Afrezza cartridges)
3.7.5
Telephone Visits (T10-T12)
The timing of telephone Visits T10, T11, and T12 is relative to Visit 9. Visit T10 should occur 
7 days (±2 days) from Visit 9, T11 is 14 days (±2 days) from Visit 9, and T12 is 31 days 
(±2 days) from Visit 9.
At these visits:

Record changes to concomitant medications

Record any AEs

Record hypoglycemic events

Titrate mealtime, correction and basal insulin dosages 

Answer subjects’ questions/concerns
3.7.6
Clinic Visit (V13)
This visit will be conducted at least 30 days (+7 days) after Visit 2. 
The following procedures will be performed at Visit 13:

Record changes to concomitant medications

Record any AEs

Record hypoglycemic events

Collect and review glucose meter data
Download and de-identify of unblinded CGM reports and pump reports for Medtronic CGM and 
pumps (
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
)
Download and de-identify of unblinded CGM reports/data and pump reports/data for Dexcom 
CGM and t:connect for Tandem pumps (
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
)

Place blinded Dexcom G6 Pro CGM sensors on all subjects

Titrate mealtime, correction and basal insulin dosages 

Record current basal insulin dosages

Provide subject with any needed supplies (e.g., glucose test strips, Afrezza cartridges)

Instruct participants to log meal announcements and Afrezza doses in the final 10 days 
3.7.7
Visit 14 / Early-Termination Visit
The following procedures will be performed at Visit 14, or if the subject discontinues early, at 
the early-termination visit:

Perform all safety assessments
Download and de-identify data from Dexcom G6 Pro device (
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
)
Download and de-identify of unblinded CGM reports and pump reports for Medtronic CGM and 
pumps (
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
)
Download and de-identify of unblinded CGM reports/data and pump reports/data for Dexcom 
CGM and t:connect for Tandem pumps (
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
)

Collect meal announcements and Afrezza dose log for final 10 days

Collect blood for laboratory tests (see Section 3.9.2.8)

Record concomitant medications

Record current basal insulin dosages 

Measure and record FEV1 

Record AEs
3.8
Post Study Interview 
An optional post-study interview may be conducted for those subjects who opt-in to participate, 
as indicated in the Informed Consent Form.  The goals of the post-study interview are to gain 
insight into the subject’s experience living with diabetes, their experience in the study (both 
positive and negative), and learn about how being in the study has affected their quality of life. 
Sites will share the subject’s contact information with the interviewer once the subject has opted 
in to participate.  Responses to the questions will be summarized and shared with the Sponsor. 
3.9
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 3.
3.9.1
Efficacy Assessments
3.9.1.1
Continuous Glucose Monitoring
Subjects will wear a blinded CGM at baseline for up to 20 days during an up to 28-day screening 
period and during the last 10 days of the study. Additionally, subjects will measure their glucose 
throughout the study using an unblinded CGM system (sensors, transmitter). Subjects will be 
instructed at Visit 2 in the operation of their CGM device.
3.9.1.2
Self-Monitored Blood Glucose
Confirmatory blood glucose values for CGM readings <70 mg/dL should be self-measured by 
the subject using a study-provided blood glucose meter and corresponding supplies (lancets, test 
strips, etc.). Subjects will also be instructed to use their blood glucose meter to take an SMBG 
value if they suspect DKA accompanied by a CGM value >250 mg/dL, or if their CGM reading 
does not match their symptoms or expectations, to make treatment decisions. 
3.9.2
Safety Assessments
3.9.2.1
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 (i.e., date of clinical diagnosis of 
T1DM, start date of current insulin treatments and treatment name). In addition, subjects will be 
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queried about drug and environmental allergies, family pulmonary disease history, and their 
smoking status. 
Demographic data, including age (years), race, ethnicity, and gender (male, female, other, or 
“decline to state”) will also be collected.
3.9.2.2
Physical Examinations
A 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, vital signs, mental status, 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. 
3.9.2.3
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.
3.9.2.4
Vital Signs
Vital signs may include body temperature, respiratory rate, pulse, and sitting systolic and 
diastolic blood pressures, as deemed appropriate by investigator. 
3.9.2.5
Pulmonary Function Tests
Subjects will undergo FEV1 testing according to American Thoracic Society and European 
Respiratory Society recommendations in the clinic. Subjects who experience respiratory 
symptoms that are not associated with an upper respiratory infection (URI) should undergo 
additional pulmonary function test to monitor clinically relevant decline (Section 4.1.3) per 
investigator’s discretion in accordance with the Afrezza USPI.  FEV1 values will be recorded in 
the CRF
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3.9.2.6
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) (ADA 2021a) on the study-
provided glucose meter. 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 challenge at Visit 2, 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).  The type of treatment given and time will be recorded and 
subjects will remain in-clinic until hypoglycemia is resolved. 
In the event that the subject accidentally enters carb intake/meal announcement for a certain meal 
and also doses with Afrezza, carbohydrates or glucagon should be administered. The subject 
should be instructed to contact the Investigator and site staff as soon as possible following the 
event to ensure prompt review and to give the Investigator the opportunity to address any further 
necessary measures for correction.
3.9.2.7
Hyperglycemic Events and Diabetic Ketoacidosis (DKA)
Investigators will educate subjects on recognizing and managing hyperglycemia and DKA using 
their CGM and study provided glucose meter, taking additional insulin and/or checking ketones 
as required. To ensure subject safety, subjects will be removed from the study if they have two 
events of DKA. Events of DKA are considered AESIs (Section 4.1.3) for which diagnostic 
criteria in Section 4.1.3.1 must be met. 
At the time of suspected DKA accompanied by a CGM value of >250 mg/dL, the subject’s blood 
glucose should be measured using the study-provided glucose meter to confirm.

If glucose is > 250 mg/dL for more than 4 consecutive hours and continues >250 mg/dL 
after the subject has taken insulin and ingested water, ketones should be measured. If 
serum ketones are >1.5mmol/L or urine ketones are “moderate” or greater, the subject  
should contact the site staff and/or their physician as soon as possible for further guidance 
and ketones should be tested every hour until serum ketones are <1.5mmol/L or urine 
ketones are less than “moderate”. Symptoms should be treated in accordance with 
standard of care instructions from the Investigator.

If glucose is > 250 mg/dL and the subject is vomiting or feels ill, ketones should be 
measured. If serum ketones are >1.5mmol/L or urine ketones are “moderate” or greater, 
the subject should contact the site staff and/or their physician as soon as possible for 
further guidance and ketones should be tested every hour until serum ketones are 
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<1.5mmol/L or urine ketones are less than “moderate”. Symptoms should be treated in 
accordance with standard of care instructions from the Investigator.
3.9.2.8
Clinical Laboratory Tests
The clinical site will collect blood samples for HbA1c, creatinine and TSH from subjects at 
Visit 1. Samples for HbA1c will be forwarded to the central laboratory for analysis. Samples for 
creatinine and TSH will be tested by a local laboratory; however, a documented normal TSH or 
creatinine within 6 months of screening can be used in lieu of testing. Urine pregnancy tests (for 
β-human chorionic gonadotropin) will be performed locally for women of child-bearing potential 
only.
3.9.2.9
Adverse Events
All AEs occurring after enrollment and through the duration of the study will be recorded. See 
Section 4 for additional information.
3.9.3
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 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:

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])
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. 
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Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. An 
SAE is not necessarily severe. Similarly, 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 adverse event of special interest (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 4.2.3. 
The following AEs are considered AESIs:

Acute bronchospasm

Clinically relevant decline in pulmonary function (>20% decline from baseline percent 
predicted FEV1 OR respiratory symptoms not associated with URI

Hypersensitivity reactions, including anaphylaxis, which can occur with insulin products, 
including Afrezza

DKA
4.1.3.1
Diagnostic Criteria for Diabetic Ketoacidosis
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

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 
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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
4.2
Reporting Procedures and Requirements
4.2.1
Adverse Events
Any AEs occurring from the date that the subject consents to participate in the study until they 
exit the study will be recorded. 
The Investigator should document all AEs in the subjects’ source documentation, on the AE 
CRF, and the SAE report (if the AE is serious). AEs of hypoglycemia that meet SAE criteria 
should be documented in the AE CRF and SAE report. 
The Investigator should specify the date of the onset of the AE, the intensity (see definitions in 
Section 4.1.1), 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) 
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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 serious AE 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 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
As soon as possible (desired within 24 hours of Investigator or study coordinator awareness), the 
investigational center staff must report all AESIs (including DKA) to the Sponsor. For these 
events, the AE 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 CRF. 
Source documents that support the event (e.g., clinic notes, hospital admission and discharge 
records, lab reports, EMT reports, ER/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 ID.
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. 
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.
4.2.4
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. 
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However, if any adverse findings in a child or fetus of a subject exposed to the study drug occur 
before conception or during pregnancy, these 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 the WHO Drug Global Dictionary. 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.
5.3
General Considerations
All statistical processing will be performed using the most current version of statistical software 
(such as MiniTab, MATLAB, or Microsoft Excel) 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 ID, visit, and time point.
Database lock will occur upon the completion of the study.
5.4
Primary Endpoint
This study will evaluate the efficacy and safety of Afrezza combined with basal insulin or AID 
with insulin pump therapy, based on the change in HbA1c from baseline to the end of study.
5.4.1
Safety Endpoints

Event rates and incidence Level 1 (<70 mg/dL) and Level 2 (<54 mg/dL) hypoglycemic 
events as confirmed by SMBG

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, AESIs, and device complaints

Change in FEV1 from screening to end of study
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5.5
Randomization
This study is an open-label, randomized, three-arm study. Subjects will be randomized 2:2:1 to 
the Afrezza + AID, Afrezza + Insulin Degludec, and AID Control groups. 
The randomization will target for a minimum of 3 subjects each who use Medtronic 670G/770G 
and Tandem Control IQ AID in each of the Afrezza groups, and a minimum of 2 subjects each 
who use Medtronic 670G/770G and Tandem Control IQ AID in the AID Control group. 
5.6
Sample Size Justification
The sample size (25 subjects completing the study) was not determined using statistical methods 
as there is no statistical significance that will be derived. 
5.7
Analysis Populations
The following analysis populations will be used:

Intent-To-Treat (ITT) Population, defined as all subjects assigned to study treatment. The 
ITT Population will be the primary efficacy population. 

Per-Protocol (PP) Population, defined as all ITT subjects who have no major protocol 
deviations that would have an impact on the primary endpoint assessment during the 90-day 
randomized treatment period.
5.8
Protocol Deviations
Major protocol deviations (number and percentage of subjects) will be summarized for the ITT 
Population. All protocol deviations will be reviewed by clinical and statistical personnel to 
identify important deviations (those anticipated to have an impact on efficacy or safety findings) 
before the primary database lock.
5.9
Subject Disposition
Disposition of subjects will be summarized for ITT Population. 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.
5.10 Demographic and Baseline Characteristics
Demographic and baseline characteristics, including usual insulin doses, will be summarized 
descriptively for the ITT Population. Summary statistics will include frequency and percentage, 
means, SD, minimum, and maximum as appropriate.
5.11 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 for 
ITT Population.
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5.12 Concomitant Medications
All nonstudy medications will be coded with the current version of the WHO Drug Global 
Dictionary. 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 for the ITT Population. 
5.13 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. 
5.14 Descriptive Summary of Efficacy
HbA1c values will be summarized at baseline and end of study for the ITT Population. CGM 
values and metrics will be summarized by visit. A summary table with descriptive statistics (n, 
mean, median, standard deviation, minimum, and maximum). CGM data will also be presented 
graphically. 
5.15 Descriptive Summary of Safety
The incidence of hypoglycemia (total, nocturnal, and severe) and percentage time below 
70 mg/dL and below 54 mg/dL will be reported. Nocturnal is defined as midnight to 0600 and 
severe hypoglycemia is defined as an event requiring assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions.
The number and percentage of subjects with treatment-emergent AEs 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 screening and end of study 
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), ICF(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.
All subjects will be insured against injury caused by their participation in the study according to 
legal requirements. They will be informed about the insurance and the resulting obligations on 
their part.
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.
6.1.5
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. 
The study may also be discontinued at the discretion of the Sponsor if:
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
Two subjects in the Afrezza+AID group and two subjects in the Afrezza+degludec group 
are discontinued from the study due to DKA
OR

Two subjects in the Afrezza+AID group and two subjects in the Afrezza+degludec group 
are discontinued from the study due to severe hypoglycemia 
6.1.6
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.
6.2
Data Management and Quality Control
6.2.1
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 or CRF. 
The Investigator site staff will enter and edit the data via a secure network, with secure access 
features (username and password) and/or on a paper CRF. A complete audit trail will be 
maintained. The Investigator will approve the data using an electronic and/or physical signature, 
and this approval will be used to confirm the accuracy of the data recorded. CRFs will be used 
for all subjects. 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.
6.3
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 
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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.
6.4
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.
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.
6.5
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.
6.6
Financial Disclosure
The Investigator will be required to disclose any financial equity interests in the Sponsor and any 
conflicts of interest.
6.7
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 
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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 
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Afrezza (insulin human) inhalation powder prescribing information. MannKind Corporation. 
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Diabetes Among Youths — Selected Counties and Indian Reservations, United States, 2002–
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Treatment in the U.S.: Updated Data from the T1D Exchange Clinic Registry. Diabetes Care. 
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