Study Comparing Prandial Insulin Aspart vs. Technosphere Insulin in Patients With Type 1 Diabetes on Multiple Daily Injections: Investigator-Initiated A Real-life Pilot Study-STAT Study
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 1
Sponsor: University of Colorado, Denver

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Study Comparing Prandial Insulin Aspart vs. Technosphere Insulin in Patients 
with Type 1 Diabetes on Multiple Daily Injections: Investigator-Initiated A Real-life 
Pilot Study—STAT Study 
 
PI:  Satish K. Garg MD 
University of Colorado, Barbara Davis Center for Diabetes 
 
Study Sites and Local PIs: 
1. PI:  Halis Kaan Akturk, MD 
University of Colorado Denver, Barbara Davis Center for Diabetes, 
1775 Aurora Court Aurora, CO 80045 
2.  PI:  Bruce Bode, MD 
Atlanta Diabetes Associates 1800, Howell Mill Rd #450, Atlanta, GA 30318 
3. PI:  Anne Peters, MD 
USC Westside Center for Diabetes, 9033 Wilshire Blvd #406, Beverly Hills, 
CA 90211 
4.  PI:  Leslie Klaff, MD and Ronald Brazg, MD 
Rainier Clinical Research Center, 723 SW 10th St #100, Renton, WA 98057 
5.  PI:  Timothy S. Bailey, MD 
AMCR Institute, 700 West El North Parkway, Suite 201, Escondido, CA  92026 
 
 

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Abbreviations: 
A1c 
 
 
Hemoglobin A1c 
AE 
 
 
Adverse Event 
AUC  
 
Area Under The Curve 
CGM  
 
Continuous Glucose Monitoring 
CBC  
 
Complete Blood Count 
CMP  
 
Complete metabolic panel 
CRO  
 
Contract Research Organization 
DKA  
 
Diabetic Ketoacidosis 
FEV1  
 
Forced Expiratory Volume In 1 Second 
FDA  
 
Food and Drug Administration 
IRB 
 
 
Intuitional Review Board 
MDI 
 
 
Multiple Daily Injections 
NL 
 
 
Novolog®, Insulin Aspart 
SAE  
 
Serious Adverse Event 
SMBG 
 
Self-Monitoring of Blood Glucose 
PPBG  
 
Post-prandial Blood glucose 
PPGE  
 
Post-prandial Glucose Excursion 
T1D 
 
 
Type 1 Diabetes 
TI 
 
 
Afrezza®, Technosphere Insulin 
 
 

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Clinical Trial Summary 
Title 
Study Comparing Prandial Insulin Aspart vs. Technosphere Insulin in 
Patients with Type 1 Diabetes on Multiple Daily Injections: 
Investigator-Initiated, A Real-life Pilot Study—STAT Study 
Trial Location 
Multi-center (USA) 
Study Objectives 
Primary objectives: 
1. Improved time in range (70-180 mg/dl) with technosphere 
insulin (TI) on continuous glucose monitoring (CGM) 
2. Better post-prandial glucose excursions (PPGE) (1-4 hours 
after meals) with TI 
Secondary objectives: 
1. To assess glucose variability (standard deviation and/or 
coefficient variation), 
2. The area under the curve (AUC) in the post-prandial blood 
glucose (PPBG) and PPGE, 
3. Change in A1c in one-month treatment, 
4. To determine above the target (>180 mg/dl) on CGM, and 
5. To evaluate hypoglycemia (below the target <70, <60, <50 
mg/dl) on CGM 
Study Design 
Randomized, open-label, parallel, multi-center, prospective, 
investigator-initiated 
Study Population 
Main Selection 
Criteria 
Inclusion criteria: 
1. Signed informed consent before any study-related activities, 
2. Male or female aged 18-70 years, 
3. Type 1 diabetes mellitus (T1D) duration more than six months, 

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4. Treatment with multiple daily injections (MDI) for at least three 
months before screening visit; stable insulin dose for the last 
one month, 
5. No use of any oral anti-diabetics, any other form of insulin other 
than mentioned in the protocol, or any other type of injections 
such as glucagon-like-peptide-1 (GLP-1) analogs, pramlintide 
or insulin/GLP-1 analog combinations, 
6. A1c between 6.5 to 10%, 
7. Willingness to routinely collect at least two blood glucose 
measurements per day to calibrate the CGM. Beyond the 
calibrations, patients may use CGM for necessary action 
without having to confirm with fingersticks self-monitoring blood 
glucose (SMBG), as approved by the Food and Drug 
Administration (FDA), 
8. BMI ≤35 kg/m2, 
9. Ability and willingness to adhere to the protocol including 
clinical and phone visits and 4-week-long CGM wear, 
10. Using insulin glargine or insulin degludec as basal insulin, 
11. Able to use and understand CGM data, 
12. Willing to complete phone and clinic visits, 
13. Patients who eat three main meals in a day (breakfast, lunch, 
and dinner), 
14. Ability to speak, read, and write English, and 
15. Patients prandial insulin need must be <18 units per meal 
 
Exclusion criteria: 
1. Use of any other diabetic medication other than allowed in the 
protocol, 
2. Pregnant or intention to become pregnant during the study, or 
not using adequate birth control methods, 

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3. Severe unexplained hypoglycemia requiring emergency 
treatment in the previous three months, 
4. Use of systemic or inhaled corticosteroids, 
5. History of hemoglobinopathies, 
6. Diagnosis of anemia, 
7. Post-renal transplantation, currently undergoing dialysis, 
creatinine >2.0 mg/dl or a calculated creatinine clearance of 
<50 mL/min, 
8. Advanced or unstable retinopathy needing laser procedure or 
vitrectomy, 
9. History of pancreatitis, 
10. Extensive skin changes/diseases that inhibit wearing a sensor 
on normal skin, 
11. Known allergy to adhesives, 
12. Known allergy to study medication, 
13. Participation in another investigational study protocol within 30 
days before enrollment, 
14. Known chronic obstructive pulmonary disease, pulmonary 
hypertension, asthma, pulmonary fibrosis, or any chronic 
pulmonary infection, or any systemic disease that primarily 
affects the lungs. History of any pulmonary nodule will be 
excluded to participate in the study, 
15. Active smokers, 
16. Marijuana users, 
17. Insulin pump users, 
18. Expected acetaminophen use during CGM, 
19. Using insulin detemir or NPH as basal insulin, 
20. Patients who use more than 18 units per meal, 
21. Any other condition, as determined by the investigator, which 
could make the subject unsuitable for the trial, impairs the 

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subject’s suitability for the trial, or impairs the validity of the 
informed consent. 
Total patients 
Up to 75 enrolled  for a total of 60 randomized patients to account for 
dropouts/screen fails 
Study Treatment 
Investigational 
medication(s) 
 
Treatment group: Technosphere insulin (Afrezza®) 
TI will be supplied as single-use cartridges of inhaled insulin of 4 or 8 
or 12 units each. 
Control group: Insulin aspart (Novolog®) {NL} 
Novolog® will be supplied as 100 U/mL solution for SC injection in the 
Novolog® Flexpen™ disposable pen. 
Routes of 
administration 
Treatment group: TI Inhaler 
Control group: Subcutaneous injection of NL 
Dose regimen and 
adjustment 
Patients will continue their routine meal and correction coverage, if 
applicable. Tables are for recommendations only and will be used as 
guidance. Since this is a real-life pilot study, patients will not be 
mandated to use corrections in the NL group. However, in the TI 
group, patients will use the conversion table from their current prandial 
insulin dosage as provided (Table 1A). Patients in the TI group will be 
recommended to use additional post-meal TI bolus as recommended 
to optimize PPBG {2-hour correction will be used only if blood glucose 
is >201 mg/dl and has not decreased by ≥ 50 mg/dl between 1 and 2-
hours} (Table 1B). 
Conversion  
Table 1A 
Injected 
mealtime insulin 
dose 
Technosphere 
insulin dose 
Up to 4 units 
4 units 
5-8 units 
8 units 
9-12 units 
12 units 
13-16 units 
16 units 

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17-20 units 
20 units 
 
Correction 
Table 1B 
 
Blood glucose 
1-hour 
2-hour 
<150 mg/dl 
- 
- 
151-200 mg/dl 
4 units 
- 
>201 mg/dl 
8 units 
4 units 
Basal insulin 
Insulin degludec (Tresiba®), insulin glargine (Lantus®, Basaglar®, 
Toujeo®) 
Route of 
administration 
Subcutaneous injection 
Dose regimen 
Patients will continue their current dose basal insulin once or twice a 
day. 
Statistical 
considerations 
Randomization: Patients will be assigned to TI or NL 1:1 
randomization. 
Sample size determination: Power Analysis is based on the studies 
done in patients with diabetes. This sample size will provide 80% 
power to detect a difference in the primary endpoint of time in the 
range of 11%, assuming a standard deviation of 15% and 97% power 
to detect a difference of 1.0 glucose excursion post-prandially, 
assuming a standard deviation of 1.0. 
Analysis population: Statistical analysis will be done after the study is 
complete. The analysis will be conducted on an intent to treat (ITT) 
population. 
Study duration 
Screening visit followed by randomization visit (up to 7 days) 
4-week treatment period (2 phone visits, 2 clinic visits) 
1-week follow-up period (1 phone visit) 
Total of 6 weeks 
 

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Sponsor:     Investigator initiated trial supported by Mannkind, Corp, Valencia, CA. 
 
Project Overview 
This is an investigator-initiated, prospective, randomized, multicenter, parallel, 
open-label, pilot clinical trial evaluating the efficacy of TI for PPBG, PPGE, and time-in-
range on CGM download in patients with T1D. TI is an inhaled, ultra-rapid-acting insulin, 
approved by the FDA for use in patients with diabetes. This is a pilot, real-life study 
where patients will continue their routine diabetes care and use post-meal correction 
dosages as deemed necessary for normalizing PPBG as per the protocol. 
This multi-center study will enroll 75 patients with T1D for a total of 60 
randomized patients to account for dropouts/screen fails, A1c values between 6.5 to 
10%. The patients will be randomized in 1:1 fashion to either TI or NL. Patients who are 
randomized into the NL arm will continue using their usual prandial insulin dose before 
meals. Patients who are randomized into the TI arm will be instructed to dose before the 
meals and take necessary corrections at 1- and 2-hours after meals to optimize PPBG 
(Table 1B). There will be a total of 7 study visits (screening visit, randomization visit, 2 
clinic, and 3 phone visits). There will be a 4-week treatment comparison between TI and 
NL and 1-week of post-study follow up. (Phone visit; Figure-1). Standard lab tests (A1c, 
complete metabolic panel {CMP}, complete blood count {CBC}) will be performed at the 
screening visit. 
All patients will use real-time CGM (Dexcom G5®, San Diego, CA), which will be 
provided at the randomization visit for their day-to-day diabetes care. CGM data will be 
downloaded at every clinic visit on a secured computer. The data will be analyzed after 

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the study for different primary and secondary end points. All patients will be allowed to 
keep the CGM after the study is over for their day-to-day diabetes care. 
 
Primary objective: 
1. Improved time in range (70-180 mg/dl) with TI on CGM 
2. Better PPGE (1-4 hours after meals) with TI 
 
Secondary objectives: 
1. To assess glucose variability (GV) (standard deviation and/or coefficient 
variation), 
2. The area under the curve (AUC) in the PPBG and PPGE, 
3. Change in HbA1c in one-month treatment, 
4. To determine above the target (>180 mg/dl) on CGM, and 
5. To evaluate hypoglycemia (below the target <70, <60, <50 mg/dl) on CGM. 
 
Research Design 
What do we intend to do? 
We plan to execute an investigator-initiated, treat-to-target (TTT), multi-center, 
prospective randomized, parallel, open-label pilot clinical trial evaluating the efficacy of 
TI for lowering PPBG and PPGE in 60 adult patients (18 to 70 years) with T1D when 
compared with NL over a 4-week treatment period. The study protocol is registered with 
the NCT Government website: ClinicalTrials.Gov. NCT03143816 
 
How are we going to do the work? 
The Barbara Davis Center for Diabetes (BDC), primarily a leading T1D clinical 
and research center equipped for large-scale clinical research, will enroll approximately 
15-20 patients (Halis Kaan Akturk, MD). The other four sites are: Atlanta Diabetes 
Associates (Bruce Bode, MD), USC Westside Center for Diabetes (Anne Peters, MD), 
AMCR Institute (Timothy Bailey, MD), and Rainier Clinical Research Center (Leslie 
Klaff, MD, and Ronald Brazg, MD). All other sites will enroll approximately 10-15 

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patients. Necessary personnel from all sites will attend an investigator’s meeting likely in 
Denver in June 2017, which will be organized and conducted before the trial initiation. 
All patients will sign an informed consent form approved by the respective institutional 
review boards (IRB). The study will be coordinated by an external contract research 
organization (CRO), and all sites will be monitored at least once during the study. 
 
How will the sites communicate? 
Throughout the duration of the study, specific events will also be communicated 
by CRO between secondary sites and the primary investigator site. These events 
include protocol exemption, and waiver requests including failed inclusion or exclusion 
criteria. The patients will be screened within 2 weeks for A1c deviation. All serious 
adverse events (SAEs) will be reported to the CRO and the principal investigator within 
24 hours. 
 
What is the study population? 
The study population will consist of patients with T1D currently receiving care at 
all respective study sites as listed on the front page. All investigators will attempt to 
recruit males and females with T1D from a variety of ethnic groups for participation in 
this study. Participants selected for this trial will be adult males and females (18-70 
years old) with BMI ≤35.0, diabetes duration >6 months, A1c between 6.5–10% with 
T1D, who have not taken any oral anti-diabetics or any other insulin other than 
mentioned in the protocol or GLP-1 analog injections or any combination of insulin/GLP-
1 analog injections in the last three months (detailed in Appendix 2 and 3). One repeat 
A1c will be allowed within two weeks of the screening phase. Patients who need more 
than 18 units of prandial insulin before meals will be excluded from the study. Only 
patients taking glulisine (Apidra®), lispro (Humalog®), or aspart (Novolog®) as their 
prandial insulin at baseline will be allowed in the study. 
 
How are patients being selected for the study? 
Patients will be randomly selected from the patient population at all sites. First 
recognized by the investigator, coordinator, or from a computer-generated list based on 

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entry criteria, patients who qualify will be offered to participate in the study on a first 
come basis. Patients who appear to fit the inclusion/exclusion criteria as mentioned in 
Appendix 2 and 3 during prescreening will be screened. 
 
What are the treatment groups? 
There are two parallel treatment groups. Beginning the day after visit 2, week 1, 
patients in the TI treatment group will use only TI for meals and corrections. Patients in 
the comparison group will be using NL for meals as they use it in real life. All patients 
will be provided with TI and insulin aspart for the duration of the study. All basal insulin 
(Toujeo®, Lantus®, Basaglar®, Tresiba®) except NPH and detemir (Levemir®) are 
allowed before and during the study as a part of MDI regimens. Basal insulin will not be 
provided throughout the study period. 
 
What is your assignment strategy? 
The patients will be assigned in a 1:1 fashion to either the TI or NL group. Sites 
will be responsible for supplying TI, NL, and other necessary materials to the patients 
related to the study. The Barbara Davis Center for Diabetes will be responsible for 
randomization using a computer system (Janet Snell-Bergeon, PhD). All patients will be 
provided with a CGM (Dexcom G5®, San Diego, CA) and six sensors for the duration of 
the study. Patients will be allowed to keep the CGM systems for their personal use after 
the study. The CGM data will be downloaded and analyzed for different GV indices at all 
clinical visits. 
 
What are sample size calculations? 
Sixty (60) patients will be randomized into the TI and NL groups, and the study 
will likely initiate in summer of 2017. Power Analysis is based on the studies done in 
patients with diabetes. This sample size will provide 80% power to detect a difference in 
the primary end point of time in the range of 11%, assuming a standard deviation of 
15%, and 97% power to detect a difference of 1.0 glucose excursion post-prandially, 
assuming a standard deviation of 1.0. 
 

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What is the schedule of events for the treatment groups? 
All patients will participate in a 1-2 hour screening visit 1, week-1. In the same 
week, patients will be randomized into one of the two treatment groups during baseline 
visit 2 (week 0). The treatment group will only use TI for rapid acting insulin for meals 
and corrections. The control group will only use NL for rapid acting insulin for meals. 
The patients in the control group will continue to use their respective treatments for four 
weeks with no predetermined change in dosage or titration. The patients in the TI group 
will use TI insulin as prandial insulin and for PPBG correction at 1- and 2-hours after 
main meals. Three main meals should be at least 4 hours apart from each other. 
Because the duration of action of TI is shorter, but ultra-rapid in onset compared to NL, 
patients in the treatment group can use TI insulin for correction dose(s) at 1-hour and 2-
hour after the meal dose, if BG is over 150 mg/dl. All patients in the treatment group will 
use a dose-conversion chart that will be provided at randomization for meals according 
to their usual prandial insulin dose (Table 1A). The study design is summarized in 
Figure-1. All patients in the treatment group will be given the option of using correction if 
PPBG at 1-hour after the meal is between 151-200 mg/dl by 4 units of TI, and if PPBG 
is over 201 mg/dl by 8 units of TI (Table 1B). If PPBG does not decrease more than 50 
mg/dl, and still over 201 mg/dl at 2-hour after the meal, they will be given the option of 
using 4 units of TI (Table 1B). All patients in the treatment group will be instructed on 
proper use of the TI inhaler. At all clinical visits, all insulin dosages will be recorded. All 
data will be downloaded and saved on a secured computer. FEV1 at baseline, after 2-
week of treatment and at the end of the study will be done for all patients. Appendix-1 
summarizes the schedule of events. 
 
Excluded medications: 
The patients who are current smokers or have any other significant pulmonary 
disease will not be allowed to participate in the study. No marijuana consumption will be 
allowed during the study (since the effects of acute marijuana inhalations on TI 
absorption are unknown). 
All oral anti-diabetics and other forms of insulin and injectable medications other 
than mentioned in the protocol should not be taken in the last three months. 

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Medications that affect blood sugar, including oral anti-diabetic medications, are not to 
be used for the duration of the study. The patients must not be taking inhaled or oral 
systemic corticosteroids. 
Other drugs that interact with TI and/or NL are to be considered on a case-by-
case basis by the investigator, including herbs with hypoglycemic properties. 
 
Visit Descriptions: 
Screening, Visit 1 (Week -1): 
A screening visit: Visit 1 (Week -1). Informed consent will be obtained before 
commencement of any trial-related activities, defined as any procedure that would not 
have been performed during standard care of the subject outside of the study. 
During this visit, patients will receive a physical exam, EKG, vitals and medical 
history, demographics, and a concomitant medications list will be recorded. A blood 
draw will be performed to assess for A1c (point of care preferred), CMP, and CBC. A 
urine pregnancy test will be administered for females of childbearing potential. If the 
patient has a qualified HbA1c done in the last two weeks, it will not be repeated at the 
screening visit unless the PI deems it necessary. All patients will receive a spirometry 
(FEV1) test for screening. 
 
Baseline/Randomization, Visit 2 (Week 0) ± 3 days: 
Patients who meet the screening criteria will be randomized into one of two 
groups and necessary study medication will be dispensed. Instructions will be given on 
how to use the study medication, TI, starting the day following this visit with meals and 
corrections with doses recommended as seen in Table 1A and 1B, and to basal insulin 
regimen throughout the trial without any dose change. However, the PI may make 

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necessary changes in patients’ insulin dosages especially keeping patient safety in 
mind. Any changes that are done by the PI out of the protocol for patient safety will be 
recorded and considered in statistical analysis. 
Patients will have their vitals, weight, any adverse events, and concomitant 
medications recorded. All patients will start real-time CGM (Dexcom G5®, San Diego, 
CA) at that visit. All patients will wear CGM throughout the study. They will be allowed to 
keep the CGM after the study. They will be trained to use CGM if they do not know how 
or if they are not already on it. Patients will be trained on study paperwork (food, 
glucose and insulin diaries). Patients will continue to check their blood glucose levels 
via SMBG as they deem necessary. However, as approved by the FDA, Dexcom G5® 
data may be used to take necessary action, but all patients must calibrate the sensor 
two times a day per the label. 
All patients in the treatment group will be given the option of using correction if 
PPBG at 1-hour after the meal is between 151-200 mg/dl by 4 units of TI and if PPBG is 
over 201 mg/dl by 8 units of TI. If PPBG does not decrease more than 50 mg/dl and still 
over 201 mg/dl at 2-hours after the meal, they will be given the option of using 4 units of 
TI. All patients in the treatment group will use the recommended conversion (Table 1A) 
when they calculate their prandial insulin dose. Since this is a real-life study, patients in 
the treatment group will be instructed to use TI for post-prandial hyperglycemia; 
however, they will not be mandated. In the control group, patients will continue their 
current NL prandial dose 15 minutes before meals according to their prandial insulin 
dose. If they use correction, they will correct; however, they will not change their routine 
pre- and post-prandial management. 

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Telephone Visits (Visits 3, 5, and 7) ± 3 days (Figure-1): 
 
A phone call will be made by the study site staff to each subject at visits 3, 5, and 
7. Although the window is ± 3 days, call time will be arranged in advance during the 
clinic visit. At this visit, staff will review any adverse events and changes in medications. 
Compliance to study protocol rules and CGM use will be reviewed. 
 
Visit 4 (Week 2) ± 3 days: 
This visit will occur at Week 2. At Visit 4, study site staff will record patients’ 
vitals, weight, review of CGM data, and any adverse events and concomitant 
medications. Glucose download, insulin use/dose, and sensor glucose data will be 
discussed with the provider or the study coordinator. 
The patients will remain in the same treatment or control group. Basal, bolus, and 
total daily dose of insulin will be recorded. The patients will receive necessary refills for 
CGM supplies and study medications. All patients will be reminded about the study 
protocol and insulin conversion and correction doses (Table 1A and 1B). Patients will 
get FEV1 spirometry test. Patients who have decline more than 20% at FEV1 test at 2-
week of treatment will be excluded. 
 
End of study, Visit 6 (Week 4) or Early Termination Visit ± 3 days: 
For patients who withdraw at any point during the trial period, this visit will also 
be offered as an early termination visit (ETV). 

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Patients who complete treatment will schedule an end of study visit. This will be 
Visit 6 at Week 4. During this visit, a physical exam will be conducted. Vitals, weight, 
review of CGM data, adverse events, and concomitant medications will be recorded. 
Additional blood will be drawn for A1c or point of care A1c will be done. Unused 
medication will be returned. Active treatment with TI will end at this visit. 
Basal, bolus, and total daily dose of insulin will be recorded. After the study, 
patients will be expected to continue their previous therapy. All patients will receive a 
spirometry (FEV1) test. 
 
Risks and Justification of Procedures 
Technosphere insulin (Afrezza®) 
 
Technosphere insulin (TI) (MannKind Corporation, Valencia, CA) is a dry powder 
formulation of regular human insulin adsorbed onto technosphere microparticles for oral 
inhalation (1). Upon inhalation, these microparticles can reach the deep lung where they 
dissolve rapidly because of the physiological pH, allowing absorption of insulin into the 
systemic circulation with a time to maximum serum insulin concentration of ∼12–15 min 
(2). TI is currently approved for the treatment of Type 1 and 2 diabetes. Hypoglycemia is 
a potential risk of taking any insulin and/or TI therapy. Typical symptoms of 
mild/moderate hypoglycemia include: cold sweats, cool pale skin, nervousness or 
tremor, anxious feeling, unusual tiredness or weakness, confusion, difficulty 
concentrating, drowsiness, excessive hunger, and/or transient vision changes (3). 
Acute bronchospasm has been observed in patients with asthma and COPD 
using TI (3). TI is contraindicated in patients with chronic lung disease. Before starting 

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TI, detailed medical history, physical exam, and a spirometry (FEV1) test are mandatory 
to identify potential lung disease in all patients (3). Patients who had >20% decrease in 
FEV1 during treatment will be discontinued from using TI. 
In patients with T1D receiving basal insulin, HbA1c reduction with TI was 
noninferior to that of aspart, with less hypoglycemia and less weight gain (3). A multi-
center randomized clinical trial in patients with Type 2 diabetes showed that patients 
had significantly lower weight gain and fewer mild-to-moderate and severe 
hypoglycemic events on TI plus insulin glargine than on biaspart insulin (4). Another 
study in patients with T1D compared insulin NPH to TI and TI was not inferior for post-
prandial blood glucose control and had better results at fasting plasma glucose (5). 
Safety Measures: 
CRO will oversee safety data throughout the study via reporting of hypoglycemic 
events, adverse events, and serious adverse events (SAEs). All AEs, reported 
spontaneously by the patients, as well as those noted by the investigator or study staff, 
regardless of seriousness, severity, expectedness, or relationship to the study drug, will 
be recorded on source documents from the time of obtaining the informed consent to 7 
days after the last dose of the study drug. 
Severe hypoglycemia, a hypoglycemic episode requiring assistance or 
hospitalization with or without an SMBG or CGM data, is to be reported as a SAE. A 
hypoglycemic event “requiring assistance” is identified when the subject is unable to 
treat the event on their own. Any untoward event resulting in hospitalization, an 
extension of hospitalization, death, or threat of death will also be considered an SAE. All 
SAEs will be reported to FDA MedWatch by the CRO. 

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Statistical Analysis Plan 
Statistical analysis will be done after the study is complete. The analysis will be 
conducted on the intent to treat (ITT) population. Sample size and power calculations 
were based on the pilot study conducted at the BDC (7). 
The primary end points are to demonstrate improved time in range (70-180mg/dl) 
with TI on CGM and better PPGE (1-4 hours after meals). The secondary end points are 
to assess hypoglycemia, measure HbA1c changes, evaluate glucose variability, and to 
assess above the target (>180mg/dl) on CGM download. 
Publication Strategy 
Study results may be presented at national and international conferences 
including: the Scientific Sessions of the American Diabetes Association, European 
Association for the Study of Diabetes, Advanced Technologies for the Treatment of 
Diabetes, etc. The PI may submit the study results for publishing to peer-reviewed 
scientific journals, particularly within the fields of diabetes and endocrinology. All study 
results and data will be shared with the sponsor. 
 
 

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References 
 
1. Rathbone M, Hadgraft J, Roberts M, Lane M, Leone-Bay A, Grant M. 
Technosphere/insulin: mimicking endogenous insulin release. In Modified-
Release Drug Delivery Technology. Vol. 2, 2nd ed. Rathbone M, Hadgraft J, 
Roberts M, Lane M, Eds. New York, Informa Healthcare USA, Inc., 2008, p. 673–
679 
2. Richardson PC, Boss AH. Technosphere insulin technology. Diabetes Technol 
Ther 2007;9(Suppl. 1):S65–S72pmid:17563306 
3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022472lbl.pdf, April 
2017 
4. Bode BW, McGill JB, Lorber DL, Gross JL, Chang PC, Bregman DB; Affinity 1 
Study Group. Inhaled Technosphere Insulin Compared With Injected Prandial 
Insulin in Type 1 Diabetes: A Randomized 24-Week Trial. Diabetes Care. 2015 
Dec;38(12):2266-73. doi: 10.2337/dc15-0075. Epub 2015 Jul 15. 
5. Rosenstock J, Lorber DL, Gnudi L, Howard CP, Bilheimer DW, Chang PC, 
Petrucci RE, Boss AH, Richardson PC. Prandial inhaled insulin plus basal insulin 
glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre 
randomised trial. Lancet. 2010 Jun 26;375(9733):2244-53. doi: 10.1016/S0140-
6736(10)60632-0. 
6. Skyler JS, Weinstock RS, Raskin P, et al; Inhaled Insulin Phase III Type 1 
Diabetes Study Group. Use of inhaled insulin in a basal/bolus insulin regimen in 
type 1 diabetic subjects: a 6-month, randomized, comparative trial. Diabetes 
Care 2005;28:1630–1635pmid:15983312 
7. Garg SK, Kelly W, Freson B, Ritchie P. Treat-to-target technosphere insulin 
study in adult subjects with type 1 diabetes. Poster presented at American 
Diabetes Association 2011 annual meeting. 
 
 

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Table-1A Injected insulin to technosphere insulin conversion chart at study 
initiation 
 
Injected 
mealtime 
insulin dose 
Technosphere 
insulin dose* 
Up to 4 units 
4 units 
5-8 units 
8 units 
9-12 units 
12 units 
13-16 units 
16 units 
17-20 units 
20 units 
 
*Investigators may change the dosage based on patient safety, this table will be used 
as a guide. Patients who take more than 18 units on insulin aspart per meal will be 
excluded from the study. 
 
 
 
 
Table-1B Correction doses for technosphere insulin group 
 
Blood glucose 
1-hour 
2-hour 
<150 mg/dl 
- 
- 
151-200 mg/dl 
4 units 
- 
>201 mg/dl 
8 units 
4 units* 
 
*2-hour correction will be used only if blood glucose is >201 mg/dl and has not 
decreased by ≥ 50 mg/dl between 1 and 2-hours. 
 
 

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Appendix-1 Schedule of events 
 
*HbA1c test may not be waived at Visit 1 if the patient had an A1C done in the last 2 weeks. 
+All insulin (basal and prandial) will be recorded in a diary provided. 
Visit 
1 
2 
3 
4 
 5 
6 
7 
Week 
-1 
0 
1 
2 
3 
4 
5 
Visit Type 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
Assessment 
Screening 
and 
Baseline 
Randomization 
Treatment 
week 
Treatment 
week 
Treatment 
week 
Treatment 
week 
Post-
study 
follow up 
 
Final 
Early 
termin
ation 
Day (±3) 
-7 
0 
7 
14 
21 
28 
35 
Informed 
consent-
Eligibility criteria 
x 
 
 
 
 
 
 
 
Demographic 
Data, Medical 
History 
x 
 
 
 
 
 
 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
 
Adverse events 
 
 
x 
x 
x 
x 
x 
Physical exam 
x 
x 
 
x 
 
x 
 
EKG 
x 
 
 
 
 
 
 
Urine 
pregnancy test 
if applicable 
x 
 
 
 
 
 
 
HbA1c* 
x 
 
 
 
 
x 
 
Complete blood 
count 
x 
 
 
 
 
 
 
Complete 
metabolic panel 
x 
 
 
 
 
 
 
Spirometry(FEV
1) 
x 
 
 
x 
 
x 
 
Vital 
signs/weight 
x 
x 
 
x 
 
x 
 
Randomization 
 
x 
 
 
 
 
 
Record 
basal,bolus, 
total insulin 
dose+ 
x 
x 
 
x 
 
x 
 
Dispense TI 
 
x 
 
x 
 
 
 
Dispense insulin 
aspart 
 
x 
 
x 
 
 
 
Dexcom CGM-
training and 
dispense CGM 
 
x 
 
 
 
 
 
CGM 
change/downloa
d/ removal 
 
 
 
x 
 
x 
 
Glucose meter 
download 
 
x 
 
x 
 
x 
 
TI-NL 
conversion 
chart dispense 
and education 
 
 
x 
 
x 
 
 
 
Compliance 
check 
 
 
x 
x 
x 
x 
 

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Appendix-2 
Inclusion Criteria: 
Patients that meet the following criteria will be considered for admission to the study: 
1. Signed informed consent before any study-related activities, 
2. Male or female aged 18-70 years, 
3. Type 1 diabetes mellitus duration more than six months, 
4. Treatment with MDI for at least three months before screening visit; stable insulin 
dose for the last month, 
5. No use of any oral anti-diabetics, any other forms of insulin other than mentioned 
in the protocol, or any other types of injections such as GLP-1 analogs, 
pramlintide or insulin/GLP-1 analog combinations, 
6. A1c between 6.5 to 10%, 
7. Willingness to routinely practice at least two blood glucose measurements per 
day needed to calibrate the CGM. Beyond the calibrations, patients may use 
CGM for necessary action without having to confirm with fingersticks (SMBG), as 
approved by the FDA, 
8. BMI ≤ 35 kg/m2, 
9. Ability and willingness to adhere to the protocol including clinical and phone visits 
and 4-week-long CGM wear, 
10. Using insulin glargine or insulin degludec as basal insulin, 
11. Able to use and understand CGM data, 
12. Willing to complete phone and clinic visits, 
13. Patients who eat three main meals in a day (breakfast, lunch, and dinner), 
14. Ability to speak, read, and write English, 
15. Patient’s prandial insulin need must be <18 units per meal. 
 
 

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Appendix-3 
Exclusion Criteria: 
Patients will be excluded from the study if any of the following apply: 
1. Use of any other diabetic medication other than allowed in the protocol, 
2. Pregnant or intent to become pregnant during the study or not using adequate 
birth control methods, 
3. Severe unexplained hypoglycemia requiring emergency treatment in the previous 
three months, 
4. Use of systemic or inhaled corticosteroids, 
5. History of hemoglobinopathies, 
6. Diagnosis of anemia, 
7. Post-renal transplantation, currently undergoing dialysis, creatinine >2.0 mg/dl or 
a calculated creatinine clearance of <50 mL/min, 
8. Advanced or unstable retinopathy needing laser procedure or vitrectomy, 
9. History of pancreatitis, 
10. Extensive skin changes/diseases that inhibit wearing a sensor on normal skin, 
11. Known allergy to adhesives, 
12. Known allergy to study medication, 
13. Participation in another investigational study protocol within 30 days before 
enrollment, 
14. Known chronic obstructive pulmonary disease, pulmonary nodule, pulmonary 
hypertension, asthma, pulmonary fibrosis or any chronic pulmonary infection, or 
any systemic disease that primarily affects the lungs, 
15. Active smokers, 
16. Marijuana users, 
17. Insulin pump users, 
18. Expected acetaminophen use during CGM, 
19. Using insulin detemir or NPH as basal insulin, 
20. Patients who use more than 18 units per meal, 

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21. Any other condition, as determined by the investigator, which could make the 
subject unsuitable for the trial, impairs the subject’s suitability for the trial, or 
impairs the validity of the informed consent 
 

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Appendix-4 
Discontinuation Criteria: 
1. A major change in exercise regimen during study participation, 
2. Diabetic ketoacidosis, 
3. Development of pancreatitis, 
4. Pregnancy, 
5. A decline in glucose control or an increase in hypoglycemia which, in the opinion 
of the PI, is considered to compromise patient safety, 
6. Initiation of any other insulin or other injectable or oral form of anti-diabetics 
during the study other than the mentioned control or intervention group 
medications, 
7. Developing significant shortness of breath or intolerance and cough to inhaled 
insulin, and/or 
8. Decline >20% in FEV1 test as compared to baseline during TI treatment. All 
patients will receive a spirometry test (FEV1) at baseline, visit-4 and at the end of 
the study. 
9. Acetaminophen use during CGM (4-week treatment period) 
 
 

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Figure-1 Flow diagram of the study