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

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT03143816
• Collaborator: Atlanta Diabetes Associates (Other), University of Southern California (Other), Rainier Clinical Research Center (Other), Mannkind Corporation (Industry)
• Enrollment: 60
• Location: 1
• Arms: 2
• Actual Duration (Months): 4
• Patients Per Site Per Month: 14.8

Study Details

Study Description

Brief Summary

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 60 patients with T1D, 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 , complete blood count ) 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 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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: Technosphere insulin	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Sep 30, 2017
• Actual Primary Completion Date: Dec 15, 2017
• Actual Study Completion Date: Jan 31, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Technosphere insulin (TI, Afrezza) -Treatment arm 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 ( post prandial blood glucose)	Drug: Technosphere insulin; This multi-center study will enroll 60 patients with T1D, 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.
No Intervention: Insulin Aspart ( Novolog) -Control arm Patients who are randomized into the NL arm will continue using their usual prandial insulin dose before meals.

Outcome Measures

Primary Outcome Measures

1. Change in Time in Range (%) (70-180 mg/dl) With TI on CGM [4 weeks]

   Difference between Time in range for TI group (treatment) and for Aspart group (control)

Secondary Outcome Measures

1. Change in Post-prandial Glucose Excursion (mg/dl) (1-4 Hours After Meals) With TI [4 weeks]

   Difference in postprandial blood glucose between treatment and control group

2. Change in Glucose Variability (GV) (mg/dl) (Standard Deviation and/or Coefficient Variation) [4 weeks]

   Difference of glucose variability metrics between treatment and control groups

3. The Area Under the Curve Calculation (AUC) (Min*mg/dl) in the PPBG and PPGE, [0, 1, 2, 3, 4 hours post-dose at 4 weeks]

   Difference of area under curve between treatment and control groups. ( 0 to 4 hours duration)

4. Change in HbA1c (%) in One-month Treatment [4 weeks]

   Difference in HbA1c between treatment and control group

5. Change in Above the Target Time (%) (>180 mg/dl) on CGM [4 weeks]

   Difference of time above range between treatment and control group

6. Hypoglycemia Frequency (%) (Below the Target <70mg/dl) on CGM [4 weeks]

   Difference of hypoglycemia frequency between treatment and control groups.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

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 needed 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. Patients who use insulin-carb ratio for bolus,

15. Ability to speak, read, and write English, and

16. 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,

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. Using insulin detemir or NPH as basal insulin, and

19. 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 -

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barbara Davis Center	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver
• Atlanta Diabetes Associates
• University of Southern California
• Rainier Clinical Research Center
• Mannkind Corporation

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 15, 2017
• Informed Consent Form - Aug 15, 2017

More Information

Publications

• 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
• 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.
• 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.
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022472lbl.pdf, April 2017
• Richardson PC, Boss AH. Technosphere insulin technology. Diabetes Technol Ther. 2007 Jun;9 Suppl 1:S65-72.
• 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.
• Skyler JS, Weinstock RS, Raskin P, Yale JF, Barrett E, Gerich JE, Gerstein HC; 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 Jul;28(7):1630-5.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT03143816
• Other Study ID Numbers: 17-0427
• First Posted: May 8, 2017
• Last Update Posted: Feb 22, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by University of Colorado, Denver: diabetes; time in range; inhaled insulin; continuous glucose monitoring; type 1 diabetes; hypoglycemia; post prandial hypergylcemia
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin

Study Results

Participant Flow

Arm/Group Title	Technosphere Insulin (TI, Afrezza) -Treatment Arm	Aspart ( Control)
Arm/Group Description	There were a total of seven clinic and phone visits during the study period.Patients were randomized 1:1 to TI or insulin aspart group using a blocked design, stratified by screening HbA1c (<8% or >8%).All patients used realtime CGM (continuous glucose monitor) during the study period. Patients randomized to aspart continued the same bolus regimen as used before randomization. If patients were using any other RAIA( rapid acting insulin analog) (other than aspart), they were switched to aspart on the same dose at the randomization visit. Patients in the aspart group were also allowed to change their premeal bolus dose and take postprandial and other correction doses as deemed clinically necessary.	There were a total of seven clinic and phone visits during the study period.Patients were randomized 1:1 to TI or insulin aspart group using a blocked design, stratified by screening HbA1c (<8% or >8%).All patients used realtime CGM (continuous glucose monitor) during the study period. Patients randomized to aspart continued the same bolus regimen as used before randomization. If patients were using any other RAIA ( rapid acting insulin analog) (other than aspart), they were switched to aspart on the same dose at the randomization visit. Patients in the aspart group were alsoallowed to change their premeal bolus dose and take postprandial and other correction doses as deemed clinically necessary.
Period Title: Overall Study
STARTED	26	34
COMPLETED	22	34
NOT COMPLETED	4	0

Baseline Characteristics

Arm/Group Title	Technosphere Insulin (TI, Afrezza) -Treatment Arm	Insulin Aspart ( Novolog) -Control Arm	Total
Arm/Group Description	This group received Technosphere insulin for bolus insulin with meals and corrections	This group received insulin aspart for bolus insulin with meals and corrections	Total of all reporting groups
Overall Participants	26	34	60
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	26 100%	34 100%	60 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41 (16)	42 (14)	41 (15)
Sex: Female, Male (Count of Participants)
Female	10 38.5%	12 35.3%	22 36.7%
Male	16 61.5%	22 64.7%	38 63.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	26 100%	34 100%	60 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	26 100%	34 100%	60 100%

Outcome Measures

1. Primary Outcome

Title	Change in Time in Range (%) (70-180 mg/dl) With TI on CGM
Description	Difference between Time in range for TI group (treatment) and for Aspart group (control)
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Insulin Aspart ( Novolog) -Control Arm	Technosphere Insulin (TI, Afrezza) -Treatment Arm
Arm/Group Description	Group received insulin aspart as bolus	Group received Technosphere insulin as bolus
Measure Participants	34	22
Mean (Standard Deviation) [percent time in range]	53.5 (1.8)	58.4 (2.2)

2. Secondary Outcome

Title	Change in Post-prandial Glucose Excursion (mg/dl) (1-4 Hours After Meals) With TI
Description	Difference in postprandial blood glucose between treatment and control group
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Technosphere Insulin (TI, Afrezza) -Treatment Arm	Insulin Aspart ( Novolog) -Control Arm
Arm/Group Description	Group using Technosphere insulin	Group using novolog ( control ) group
Measure Participants	22	34
Mean (Standard Deviation) [mg/dl]	45 (6)	60 (8)

3. Secondary Outcome

Title	Change in Glucose Variability (GV) (mg/dl) (Standard Deviation and/or Coefficient Variation)
Description	Difference of glucose variability metrics between treatment and control groups
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Technosphere Insulin (TI, Afrezza) -Treatment Arm	Insulin Aspart ( Novolog) -Control Arm
Arm/Group Description	Group using Technosphere insulin as bolus	Group using insulin aspart as bolus
Measure Participants	22	34
Mean (Standard Deviation) [mg/dl]	57.8 (2.4)	66.3 (1.9)

4. Secondary Outcome

Title	The Area Under the Curve Calculation (AUC) (Min*mg/dl) in the PPBG and PPGE,
Description	Difference of area under curve between treatment and control groups. ( 0 to 4 hours duration)
Time Frame	0, 1, 2, 3, 4 hours post-dose at 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Technosphere Insulin (TI, Afrezza) -Treatment Arm	Insulin Aspart ( Novolog) -Control Arm
Arm/Group Description	The group receiving Technosphere insulin	The group receiving insulin aspart (control)
Measure Participants	22	34
Mean (Standard Deviation) [min*mg/dl]	15020 (560)	20020 (680)

5. Secondary Outcome

Title	Change in HbA1c (%) in One-month Treatment
Description	Difference in HbA1c between treatment and control group
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Technosphere Insulin (TI, Afrezza) -Treatment Arm	Insulin Aspart ( Novolog) -Control Arm
Arm/Group Description	Group using Technosphere insulin as bolus	Group using insulin aspart as bolus
Measure Participants	22	34
Mean (Standard Deviation) [percentage (%)]	0.25 (0.31)	0.02 (0.36)

6. Secondary Outcome

Title	Change in Above the Target Time (%) (>180 mg/dl) on CGM
Description	Difference of time above range between treatment and control group
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Technosphere Insulin (TI, Afrezza) -Treatment Arm	Insulin Aspart ( Novolog) -Control Arm
Arm/Group Description	Group using Technosphere insulin as bolus	Group using insulin aspart as bolus
Measure Participants	22	34
Mean (Standard Deviation) [percent time above target]	38.1 (0.3)	41.2 (1.8)

7. Secondary Outcome

Title	Hypoglycemia Frequency (%) (Below the Target <70mg/dl) on CGM
Description	Difference of hypoglycemia frequency between treatment and control groups.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Technosphere Insulin (TI, Afrezza) -Treatment Arm	Insulin Aspart ( Novolog) -Control Arm
Arm/Group Description	Group using Technosphere insulin as bolus	Group using insulin aspart as bolus
Measure Participants	22	34
Mean (Standard Deviation) [percent time below range]	2.2 (0.7)	4.0 (0.6)

Adverse Events

Time Frame	5 weeks ( 4 weeks treatment and 1 week follow up)
Adverse Event Reporting Description	This is a 4-week study, all medications used in this study were FDA approved.
Arm/Group Title	Technosphere Insulin (TI, Afrezza) -Treatment Arm		Insulin Aspart ( Novolog) -Control Arm
Arm/Group Description	Group using Technosphere insulin as bolus		Group using insulin aspart as bolus
All Cause Mortality
	Technosphere Insulin (TI, Afrezza) -Treatment Arm		Insulin Aspart ( Novolog) -Control Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/34 (0%)
Serious Adverse Events
	Technosphere Insulin (TI, Afrezza) -Treatment Arm		Insulin Aspart ( Novolog) -Control Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/34 (0%)
Other (Not Including Serious) Adverse Events
	Technosphere Insulin (TI, Afrezza) -Treatment Arm		Insulin Aspart ( Novolog) -Control Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/26 (11.5%)		0/34 (0%)
Respiratory, thoracic and mediastinal disorders
mild cough	3/26 (11.5%)	3	0/34 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.