Clinical Trial Evaluating Technosphere® Insulin Versus Insulin Aspart in Subjects With Type 1 Diabetes Mellitus Over a 24-week Treatment Period

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ClinicalTrials.gov Identifier: NCT01445951

Recruitment Status : Completed

First Posted : October 4, 2011

Results First Posted : October 22, 2014

Last Update Posted : October 22, 2014

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Mannkind Corporation

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Type 1 Diabetes Mellitus
Interventions	Drug: Technosphere® Insulin with MedTone C Inhaler Drug: Technosphere ®Insulin with Gen2 Inhaler Drug: Insulin Aspart in combination with a basal insulin
Enrollment	518

Participant Flow

Recruitment Details	First Patient enrolled Sept 2011. Multi-national trial conducted in US, Russia, Ukraine and Brazil.
Pre-assignment Details	3 week Screening Period prior to run-in (basal insulin optimization period). 1401 Screened / 621 Eligible of which 614 entered the run-in period. 538 met randomization criteria at end of run-in of which 518 were randomized.


Arm/Group Title	Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin
Arm/Group Description	Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...
Arm/Group Description	Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient
Period Title: Overall Study
Started	174	174	170
Completed	130	138	151
Not Completed	44	36	19
Reason Not Completed
Adverse Event	16	9	0
Protocol Violation	2	2	2
Withdrawal by Subject	21	16	8
Physician Decision	3	1	0
Lost to Follow-up	1	2	4
Pregnancy	0	1	4
Death	0	0	1
Non-compliance with study drug	1	2	0
Non-compliance with protocol	0	1	0
Sponsor decision - subject travel	0	1	0
Cough	0	1	0

Baseline Characteristics

Arm/Group Title		Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin	Total
Arm/Group Description		Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...	Total of all reporting groups
Arm/Group Description		Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient	Total of all reporting groups
Overall Number of Baseline Participants		174	174	170	518
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Full analysis set
Age, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	174 participants	174 participants	170 participants	518 participants
18-30 years		56	48	46	150
31-49 years		93	84	88	265
50-64 years		18	33	28	79
>= 65 years		7	9	8	24
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	174 participants	174 participants	170 participants	518 participants
	Female	97 55.7%	94 54.0%	96 56.5%	287 55.4%
	Male	77 44.3%	80 46.0%	74 43.5%	231 44.6%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	174 participants	174 participants	170 participants	518 participants
	Hispanic or Latino	17 9.8%	22 12.6%	18 10.6%	57 11.0%
	Not Hispanic or Latino	157 90.2%	152 87.4%	152 89.4%	461 89.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	174 participants	174 participants	170 participants	518 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	1 0.6%	1 0.6%	0 0.0%	2 0.4%
	Native Hawaiian or Other Pacific Islander	1 0.6%	0 0.0%	0 0.0%	1 0.2%
	Black or African American	8 4.6%	5 2.9%	3 1.8%	16 3.1%
	White	164 94.3%	167 96.0%	166 97.6%	497 95.9%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	1 0.6%	1 0.6%	2 0.4%
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	174 participants	174 participants	170 participants	518 participants
United States		71	69	67	207
Brazil		14	15	13	42
Ukraine		44	38	38	120
Russian Federation		45	52	52	149
Duration of Diabetes Mean (Full Range) Unit of measure: Years
	Number Analyzed	174 participants	174 participants	170 participants	518 participants
		16.0 (1.1 to 57.3)	17.7 (1.1 to 49.5)	16.7 (1.0 to 42.2)	16.8 (1.0 to 57.3)
Weight Mean (Full Range) Unit of measure: Kg
	Number Analyzed	174 participants	174 participants	170 participants	518 participants
		75.7 (41.7 to 129.4)	76.8 (47.6 to 124.0)	72.6 (46.6 to 120.2)	75.1 (41.7 to 129.4)
BMI Mean (Full Range) Unit of measure: Kg/m^2
	Number Analyzed	174 participants	174 participants	170 participants	518 participants
		26.0 (16.6 to 38.6)	26.2 (18.1 to 36.4)	25.4 (17.4 to 37.2)	25.9 (16.6 to 38.6)
Fasting Plasma Glucose Mean (Full Range) Unit of measure: mg/dL
	Number Analyzed	174 participants	174 participants	170 participants	518 participants
		155.0 (21.0 to 403.0)	144.3 (43.0 to 358.0)	151.2 (23.0 to 375.0)	150.2 (21.0 to 403.0)
HbA1c Mean (Full Range) Unit of measure: Percent of hemoglobin
	Number Analyzed	174 participants	174 participants	170 participants	518 participants
		7.98 (6.20 to 10.60)	8.00 (6.10 to 10.20)	7.88 (5.80 to 10.10)	7.95 (5.80 to 10.60)

Outcome Measures

1.Primary Outcome


Title	Change From Baseline to Week 24 in HbA1c
Description	Effect of treatment as measured by change from baseline in glycated he...
Description	Effect of treatment as measured by change from baseline in glycated hemoglobin (HbA1c). Primary treatment difference is TI-Gen2 vs. Insulin Aspart at Week 24
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin
Arm/Group Description:	Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...
Arm/Group Description:	Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient
Overall Number of Participants Analyzed	174	174	170
Least Squares Mean (Standard Error) Unit of Measure: Percent of hemoglobin
	-0.21 (0.062)	-0.29 (0.061)	-0.40 (0.060)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Technosphere Insulin-Gen2 + Basal Insulin, Insulin Aspart + Basal Insulin
	Comments	MMRM (mixed model repeated measures) model with auto-regression (1): HbA1c = Baseline HbA1c + region + basal insulin stratum + visit + treatment + (visit*treatment)
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority with 0.4 margin

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95% 0.02 to 0.36
	Parameter Dispersion	Type: Standard Error of the mean Value: 0.086
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	FEV1 Change From Baseline to Week 24
Description	Forced Expiratory Volume in 1 second - change from baseline to week 24
Description	Forced Expiratory Volume in 1 second - change from baseline to week 24
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Safety population


Arm/Group Title	Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin
Arm/Group Description:	Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...
Arm/Group Description:	Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient
Overall Number of Participants Analyzed	174	173	171
Least Squares Mean (Standard Error) Unit of Measure: Liters
	-0.07 (0.012)	-0.08 (0.012)	-0.04 (0.011)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Technosphere Insulin-Gen2 + Basal Insulin, Technosphere Insulin-MedTone + Basal Insulin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95% -0.02 to 0.04
	Parameter Dispersion	Type: Standard Error of the mean Value: 0.016
	Estimation Comments	Mixed Model Repeated Measure (MMRM): FEV1 = Baseline FEV1 + Age + Gender + Race + Baseline Height + Visit + Treatment + (Visit*Treatment)

3.Secondary Outcome


Title	FPG Change From Baseline to Week 24
Description	Comparison of mean change from Baseline to Week 24 visit in fasting pl...
Description	Comparison of mean change from Baseline to Week 24 visit in fasting plasma glucose (FPG) levels (central laboratory results)
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin
Arm/Group Description:	Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...
Arm/Group Description:	Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient
Overall Number of Participants Analyzed	174	174	170
Least Squares Mean (Standard Error) Unit of Measure: mg/dL
	-25.27 (7.62)	7.15 (7.53)	10.15 (7.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Technosphere Insulin-Gen2 + Basal Insulin, Insulin Aspart + Basal Insulin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-35.42
	Confidence Interval	(2-Sided) 95% -56.25 to -14.59
	Parameter Dispersion	Type: Standard Error of the mean Value: 10.622
	Estimation Comments	MMRM: FPG = Baseline FPG + Region + Basal insulin stratum + Visit + Treatment + (Visit*Treatment)

4.Secondary Outcome


Title	Mean 7-point Glucose Baseline Values
Description	Mean 7-point glucose at baseline
Description	Mean 7-point glucose at baseline
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin
Arm/Group Description:	Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...
Arm/Group Description:	Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient
Overall Number of Participants Analyzed	174	174	170
Mean (Standard Deviation) Unit of Measure: mg/dL
Before breakfast	154.1 (38.85)	151.8 (40.32)	147.0 (39.09)
After breakfast	173.3 (48.77)	173.5 (48.36)	162.6 (49.50)
Before lunch	158.0 (47.39)	156.6 (42.91)	142.3 (37.86)
After lunch	169.5 (52.25)	169.7 (49.23)	157.6 (48.08)
Before dinner	169.9 (47.12)	168.1 (45.24)	154.0 (46.53)
After dinner	176.2 (51.55)	177.0 (53.17)	158.5 (47.64)
Bedtime	178.3 (51.38)	175.1 (43.99)	164.4 (49.97)

5.Secondary Outcome


Title	Mean 7-point Glucose Week 24 Values
Description	[Not Specified]
Description	[Not Specified]
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin
Arm/Group Description:	Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...
Arm/Group Description:	Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient
Overall Number of Participants Analyzed	174	174	170
Mean (Standard Deviation) Unit of Measure: mg/dL
Before breakfast	148.2 (40.64)	147.9 (43.17)	155.3 (48.44)
After breakfast	169.7 (67.53)	164.1 (60.97)	163.0 (58.00)
Before lunch	168.2 (56.93)	165.9 (59.95)	149.1 (50.58)
After lunch	173.7 (57.09)	163.1 (50.92)	158.2 (50.04)
Before dinner	177.8 (59.96)	177.3 (56.71)	156.8 (48.30)
After dinner	180.8 (63.50)	168.2 (60.77)	157.8 (52.62)
Bedtime	185.2 (62.36)	185.6 (54.96)	175.4 (57.37)

6.Secondary Outcome


Title	Change in Body Weight From Baseline to Week 24
Description	Change in body weight from Baseline to Week 24
Description	Change in body weight from Baseline to Week 24
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set (subjects with data available at Baseline and at Week 24)


Arm/Group Title	Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin
Arm/Group Description:	Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...
Arm/Group Description:	Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient
Overall Number of Participants Analyzed	132	140	153
Least Squares Mean (Standard Error) Unit of Measure: kg
	-0.39 (0.438)	-0.19 (0.428)	0.93 (0.441)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Technosphere Insulin-Gen2 + Basal Insulin, Insulin Aspart + Basal Insulin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0102
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	ANCOVA: Weight change from baseline = Baseline weight + Change from baseline in HbA1c + Region + Basal insulin stratum + Treatment

Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.32
	Confidence Interval	(2-Sided) 95% -2.33 to -0.31
	Parameter Dispersion	Type: Standard Error of the mean Value: 0.512
	Estimation Comments	ANCOVA: Weight change from baseline = Baseline weight + Change from baseline in HbA1c + Region + Basal insulin stratum + Treatment

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Technosphere Insulin-Gen2 + Basal Insulin
	Comments	Within treatment analysis of change from Baseline comparing if change was different from zero
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4955
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Technosphere Insulin-MedTone + Basal Insulin
	Comments	Within treatment analysis of change from Baseline comparing if change was different from zero
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6807
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Insulin Aspart + Basal Insulin
	Comments	Within treatment analysis of change from Baseline comparing if change was different from zero
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0079
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]

7.Secondary Outcome


Title	Proportion of Responders Achieving HbA1c <= 7.0%
Description	Efficacy as measured in proportion of subjects achieving HbA1c < or...
Description	Efficacy as measured in proportion of subjects achieving HbA1c < or = to 7.0%
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set


Arm/Group Title	Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin
Arm/Group Description:	Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...
Arm/Group Description:	Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient
Overall Number of Participants Analyzed	131	138	150
Measure Type: Number Unit of Measure: percentage of participants
	18.3	21.7	30.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Technosphere Insulin-Gen2 + Basal Insulin, Insulin Aspart + Basal Insulin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0158
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Model: Treatment + Basal insulin stratum + Region + Baseline HbA1c

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.449
	Confidence Interval	(2-Sided) 95% 0.23 to 0.86
	Estimation Comments	Gen2 in the numerator, Aspart in the denominator

8.Other Pre-specified Outcome


Title	Incidence of Total Hypoglycemia
Description	Hypoglycemia, defined as blood glucose <= 70 mg/dL or in absence of...
Description	Hypoglycemia, defined as blood glucose <= 70 mg/dL or in absence of blood glucose, symptoms that are resolved by the administration of carbohydrates.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Safety population


Arm/Group Title	Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin
Arm/Group Description:	Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...
Arm/Group Description:	Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient
Overall Number of Participants Analyzed	174	173	171
Measure Type: Number Unit of Measure: percentage of participants
	96.0	96.0	99.4

9.Other Pre-specified Outcome


Title	Incidence of Severe Hypoglycemia
Description	Severe Hypoglycemia defined as: Requiring 3rd party assistance.
Description	Severe Hypoglycemia defined as: Requiring 3rd party assistance.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Safety population


Arm/Group Title	Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin
Arm/Group Description:	Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...
Arm/Group Description:	Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient
Overall Number of Participants Analyzed	174	173	171
Measure Type: Number Unit of Measure: percentage of participants
	18.4	21.4	29.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Technosphere Insulin-Gen2 + Basal Insulin, Insulin Aspart + Basal Insulin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0156
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Logistic model with affects for Region, Basal insulin stratum, and Treatment

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.5328
	Confidence Interval	(2-Sided) 95% 0.3198 to 0.8877
	Estimation Comments	[Not Specified]

10.Other Pre-specified Outcome


Title	Total Hypoglycemia Event Rate
Description	Number of Hypoglycemic Events/Total Subject Exposure Time (in months)
Description	Number of Hypoglycemic Events/Total Subject Exposure Time (in months)
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Safety population


Arm/Group Title	Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin
Arm/Group Description:	Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...
Arm/Group Description:	Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient
Overall Number of Participants Analyzed	174	173	171
Measure Type: Number Unit of Measure: Events/Subject-Month
	9.80	10.30	13.97

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Technosphere Insulin-Gen2 + Basal Insulin, Insulin Aspart + Basal Insulin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Negative Binomial Regression
	Comments	Model: Region + Basal Insulin Stratum + Treatment + Exposure Time

11.Other Pre-specified Outcome


Title	Severe Hypoglycemia Event Rate
Description	Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in m...
Description	Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months)
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Safety population


Arm/Group Title	Technosphere Insulin-Gen2 + Basal Insulin	Technosphere Insulin-MedTone + Basal Insulin	Insulin Aspart + Basal Insulin
Arm/Group Description:	Technosphere Insulin delivered via ...	Technosphere Insulin delivered via ...	Subcutaneous insulin aspart plus su...
Arm/Group Description:	Technosphere Insulin delivered via the Gen2 Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Technosphere Insulin delivered via the MedTone C Inhaler plus subcutaneous basal insulin, doses individualized for each patient	Subcutaneous insulin aspart plus subcutaneous basal insulin, doses individualized for each patient
Overall Number of Participants Analyzed	174	173	171
Measure Type: Number Unit of Measure: Events/Subject-Month
	8.05	9.99	14.45

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Technosphere Insulin-Gen2 + Basal Insulin, Insulin Aspart + Basal Insulin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1022
	Comments	[Not Specified]
	Method	Negative Binomial Regression
	Comments	Model: Region + Basal Insulin Stratum + Treatment + Exposure Time

Adverse Events

Time Frame	Baseline to Week 24
Adverse Event Reporting Description	Adverse Events (AE) are summarized according to how subjects were treated, not randomized. One subject that was randomized to the Technosphere Insulin-MedTone + Basal Insulin arm was treated with Insulin aspart + Basal Insulin throughout the trial.

Arm/Group Title	Technosphere ® Insulin-Gen2 Group	Technosphere® Insulin With MedTone C Inhaler	Aspart Group
Arm/Group Description	Subject will receive Technosphere I...	Subjects will receive TI with the M...	Subjects will receive insulin aspar...
Arm/Group Description	Subject will receive Technosphere Insulin with Gen2 Inhaler and remain on the basal insulin they were taking prior to study entry Technosphere ®Insulin with Gen2 Inhaler: Inhalation Powder and injectable insulin	Subjects will receive TI with the MedToneC inhaler and remain on the basal insulin they were taking prior to study entry Technosphere® Insulin with MedTone C Inhaler: Inhalation Powder and injectable insulin	Subjects will receive insulin aspart and remain on the basal insulin they were taking prior to study entry Insulin Aspart in combination with a basal insulin: Injectable insulin
All-Cause Mortality
	Technosphere ® Insulin-Gen2 Group	Technosphere® Insulin With MedTone C Inhaler	Aspart Group
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events Serious Adverse Events
	Technosphere ® Insulin-Gen2 Group	Technosphere® Insulin With MedTone C Inhaler	Aspart Group
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	5/174 (2.87%)	9/173 (5.20%)	7/171 (4.09%)
General disorders
Chest Discomfort ^† 1	0/174 (0.00%)	1/173 (0.58%)	0/171 (0.00%)
Drowning ^† 1	0/174 (0.00%)	0/173 (0.00%)	1/171 (0.58%)
Infections and infestations
Cytomegalovirus Infection ^† 1	1/174 (0.57%)	0/173 (0.00%)	0/171 (0.00%)
Appendicitis ^† 1	0/174 (0.00%)	0/173 (0.00%)	1/171 (0.58%)
Injury, poisoning and procedural complications
Joint Dislocation ^† 1	1/174 (0.57%)	0/173 (0.00%)	0/171 (0.00%)
Metabolism and nutrition disorders
Hypoglycaemia ^† 1	1/174 (0.57%)	2/173 (1.16%)	1/171 (0.58%)
Musculoskeletal and connective tissue disorders
Spinal Osteoarthritis ^† 1	0/174 (0.00%)	0/173 (0.00%)	1/171 (0.58%)
Nervous system disorders
Hypoglycaemic Unconsciousness ^† 1	1/174 (0.57%)	4/173 (2.31%)	2/171 (1.17%)
Hypoglycaemic Seizure ^† 1	1/174 (0.57%)	1/173 (0.58%)	1/171 (0.58%)
Psychiatric disorders
Mental Status Changes ^† 1	0/174 (0.00%)	0/173 (0.00%)	1/171 (0.58%)
Reproductive system and breast disorders
Cervical Polyp ^† 1	0/174 (0.00%)	1/173 (0.58%)	0/171 (0.00%)
Respiratory, thoracic and mediastinal disorders
Bronchial Hyperreactivity ^† 1	1/174 (0.57%)	0/173 (0.00%)	0/171 (0.00%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA (15.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	Technosphere ® Insulin-Gen2 Group	Technosphere® Insulin With MedTone C Inhaler	Aspart Group
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	81/174 (46.55%)	74/173 (42.77%)	50/171 (29.24%)
Gastrointestinal disorders
Diarrhoea ^† 1	4/174 (2.30%)	2/173 (1.16%)	5/171 (2.92%)
Vomiting ^† 1	2/174 (1.15%)	3/173 (1.73%)	5/171 (2.92%)
Nausea ^† 1	1/174 (0.57%)	5/173 (2.89%)	6/171 (3.51%)
Infections and infestations
Upper Respiratory Tract Infection ^† 1	14/174 (8.05%)	16/173 (9.25%)	12/171 (7.02%)
Bronchitis ^† 1	6/174 (3.45%)	1/173 (0.58%)	4/171 (2.34%)
Nasopharyngitis ^† 1	5/174 (2.87%)	13/173 (7.51%)	12/171 (7.02%)
Influenza ^† 1	2/174 (1.15%)	9/173 (5.20%)	3/171 (1.75%)
Urinary Tract Infection ^† 1	1/174 (0.57%)	6/173 (3.47%)	3/171 (1.75%)
Investigations
Blood Creatine Phosphokinase Increase ^† 1	0/174 (0.00%)	2/173 (1.16%)	4/171 (2.34%)
Nervous system disorders
Headache ^† 1	7/174 (4.02%)	5/173 (2.89%)	4/171 (2.34%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	55/174 (31.61%)	39/173 (22.54%)	4/171 (2.34%)
Dyspnoea ^† 1	7/174 (4.02%)	0/173 (0.00%)	0/171 (0.00%)
Throat Irritation ^† 1	5/174 (2.87%)	3/173 (1.73%)	1/171 (0.58%)
Oropharyngeal Pain ^† 1	3/174 (1.72%)	6/173 (3.47%)	3/171 (1.75%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA (15.1)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.

MannKind has right to 1st joint multicenter publication. After 1st publication PI may publish data only if PI submits proposed publication to MNKD for review 60 days prior to publication date. MNKD may remove any confidential information. If a multicenter publication is not submitted 12 months after conclusion, abandonment, or termination of the Study at all sites, or if MNKD confirms there will be no multicenter Study publication, PI may publish the Study results subject to MNKD rights herein.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Chief Medical Officer
Organization:	MannKind Corporation
Phone:	201-983-5000
EMail:	aboss@mannkindcorp.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Seaquist ER, Blonde L, McGill JB, Heller SR, Kendall DM, Bumpass JB, Pompilio FM, Grant ML. Hypoglycaemia is reduced with use of inhaled Technosphere(R) Insulin relative to insulin aspart in type 1 diabetes mellitus. Diabet Med. 2020 May;37(5):752-759. doi: 10.1111/dme.14202. Epub 2019 Dec 19.

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.

Layout table for additonal information

Responsible Party:	Mannkind Corporation
ClinicalTrials.gov Identifier:	NCT01445951
Other Study ID Numbers:	MKC-TI-171
First Submitted:	September 30, 2011
First Posted:	October 4, 2011
Results First Submitted:	July 22, 2014
Results First Posted:	October 22, 2014
Last Update Posted:	October 22, 2014

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