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

• Sponsor: Mannkind Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01445951
• Collaborator: (none)
• Enrollment: 518
• Locations: 90
• Arms: 3
• Duration (Months): 21
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Open-label, randomized, forced-titration clinical trial evaluating the efficacy and safety of TI Inhalation Power in combination with a basal insulin versus insulin aspart in combination with a basal insulin

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus	Drug: Technosphere® Insulin with MedTone C Inhaler; Drug: Technosphere ®Insulin with Gen2 Inhaler; Drug: Insulin Aspart in combination with a basal insulin	Phase 3

Detailed Description

Phase 3 clinical trial designed to examine the efficacy and safety of inhaled prandial TI Inhalation Power in combination with basal insulin versus insulin aspart in combination with basal insulin in subjects with type 1 diabetes who are suboptimally controlled with their current insulin regimens. This trial will employ a variety of methods to intensively manage these subjects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 518 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Open-label, Randomized, Forced-titration Clinical Trial Evaluating the Efficacy and Safety of Technosphere® Insulin Inhalation Powder in Combination With a Basal Insulin Versus Insulin Aspart in Combination With a Basal Insulin in Subjects With Type 1 Diabetes Mellitus Over a 24-week Treatment Period
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Technosphere® Insulin with MedTone C Inhaler Subjects will receive TI with the MedToneC inhaler and remain on the basal insulin they were taking prior to study entry	Drug: Technosphere® Insulin with MedTone C Inhaler; Inhalation Powder and injectable insulin
Active Comparator: Aspart Group Subjects will receive insulin aspart and remain on the basal insulin they were taking prior to study entry	Drug: Insulin Aspart in combination with a basal insulin; Injectable insulin
Experimental: Technosphere ® Insulin-Gen2 Group Subject will receive Technosphere Insulin with Gen2 Inhaler and remain on the basal insulin they were taking prior to study entry	Drug: Technosphere ®Insulin with Gen2 Inhaler; Inhalation Powder and injectable insulin

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 24 in HbA1c [Baseline to Week 24]

   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

Secondary Outcome Measures

1. FEV1 Change From Baseline to Week 24 [Baseline to Week 24]

   Forced Expiratory Volume in 1 second - change from baseline to week 24

2. FPG Change From Baseline to Week 24 [Baseline to Week 24]

   Comparison of mean change from Baseline to Week 24 visit in fasting plasma glucose (FPG) levels (central laboratory results)

3. Mean 7-point Glucose Baseline Values [Baseline]

   Mean 7-point glucose at baseline

4. Mean 7-point Glucose Week 24 Values [Week 24]

5. Change in Body Weight From Baseline to Week 24 [Baseline to Week 24]

   Change in body weight from Baseline to Week 24

6. Proportion of Responders Achieving HbA1c <= 7.0% [Week 24]

   Efficacy as measured in proportion of subjects achieving HbA1c < or = to 7.0%

Other Outcome Measures

1. Incidence of Total Hypoglycemia [Baseline to Week 24]

   Hypoglycemia, defined as blood glucose <= 70 mg/dL or in absence of blood glucose, symptoms that are resolved by the administration of carbohydrates.

2. Incidence of Severe Hypoglycemia [Baseline to Week 24]

   Severe Hypoglycemia defined as: Requiring 3rd party assistance.

3. Total Hypoglycemia Event Rate [Baseline to Week 24]

   Number of Hypoglycemic Events/Total Subject Exposure Time (in months)

4. Severe Hypoglycemia Event Rate [Baseline to Week 24]

   Number of Severe Hypoglycemic Events/Total Subject Exposure Time (in months)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and women = 18 years of age

• Clinical diagnosis of type 1 diabetes mellitus for at least 12 months

• Body mass index (BMI) = 38 kg/m2

• Stable dose of basal/bolus insulin therapy for at least 3 months with an FPG consistently < 220 mg/dL:

• HbA1c = 7.5% and = 10.0%

• Fasting C-peptide = 0.30 pmol/mL

• Subject willingness to not use CGM during the entire course of the trial

• Nonsmoking (includes cigarettes, cigars, pipes, and chewing tobacco) for the preceding 6 months

• Negative urine cotinine test, defined as = 100 ng/mL

• Lung function tests: • Forced expiratory volume in 1 second (FEV1) = 70% Third National Health and Nutrition Examination Survey (NHANES III) predicted

• Written informed consent

Exclusion Criteria:

• Total daily insulin dose = 2 IU/kg/day. History of insulin pump use within 3 months of Screening or use of continuous glucose monitoring within 6 weeks of Screening

• History of inhaled insulin use in the previous 6 months

• Two or more unexplained severe hypoglycemic episodes within 3 months of Screening or an episode of severe hypoglycemia between Visit 1 and Visit 2. Unexplained refers to episodes of severe hypoglycemia that are not related to a dosing error, lack of or a change in meal size, or related to additional/unanticipated exercise

• Any hospitalization or emergency room visit due to poor diabetic control within 6 months of Screening, or hospitalization or emergency room visit due to poor diabetic control between Visit 1 and Visit 2

• Allergy or known hypersensitivity to insulin or to any of the drugs to be used in the study, or a history of hypersensitivity to TI Inhalation Powder or to drugs with a similar chemical structure

• History of recent blood transfusions (within previous 3 months), hemoglobinopathies, or any other conditions that affect HbA1c measurements.

• History of COPD, asthma, or any other clinically important pulmonary disease (eg, pulmonary fibrosis), or use of any medications for these conditions

• Any clinically significant radiological findings on screening chest x-ray

• Active respiratory infection within 30 days before Screening (subject may return after 30 days from resolution for rescreening)

• Major organ system diseases, including: ? Seizure disorder; systemic autoimmune or collagen vascular disease requiring previous or current treatment with systemic corticosteroids, cytotoxic drugs, or penicillamine; cancer (other than excised cutaneous basal cell carcinoma) or any history of lung neoplasms

• Current or previous chemotherapy or radiation therapy that may result in pulmonary toxicity; use of medications for weight loss (eg, sibutramine, orlistat) within 12 weeks of Screening; treatment with amiodarone within 12 weeks of Screening

• Clinically significant abnormalities on screening laboratory evaluation or chest x-ray

• Severe complications of diabetes, in the opinion of the PI, including symptomatic autonomic neuropathy; disabling peripheral neuropathy; active proliferative retinopathy; nephropathy with renal failure, renal transplant, or dialysis; nontraumatic amputations due to gangrene; or vascular claudication

• Women who are pregnant, lactating, or planning to become pregnant during the clinical study period; women of childbearing potential (defined as premenopausal and not surgically sterilized or postmenopausal for fewer than 2 years) not practicing adequate birth control. Adequate birth control is defined as using oral, percutaneous, or transdermal contraceptives; condoms and diaphragms (double barrier) with a spermicide; or intrauterine devices. Postmenopausal for this study includes amenorrhea f

• Current drug or alcohol abuse or a history of drug or alcohol abuse that, in the opinion of the PI, would make the subject an unsuitable candidate for participation in the study

• Exposure to any investigational medications or devices within the previous 30 days before study entry

• Unable to read or write, or unlikely to comprehend and follow the study protocol procedures; lack of compliance with medication or procedures that, in the PI's opinion, may affect the study data or subject safety and that precludes the subject from participation in the study; or any other concurrent medical or major psychiatric condition that, in the opinion of the PI, makes the subject unsuitable for the clinical study or could limit the validity of the informed consent or impair the subject'

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Burlingame	California	United States	94010
2		Escondido	California	United States	92026
3		Huntington Beach	California	United States	92648
4		La Jolla	California	United States	92037
5		La Mesa	California	United States	91942
6		Long Beach	California	United States	90806
7		Los Angeles	California	United States	90017
8		Los Angeles	California	United States	90036
9		Los Gatos	California	United States	95032
10		San Mateo	California	United States	94401
11		Santa Barbara	California	United States	93105
12		Tustin	California	United States	92780
13		Aurora	Colorado	United States	80045
14		Hialeah	Florida	United States	33012
15		Hollywood	Florida	United States	33021
16		Miami	Florida	United States	33156
17		Miami	Florida	United States	33173
18		New Port Richey	Florida	United States	34652
19		Palm Harbor	Florida	United States	34652
20		West Palm Beach	Florida	United States	33401
21		Atlanta	Georgia	United States	30308
22		Atlanta	Georgia	United States	30318
23		Dunwoody	Georgia	United States	30338
24		Lawrenceville	Georgia	United States	30045
25		Roswell	Georgia	United States	30076
26		Chicago	Illinois	United States	60602
27		Vincennes	Indiana	United States	47591
28		Des Moines	Iowa	United States	50314
29		Baton Rouge	Louisiana	United States	70808
30		Metairie	Louisiana	United States	70006
31		New Orleans	Louisiana	United States	70112
32		Edina	Minnesota	United States	55435
33		Jefferson City	Missouri	United States	65109
34		St Peters	Missouri	United States	63376
35		St. Louis	Missouri	United States	63110
36		Billings	Montana	United States	59101
37		Omaha	Nebraska	United States	68114
38		Omaha	Nebraska	United States	68131
39		Paramus	New Jersey	United States	07652
40		Albuquerque	New Mexico	United States	87131
41		Flushing	New York	United States	11365
42		New Hyde Park	New York	United States	11042
43		New York	New York	United States	10016
44		Asheville	North Carolina	United States	28803
45		Greenville	North Carolina	United States	27834
46		Morehead City	North Carolina	United States	28557
47		Portland	Oregon	United States	97239
48		Greer	South Carolina	United States	29651
49		Bartlett	Tennessee	United States	38133
50		Arlington	Texas	United States	76014
51		Dallas	Texas	United States	75230
52		Dallas	Texas	United States	75246
53		Houston	Texas	United States	77095
54		San Antonio	Texas	United States	78229
55		Murray	Utah	United States	84123
56		Federal Way	Washington	United States	98003
57		Renton	Washington	United States	98057
58		Wenatchee	Washington	United States	98801
59		Porto Alegre	RS	Brazil	90035-170
60		Sao Paulo	SP	Brazil	01244-030
61		St. Petersburg	Russia	Russian Federation	191186
62		St. Petersburg	Russia	Russian Federation	193312
63		Kemerovo	RUS	Russian Federation	650066
64		Moscow	RUS	Russian Federation	105120
65		Moscow	RUS	Russian Federation	109240
66		Moscow	RUS	Russian Federation	117036
67		Moscow	RUS	Russian Federation	117593
68		Moscow	RUS	Russian Federation	119048
69		Moscow	RUS	Russian Federation	119435
70		Moscow	RUS	Russian Federation	125299
71		Moscow	RUS	Russian Federation	125315
72		Petrozavodsk	RUS	Russian Federation	185019
73		Smolensk	RUS	Russian Federation	214018
74		St Petersburg	RUS	Russian Federation	194291
75		St Petersburg	RUS	Russian Federation	195257
76		St Petersburg	RUS	Russian Federation	198013
77		St. Petersburg	RUS	Russian Federation	192148
78		St. Petersburg	RUS	Russian Federation	194044
79		St. Petersburg	RUS	Russian Federation	194354
80		Yaroslavl	RUS	Russian Federation	150003
81		Yaroslavl	RUS	Russian Federation	150062
82		Dnipropetrovsk	UKR	Ukraine	49023
83		Donetsk	UKR	Ukraine	83114
84		Kharkiv	UKR	Ukraine	61070
85		Kiev	UKR	Ukraine	04053
86		Kiev	UKR	Ukraine	04114
87		Kyiv	UKR	Ukraine	02175
88		Odesa	UKR	Ukraine	65039
89		Odesa	UKR	Ukraine	65114
90		Vinnytsya	UKR	Ukraine	21010

Sponsors and Collaborators

• Mannkind Corporation

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mannkind Corporation
• ClinicalTrials.gov Identifier: NCT01445951
• Other Study ID Numbers: MKC-TI-171
• First Posted: Oct 4, 2011
• Last Update Posted: Oct 22, 2014
• Last Verified: Oct 1, 2014

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin; Insulin, Globin Zinc; Insulin Aspart

Study Results

Participant Flow

Recruitment Details	First Patient enrolled Sept 2011. Multi-national trial conducted in US, Russia, Ukraine and Brazil.
Pre-assignment Detail	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 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

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 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 Participants	174	174	170	518
Age, Customized (participants) [Number]
18-30 years	56 32.2%	48 27.6%	46 27.1%	150 29%
31-49 years	93 53.4%	84 48.3%	88 51.8%	265 51.2%
50-64 years	18 10.3%	33 19%	28 16.5%	79 15.3%
>= 65 years	7 4%	9 5.2%	8 4.7%	24 4.6%
Sex: Female, Male (Count of Participants)
Female	97 55.7%	94 54%	96 56.5%	287 55.4%
Male	77 44.3%	80 46%	74 43.5%	231 44.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	17 9.8%	22 12.6%	18 10.6%	57 11%
Not Hispanic or Latino	157 90.2%	152 87.4%	152 89.4%	461 89%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 0.6%	1 0.6%	0 0%	2 0.4%
Native Hawaiian or Other Pacific Islander	1 0.6%	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%	166 97.6%	497 95.9%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 0.6%	1 0.6%	2 0.4%
Region of Enrollment (participants) [Number]
United States	71 40.8%	69 39.7%	67 39.4%	207 40%
Brazil	14 8%	15 8.6%	13 7.6%	42 8.1%
Ukraine	44 25.3%	38 21.8%	38 22.4%	120 23.2%
Russian Federation	45 25.9%	52 29.9%	52 30.6%	149 28.8%
Duration of Diabetes (years) [Mean (Full Range) ]
Mean (Full Range) [years]	16.0	17.7	16.7	16.8
Weight (kg) [Mean (Full Range) ]
Mean (Full Range) [kg]	75.7	76.8	72.6	75.1
BMI (kg/m^2) [Mean (Full Range) ]
Mean (Full Range) [kg/m^2]	26.0	26.2	25.4	25.9
Fasting Plasma Glucose (mg/dL) [Mean (Full Range) ]
Mean (Full Range) [mg/dL]	155.0	144.3	151.2	150.2
HbA1c (Percent of hemoglobin) [Mean (Full Range) ]
Mean (Full Range) [Percent of hemoglobin]	7.98	8.00	7.88	7.95

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 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 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
Measure Participants	174	174	170
Least Squares Mean (Standard Error) [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
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
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

2. Secondary Outcome

Title	FEV1 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 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
Measure Participants	174	173	171
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
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 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 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
Measure Participants	174	174	170
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
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
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 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
Measure Participants	174	174	170
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
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 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
Measure Participants	174	174	170
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
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 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
Measure Participants	132	140	153
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0102
	Comments
	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
Statistical Test of Hypothesis	p-Value	0.4955
	Comments
	Method	t-test, 2 sided
	Comments

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
Statistical Test of Hypothesis	p-Value	0.6807
	Comments
	Method	t-test, 2 sided
	Comments

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
Statistical Test of Hypothesis	p-Value	0.0079
	Comments
	Method	t-test, 2 sided
	Comments

7. Other Pre-specified Outcome

Title	Incidence of Total Hypoglycemia
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 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
Measure Participants	174	173	171
Number [percentage of participants]	96.0 55.2%	96.0 55.2%	99.4 58.5%

8. Other Pre-specified Outcome

Title	Incidence of Severe Hypoglycemia
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 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
Measure Participants	174	173	171
Number [percentage of participants]	18.4 10.6%	21.4 12.3%	29.2 17.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Technosphere Insulin-Gen2 + Basal Insulin, Insulin Aspart + Basal Insulin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0156
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Other Pre-specified Outcome

Title	Total Hypoglycemia Event Rate
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 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
Measure Participants	174	173	171
Number [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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Negative Binomial Regression
	Comments	Model: Region + Basal Insulin Stratum + Treatment + Exposure Time

10. Other Pre-specified Outcome

Title	Severe Hypoglycemia Event Rate
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 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
Measure Participants	174	173	171
Number [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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1022
	Comments
	Method	Negative Binomial Regression
	Comments	Model: Region + Basal Insulin Stratum + Treatment + Exposure Time

11. Secondary Outcome

Title	Proportion of Responders Achieving HbA1c <= 7.0%
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 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
Measure Participants	131	138	150
Number [percentage of participants]	18.3 10.5%	21.7 12.5%	30.7 18.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Technosphere Insulin-Gen2 + Basal Insulin, Insulin Aspart + Basal Insulin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0158
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments	Gen2 in the numerator, Aspart in the denominator

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 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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Technosphere ® Insulin-Gen2 Group		Technosphere® Insulin With MedTone C Inhaler		Aspart Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/174 (2.9%)		9/173 (5.2%)		7/171 (4.1%)
General disorders
Chest Discomfort	0/174 (0%)		1/173 (0.6%)		0/171 (0%)
Drowning	0/174 (0%)		0/173 (0%)		1/171 (0.6%)
Infections and infestations
Cytomegalovirus Infection	1/174 (0.6%)		0/173 (0%)		0/171 (0%)
Appendicitis	0/174 (0%)		0/173 (0%)		1/171 (0.6%)
Injury, poisoning and procedural complications
Joint Dislocation	1/174 (0.6%)		0/173 (0%)		0/171 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	1/174 (0.6%)		2/173 (1.2%)		1/171 (0.6%)
Musculoskeletal and connective tissue disorders
Spinal Osteoarthritis	0/174 (0%)		0/173 (0%)		1/171 (0.6%)
Nervous system disorders
Hypoglycaemic Unconsciousness	1/174 (0.6%)		4/173 (2.3%)		2/171 (1.2%)
Hypoglycaemic Seizure	1/174 (0.6%)		1/173 (0.6%)		1/171 (0.6%)
Psychiatric disorders
Mental Status Changes	0/174 (0%)		0/173 (0%)		1/171 (0.6%)
Reproductive system and breast disorders
Cervical Polyp	0/174 (0%)		1/173 (0.6%)		0/171 (0%)
Respiratory, thoracic and mediastinal disorders
Bronchial Hyperreactivity	1/174 (0.6%)		0/173 (0%)		0/171 (0%)
Other (Not Including Serious) Adverse Events
	Technosphere ® Insulin-Gen2 Group		Technosphere® Insulin With MedTone C Inhaler		Aspart Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	81/174 (46.6%)		74/173 (42.8%)		50/171 (29.2%)
Gastrointestinal disorders
Diarrhoea	4/174 (2.3%)		2/173 (1.2%)		5/171 (2.9%)
Vomiting	2/174 (1.1%)		3/173 (1.7%)		5/171 (2.9%)
Nausea	1/174 (0.6%)		5/173 (2.9%)		6/171 (3.5%)
Infections and infestations
Upper Respiratory Tract Infection	14/174 (8%)		16/173 (9.2%)		12/171 (7%)
Bronchitis	6/174 (3.4%)		1/173 (0.6%)		4/171 (2.3%)
Nasopharyngitis	5/174 (2.9%)		13/173 (7.5%)		12/171 (7%)
Influenza	2/174 (1.1%)		9/173 (5.2%)		3/171 (1.8%)
Urinary Tract Infection	1/174 (0.6%)		6/173 (3.5%)		3/171 (1.8%)
Investigations
Blood Creatine Phosphokinase Increase	0/174 (0%)		2/173 (1.2%)		4/171 (2.3%)
Nervous system disorders
Headache	7/174 (4%)		5/173 (2.9%)		4/171 (2.3%)
Respiratory, thoracic and mediastinal disorders
Cough	55/174 (31.6%)		39/173 (22.5%)		4/171 (2.3%)
Dyspnoea	7/174 (4%)		0/173 (0%)		0/171 (0%)
Throat Irritation	5/174 (2.9%)		3/173 (1.7%)		1/171 (0.6%)
Oropharyngeal Pain	3/174 (1.7%)		6/173 (3.5%)		3/171 (1.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.