Comparison of Technosphere® Insulin Versus Technosphere Powder (Placebo) in Insulin-Naive Subjects With Type 2 Diabetes Mellitus

• Sponsor: Mannkind Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01451398
• Collaborator: (none)
• Enrollment: 353
• Locations: 76
• Arms: 2
• Duration (Months): 20
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Insulin-naive subjects with Type 2 Diabetes Mellitus who are sub-optimally controlled on either maximum tolerated dose of metformin or maximum tolerated dose of metformin plus one or two other oral anti-diabetic medications will have either Prandial Technosphere® Insulin or Technosphere Powder (placebo) added to their oral antidiabetic drugs.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: Technosphere® Insulin; Drug: Technosphere Powder	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 353 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Double-blind, Placebo-controlled, Randomized, Clinical Trial Evaluating the Efficacy and Safety of Prandial Technosphere® Insulin Inhalation Powder Versus Technosphere Inhalation Powder in Insulin Naïve Subjects With Type 2 Diabetes Mellitus Poorly Controlled With Oral Antidiabetic Agents Over a 24 Week Treatment Period
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TI inhalation powder Technosphere® Insulin powder administered via the Gen2 inhaler added to 2 or more stable OADs	Drug: Technosphere® Insulin; Technosphere® Insulin Inhalation Powder
Placebo Comparator: Technosphere powder Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable OADs	Drug: Technosphere Powder; Placebo Comparator

Outcome Measures

Primary Outcome Measures

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

   Efficacy as measured by change in glycated hemoglobin (HbA1c) at Week 24

Secondary Outcome Measures

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

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

2. Proportion of Responders Achieving HbA1c <= 6.5% [Week 24]

   Efficacy as measured in proportion of subjects achieving HbA1c < or = to 6.5% at Week 24

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

   Efficacy as measured by mean change in fasting plasma glucose (FPG)

4. Proportion of Subjects Requiring Rescue Therapy [Baseline to Week 24]

5. Time to Rescue [Baseline to Week 24]

   Time from Week 0 (baseline) to initiation of rescue therapy (up to a maximum of 24 weeks/end of treatment) for subjects not responding to treatment

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

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

7. 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.

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

   Severe Hypoglycemia defined as: Requiring 3rd party assistance.

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

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

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

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

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

    Mean 7-point self-monitored glucose at baseline

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

    Mean 7-point self-monitored blood glucose at Week 24

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

    Change in body weight from Baseline to Week 24

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• HbA1c > or = to 7.5% and < or = to 10.0%

• Body mass index (BMI) < or = to 45 kg/m2

• Non smoker for at least 6 months before Screening

• Clinical diagnosis of type 2 diabetes mellitus for more than 12 months

• Currently receiving as diabetes treatment only metformin or 2 or more OADs and on stable doses for at least 3 months before enrollment

• Subjects receiving metformin must be on at least 1.5gm daily, or up to the maximum tolerated dose

• Subjects treated with a sulfonylurea must be on at least 50% of the total maximum approved dose for a given agent

• Subjects receiving a DPP-4 inhibitor must receive the maximum approved dose specific for that agent

• Metiglinide and alpha-glucoside inhibitors must be taken at the highest tolerated dose within the approved dose range

• No previous or current treatment with insulin, except during an acute illness, gestational diabetes, or at time of initial diagnosis of diabetes

• Forced expiratory volume in one second (FEV1) > or = to 70% Third National Health and Nutrition Examination Survey (NHANES III) predicted

• Forced vital capacity (FVC) > or = to 70% NHANES III predicted

• Forced expiratory volume in one second as a percentage of forced vital capacity (FEV1/FVC) > or = to NHANES III lower limit of normal (LLN)

Exclusion Criteria:

• History of chronic obstructive pulmonary disease (COPD), clinically proven asthma, or any other clinically important pulmonary disease (eg, pulmonary fibrosis)

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

• Use of medications for asthma, COPD, or any other chronic respiratory conditions

• Evidence of serious complications of diabetes (proliferative retinopathy, autonomic neuropathy with symptoms of gastroparesis or cardiac arrhythmia; sensory neuropathy that makes manipulation of the Gen2C inhaler difficult)

• Renal disease or renal dysfunction

• Significant cardiovascular dysfunction or history thereof within 12 months of screening; serious arrhythmia, treatment with medications to control/treat arrhythmias; myocardial infarction; cardiac surgery; history of valvular heart disease

• Previous or current use of amiodarone

• Treatment with glucagon-like peptide-1 (GLP-1) analogs, thiazolidinediones (TZD), or weight loss drugs (eg, sibutramine, orlistat) within 3 months of screening

• History of pulmonary embolism or deep venous thrombosis in the 12 months before Screening

• History of recent blood transfusion (within previous 3 months) or diagnosis of hemoglobinopathies that may affect HbA1c measurements

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Anaheim	California	United States	92807
2		Huntington Beach	California	United States	92648
3		Laguna Hills	California	United States	92653
4		Long Beach	California	United States	90806
5		Los Angeles	California	United States	90036
6		Los Gatos	California	United States	95032
7		Tustin	California	United States	92780
8		West Hills	California	United States	91307
9		Hialeah	Florida	United States	33012
10		Hollywood	Florida	United States	33021
11		Miami	Florida	United States	33156
12		Miami	Florida	United States	33173
13		New Port Richey	Florida	United States	34652
14		North Miami Beach	Florida	United States	33179
15		Pembroke Pines	Florida	United States	33026
16		Pinellas Park	Florida	United States	33781
17		West Palm Beach	Florida	United States	33401
18		Atlanta	Georgia	United States	30308
19		Atlanta	Georgia	United States	30318
20		Dunwoody	Georgia	United States	30338
21		Lawrenceville	Georgia	United States	30045
22		Roswell	Georgia	United States	30076
23		Chicago	Illinois	United States	60607
24		Baton Rouge	Louisiana	United States	70808
25		Edina	Minnesota	United States	55435
26		Jefferson City	Missouri	United States	65109
27		St Peters	Missouri	United States	63376
28		St. Louis	Missouri	United States	63110
29		St. Louis	Missouri	United States	63117
30		Omaha	Nebraska	United States	68114
31		Omaha	Nebraska	United States	68131
32		Clifton	New Jersey	United States	07012
33		Hackensack	New Jersey	United States	07601
34		Paramus	New Jersey	United States	07652
35		Flushing	New York	United States	11365
36		New Hyde	New York	United States	11042
37		Greenville	North Carolina	United States	27834
38		Perrysburg	Ohio	United States	43551
39		Portland	Oregon	United States	97239
40		Greer	South Carolina	United States	29651
41		Memphis	Tennessee	United States	38119
42		Arlington	Texas	United States	76014
43		Dallas	Texas	United States	75230
44		Dallas	Texas	United States	75246
45		Houston	Texas	United States	77095
46		San Antonio	Texas	United States	78229
47		San Antonio	Texas	United States	78249
48		Magna	Utah	United States	84044
49		Renton	Washington	United States	98057
50		Wenatchee	Washington	United States	98801
51		Porto Alegre		Brazil	90035
52		Sao Paulo		Brazil	01244
53		Kemerovo		Russian Federation	650066
54		Leningrad Region		Russian Federation
55		Moscow		Russian Federation	105120
56		Moscow		Russian Federation	117036
57		Moscow		Russian Federation	119435
58		Moscow		Russian Federation	119991
59		Moscow		Russian Federation	121374
60		Moscow		Russian Federation	129128
61		Moscow		Russian Federation	143420
62		Petrozavodsk		Russian Federation	185019
63		Smolensk		Russian Federation	214018
64		St. Petersburg		Russian Federation	194044
65		St. Petersburg		Russian Federation	194354
66		St. Petersburg		Russian Federation	195257
67		St. Petersburg		Russian Federation	196601
68		St. Petersburg		Russian Federation	198013
69		Yaroslavl		Russian Federation	150003
70		Yaroslavl		Russian Federation	150023
71		Kharkiv	UKR	Ukraine	61070
72		Kiev	UKR	Ukraine	04053
73		Kyiv	UKR	Ukraine	02175
74		Odesa	UKR	Ukraine	65039
75		Vinnytsya	UKR	Ukraine	21010
76		Kiev		Ukraine	04114

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: NCT01451398
• Other Study ID Numbers: MKC-TI-175; Affinity2
• First Posted: Oct 13, 2011
• Last Update Posted: Oct 17, 2014
• Last Verified: Oct 1, 2014

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin

Study Results

Participant Flow

Recruitment Details	First Patient enrolled November 2011. Multi-national trial conducted in US, Russia, Ukraine and Brazil
Pre-assignment Detail	6 week Screening Period prior to OAD run-in period. 1379 Screened /539 Eligible of which 535 entered the run-in period. 439 met randomization criteria at end of run-in of which 353 were randomized.

Arm/Group Title	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Period Title: Overall Study
STARTED	177	176
COMPLETED	150	139
NOT COMPLETED	27	37

Baseline Characteristics

Arm/Group Title	TI Inhalation Powder + OADs	Technosphere Powder	Total
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Total of all reporting groups
Overall Participants	177	176	353
Age, Customized (participants) [Number]
18-30 years	1 0.6%	0 0%	1 0.3%
31-49 years	37 20.9%	33 18.8%	70 19.8%
50-64 years	102 57.6%	110 62.5%	212 60.1%
>=65 years	37 20.9%	33 18.8%	70 19.8%
Sex: Female, Male (Count of Participants)
Female	95 53.7%	102 58%	197 55.8%
Male	82 46.3%	74 42%	156 44.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.6%	1 0.6%	2 0.6%
Asian	1 0.6%	2 1.1%	3 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	21 11.9%	17 9.7%	38 10.8%
White	151 85.3%	155 88.1%	306 86.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 1.7%	1 0.6%	4 1.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	43 24.3%	41 23.3%	84 23.8%
Not Hispanic or Latino	134 75.7%	135 76.7%	269 76.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	88 49.7%	87 49.4%	175 49.6%
Brazil	15 8.5%	14 8%	29 8.2%
Ukraine	19 10.7%	19 10.8%	38 10.8%
Russian Federation	55 31.1%	56 31.8%	111 31.4%
Duration of Diabetes (years) [Mean (Full Range) ]
Mean (Full Range) [years]	9.7	9.2	9.5
Weight (kg) [Mean (Full Range) ]
Mean (Full Range) [kg]	90.2	90.8	90.5
BMI (kg/m^2) [Mean (Full Range) ]
Mean (Full Range) [kg/m^2]	31.8	32.4	32.1
Fasting Plasma Glucose (FPG) (mg/dL) [Mean (Full Range) ]
Mean (Full Range) [mg/dL]	179.1	177.2	178.2
HbA1c (Percent of hemoglobin) [Mean (Full Range) ]
Mean (Full Range) [Percent of hemoglobin]	8.26	8.35	8.31
Oral Anti-Diabetic Drug (OAD) Type (participants) [Number]
Metformin Only	42 23.7%	40 22.7%	82 23.2%
Metformin + Sulfonylurea	114 64.4%	115 65.3%	229 64.9%
Metformin + DPP-4 Inhibitor	9 5.1%	9 5.1%	18 5.1%
Metformin + 1 or more OADs not specified above	9 5.1%	9 5.1%	18 5.1%
2 or more OADs (not including Metformin)	3 1.7%	3 1.7%	6 1.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 24 in HbA1c
Description	Efficacy as measured by change in glycated hemoglobin (HbA1c) at Week 24
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	177	176
Least Squares Mean (Standard Error) [percentage of hemoglobin]	-0.82 (0.061)	-0.42 (0.062)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI Inhalation Powder + OADs, Technosphere Powder
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Change in HbA1c = Baseline HbA1c + Region + Pooled OAD Strata + Visit + Treatment + (Treatment*Visit), using AR(1) variance/covariance structure.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.40
	Confidence Interval	(2-Sided) 95%; -0.57 to -0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. 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 for subjects with available data at Week 24

Arm/Group Title	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	151	142
Number [percentage of participants]	37.7 21.3%	19.0 10.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI Inhalation Powder + OADs, Technosphere Powder
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Regression, Logistic
	Comments	Model: Treatment + Pooled OAD Stratum + Region + Baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.726
	Confidence Interval	(2-Sided) 95%; 1.55 to 4.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Proportion of Responders Achieving HbA1c <= 6.5%
Description	Efficacy as measured in proportion of subjects achieving HbA1c < or = to 6.5% at Week 24
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set for subjects with available data at Week 24

Arm/Group Title	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	151	142
Number [percentage of participants]	15.9 9%	4.2 2.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI Inhalation Powder + OADs, Technosphere Powder
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments
	Method	Regression, Logistic
	Comments	Model: Treatment + Pooled OAD Stratum + Region + Baseline HbA1c
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.361
	Confidence Interval	(2-Sided) 95%; 1.70 to 11.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	FPG Change From Baseline to Week 24
Description	Efficacy as measured by mean change in fasting plasma glucose (FPG)
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set for subjects with data at both Baseline and at Week 24

Arm/Group Title	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	139	128
Least Squares Mean (Standard Error) [mg/dL]	-11.20 (3.776)	-3.78 (3.864)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI Inhalation Powder + OADs, Technosphere Powder
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1698
	Comments
	Method	Mixed Models Analysis
	Comments	Model: FPG = Baseline FPG + Region + Pooled OAD Stratum + Visit + Treatment + (Treatment * Visit) Variance/Covariance Matrix is Autoregression 1
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.42
	Confidence Interval	(2-Sided) 95%; -18.03 to 3.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.400
	Estimation Comments

5. Secondary Outcome

Title	Proportion of Subjects Requiring Rescue Therapy
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	177	176
Number [percentage of participants]	6.8 3.8%	9.7 5.5%

6. Secondary Outcome

Title	Time to Rescue
Description	Time from Week 0 (baseline) to initiation of rescue therapy (up to a maximum of 24 weeks/end of treatment) for subjects not responding to treatment
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	177	176
Median (Full Range) [Days]	95	85

7. 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

Full analysis set for patients with data at both Baseline and at Week 24

Arm/Group Title	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	141	122
Mean (Standard Deviation) [Liters]	-0.13 (0.175)	-0.04 (0.147)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI Inhalation Powder + OADs, Technosphere Powder
	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 (Final Values)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.12 to -0.05
	Parameter Dispersion	Type: Standard Deviation; Value: 0.018
	Estimation Comments

8. Secondary 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	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	177	176
Number [percentage of participants]	67.8 38.3%	30.7 17.4%

9. Secondary 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	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	177	176
Number [percentage of participants]	5.1 2.9%	1.7 1%

10. Secondary 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	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	177	176
Number [Events/Subject-Month]	1.16	0.50

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI Inhalation Powder + OADs, Technosphere Powder
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Negative binomial regression
	Comments	Model: Treatment + Region + OAD Stratum + Exposure Time

11. Secondary 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	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	177	176
Number [Events/100 Subject-Month]	2.37	0.60

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI Inhalation Powder + OADs, Technosphere Powder
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2024
	Comments
	Method	Negative Binomial Regression
	Comments	Model: Treatment + Region + OAD Stratum + Exposure Time

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	177	176
Before Breakfast	178.5 (37.58)	182.2 (40.50)
After Breakfast	212.8 (51.01)	219.9 (51.77)
Before Lunch	176.7 (49.58)	183.6 (53.76)
After Lunch	197.0 (46.94)	209.1 (44.37)
Before Dinner	176.8 (41.81)	187.6 (50.04)
After Dinner	205.2 (48.72)	211.2 (50.44)
Bedtime	203.3 (50.55)	203.8 (46.52)

13. Secondary Outcome

Title	Mean 7-point Glucose Week 24 Values
Description	Mean 7-point self-monitored blood glucose at Week 24
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set for patients with data at Week 24

Arm/Group Title	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	150	139
Before Breakfast	156.6 (30.80)	160.9 (36.7)
After Breakfast	170.3 (44.23)	194.7 (50.02)
Before Lunch	152.4 (48.13)	163.4 (49.8)
After Lunch	158.0 (42.79)	183.8 (47.73)
Before Dinner	157.4 (49.34)	164.7 (40.60)
After Dinner	164.3 (44.84)	188.5 (43.93)
Bedtime	163.0 (42.66)	178.7 (44.50)

14. 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 for patients with data at both Baseline and at Week 24

Arm/Group Title	TI Inhalation Powder + OADs	Technosphere Powder
Arm/Group Description	Technosphere Insulin powder administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient	Technosphere powder (with no insulin) administered via the Gen2 inhaler added to 2 or more stable Oral Antidiabetic Drugs (OADs), doses individualized for each patient
Measure Participants	152	142
Least Squares Mean (Standard Error) [kg]	0.49 (0.333)	-1.13 (0.347)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TI Inhalation Powder + OADs, Technosphere Powder
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.62
	Confidence Interval	(2-Sided) 95%; 0.90 to 2.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.365
	Estimation Comments	Model: Baseline Weight + Change in HbA1c at Week 24 + Region + OAD Stratum + Treatment

Adverse Events

Time Frame	24 Weeks
Arm/Group Title	TI Inhalation Powder		Technosphere Powder
Arm/Group Description	Technosphere® Insulin powder administered via the Gen2 inhaler added to 1 - 3 stable OADs Technosphere® Insulin: Technosphere® Insulin Inhalation Powder		technosphere powder (with no insulin) administered via the Gen2 inhaler added to 1 - 3 stable OADs Technosphere Powder: Placebo Comparator
All Cause Mortality
	TI Inhalation Powder		Technosphere Powder
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	TI Inhalation Powder		Technosphere Powder
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/177 (2.8%)		9/176 (5.1%)
Cardiac disorders
Angina Pectoris	0/177 (0%)		1/176 (0.6%)
Coronary Artery Disease	0/177 (0%)		1/176 (0.6%)
Cyanosis	0/177 (0%)		1/176 (0.6%)
Myocardial Infarction	2/177 (1.1%)		0/176 (0%)
Congenital, familial and genetic disorders
Skull Malformation	0/177 (0%)		1/176 (0.6%)
Infections and infestations
Urinary Tract Infection	1/177 (0.6%)		0/176 (0%)
Injury, poisoning and procedural complications
Humerus Fracture	0/177 (0%)		1/176 (0.6%)
Investigations
Heart Rate Decreased	0/177 (0%)		1/176 (0.6%)
Metabolism and nutrition disorders
Hypoglycaemia	1/177 (0.6%)		0/176 (0%)
Musculoskeletal and connective tissue disorders
Back Pain	0/177 (0%)		1/176 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Rectal Cancer	1/177 (0.6%)		0/176 (0%)
Squamous Cell Carcinoma	0/177 (0%)		1/176 (0.6%)
Nervous system disorders
Ischemic Stroke	0/177 (0%)		1/176 (0.6%)
Skin and subcutaneous tissue disorders
Angioedema	0/177 (0%)		1/176 (0.6%)
Hyperhydrosis	0/177 (0%)		1/176 (0.6%)
Other (Not Including Serious) Adverse Events
	TI Inhalation Powder		Technosphere Powder
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	108/177 (61%)		82/176 (46.6%)
Gastrointestinal disorders
Diarrhoea	6/177 (3.4%)		3/176 (1.7%)
Nausea	4/177 (2.3%)		0/176 (0%)
General disorders
Oedema Peripheral	4/177 (2.3%)		0/176 (0%)
Infections and infestations
Nasopharyngitis	15/177 (8.5%)		8/176 (4.5%)
Influenza	10/177 (5.6%)		3/176 (1.7%)
Upper Respiratory Tract Infection	9/177 (5.1%)		5/176 (2.8%)
Urinary Tract Infection	6/177 (3.4%)		2/176 (1.1%)
Bronchitis	5/177 (2.8%)		7/176 (4%)
Respiratory Tract Infection Viral	2/177 (1.1%)		5/176 (2.8%)
Musculoskeletal and connective tissue disorders
Back Pain	0/177 (0%)		5/176 (2.8%)
Nervous system disorders
Headache	7/177 (4%)		5/176 (2.8%)
Respiratory, thoracic and mediastinal disorders
Cough	42/177 (23.7%)		35/176 (19.9%)
Oropharyngeal Pain	8/177 (4.5%)		4/176 (2.3%)

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.