Long-Term Safety Study of Inhaled Insulin: An Up to Four-Year Extension of Therapy in Subjects With Type 1 or Type 2 Diabetes Mellitus

• Sponsor: Pfizer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00143247
• Collaborator: (none)
• Enrollment: 173
• Locations: 12
• Arm: 1
• Duration (Months): 58.1
• Patients Per Site: 14.4
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a long-term safety study for Phase 2 subjects who choose to remain on Exubera® (inhaled insulin).

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: Exubera® (inhaled insulin)	Phase 2

Detailed Description

The study was terminated on Oct. 18, 2007. This study is not a post approval commitment study. Pfizer decided to cancel new trials because of the decision to withdraw Exubera® (inhaled insulin) due to lack of market performance and not for safety reasons.

Study Design

• Study Type: Interventional
• Actual Enrollment: 173 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Phase 2, Long-Term Safety Study of Inhaled Insulin: An Up to Four-Year Extension of Therapy in Subjects With Type 1 or Type 2 Diabetes Mellitus Participating in Extension Protocols 217-102, 103, or 104
• Study Start Date: Mar 1, 2003
• Actual Primary Completion Date: Jan 1, 2008
• Actual Study Completion Date: Jan 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Exubera® (inhaled insulin) Open label, no comparator	Drug: Exubera® (inhaled insulin); Treatment of type 1 and type 2 diabetes with short-acting insulin; Other Names: Exubera®

Outcome Measures

Primary Outcome Measures

1. Change in Forced Expiratory Volume in 1 Second (L) by Time on Exubera Treatment [Baseline to 126 months]

   Change from Baseline: mean of (value of observed forced expiratory volume in 1 second (FEV1) (liters) at treatment duration minus baseline value). Duration of treatment is based on the elapsed duration of treatment in the controlled and uncontrolled studies. Baseline was based on pre-inhaled insulin measurements.

2. Change in Carbon Monoxide Diffusing Capacity (mL/Min/mm Hg) by Time on Exubera Treatment [baseline to 126 months]

   Change from Baseline: mean of (value of observed Carbon Monoxide Diffusing Capacity (mL/min/mm Hg) at treatment duration minus baseline value). Duration of treatment is based on the elapsed duration of treatment in the controlled and uncontrolled studies. Baseline was based on pre-inhaled insulin measurements.

Secondary Outcome Measures

1. Change in Glycosylated Hemoglobin by Duration of Exubera Treatment [Baseline to 126 months]

   Change from Baseline: mean of (value of observed glycosylated hemoglobin (HbA1C) (percent) at treatment duration minus baseline value). Duration of treatment is based on the elapsed duration of treatment in the controlled and uncontrolled studies. Baseline was based on pre-inhaled insulin measurements.

2. Hypoglycemic Event Rates by Interval of Exubera Treatment [0 to 132 months]

   Number of hypoglycemic events per subject-month. Subject-month determined by time on treatment. Interval of treatment based on elapsed duration of treatment in the controlled & uncontrolled studies.Overall represents entire duration of treatment. Hypoglycemia: Characteristic symptoms of hypoglycemia with no blood glucose check. Clinical picture must include prompt resolution with food intake, subcutaneous glucagon or intravenous glucose.OR,Characteristic symptoms of hypoglycemia with blood glucose check showing glucose <=59 mg/dl.OR,Any glucose measurement <=49 mg/dl,with or without symptoms.

3. Severe Hypoglycemic Event Rates by Interval of Exubera Treatment [0-132 months]

   Number of severe hypoglycemic events per 100 subject-months.Subject-month determined by time on treatment.Interval of treatment based on elapsed duration of treatment in controlled & uncontrolled studies.Overall represents entire duration of treatment.A severe hypoglycemic event must have met all 3of following:1.subject unable to treat self.2.subject exhibited 1 or more of neurological symptoms defined in protocol.3.blood glucose must be <=49 mg/dl if measured.If not measured,clinical manifestations must have been reversed by oral carbohydrates,subcutaneous glucagon,or intravenous glucose.

4. Insulin Antibodies (Percent Binding) by Time on Exubera Treatment - Subjects With Type 1 Diabetes [36 months to 126 months]

   Observed values by duration of treatment.

5. Insulin Antibodies (Percent Binding) by Time on Exubera Treatment - Subjects With Type 2 Diabetes (Using Insulin at Study Entry) [36 to 126 months]

   observed values by duration of treatment.

6. Insulin Antibodies (Percent Binding) by Time on Exubera Treatment - Subjects With Type 2 Diabetes (Not Using Insulin at Study Entry) [6 to 120 months]

   Observed values by duration of treatment.

7. Number of Decliners in Either Forced Expiratory Volume in 1 Second (L) or Carbon Monoxide Diffusing Capacity (ml/Min/mm Hg), by Duration of Exubera Treatment [3 to >=108 months]

   Decliners = decline of ≥15% in forced expiratory volume or ≥20% in carbon monoxide diffusing capacity.

8. Number of Decliners in Forced Expiratory Volume in 1 Second (L) by Duration of Exubera Treatment [3 to >=108 months]

   Decliners at particular timepoint were defined as any decline of ≥15% in forced expiratory volume.

9. Number of Decliners in Carbon Monoxide Diffusing Capacity (ml/Min/mm Hg) by Duration of Exubera Treatment [6 to >=108 months]

   Decliners at particular timepoint were defined as any decline of ≥20% in carbon monoxide diffusing capacity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects with Type 1 or Type 2 Diabetes Mellitus who participated in previous Phase 2 extension protocols

Exclusion Criteria:

• Smoking

• Pregnancy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	San Diego	California	United States	92123
2	Pfizer Investigational Site	New Haven	Connecticut	United States	06504
3	Pfizer Investigational Site	Miami	Florida	United States	33136
4	Pfizer Investigational Site	Chicago	Illinois	United States	60610
5	Pfizer Investigational Site	Albuquerque	New Mexico	United States	87131-5666
6	Pfizer Investigational Site	Durham	North Carolina	United States	27710
7	Pfizer Investigational Site	Winston Salem	North Carolina	United States	27157
8	Pfizer Investigational Site	Austin	Texas	United States	78752
9	Pfizer Investigational Site	Austin	Texas	United States	78758
10	Pfizer Investigational Site	Dallas	Texas	United States	75230
11	Pfizer Investigational Site	Dallas	Texas	United States	75243
12	Pfizer Investigational Site	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00143247
• Other Study ID Numbers: A2171036
• First Posted: Sep 2, 2005
• Last Update Posted: Apr 15, 2010
• Last Verified: Jul 1, 2009

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

Study Results

Participant Flow

Recruitment Details	Subjects with type 1 or 2 diabetes in 1 of parent Phase 2 protocols (217-102,103,or 104)& received EXUBERA® (EXU)were enrolled. 173 subjects were screened,assigned to treatment,and treated for at least 1 day.For each subject,data from controlled and extension studies were combined to represent each subject's entire EXU exposure experience.
Pre-assignment Detail	The objective of the study was to observe,in subjects with long-term exposure to EXUBERA®,pulmonary function over time.For each subject,data from the controlled study (217-102,103,and 104) were combined with data from the respective extension studies as well as the A2171036 extension study to represent each subject's entire EXU exposure experience.

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Period Title: Overall Study
STARTED	173
COMPLETED	17
NOT COMPLETED	156

Baseline Characteristics

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Overall Participants	173
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.6 (10.7)
Sex: Female, Male (Count of Participants)
Female	70 40.5%
Male	103 59.5%

Outcome Measures

1. Secondary Outcome

Title	Change in Glycosylated Hemoglobin by Duration of Exubera Treatment
Description	Change from Baseline: mean of (value of observed glycosylated hemoglobin (HbA1C) (percent) at treatment duration minus baseline value). Duration of treatment is based on the elapsed duration of treatment in the controlled and uncontrolled studies. Baseline was based on pre-inhaled insulin measurements.
Time Frame	Baseline to 126 months

Outcome Measure Data

Analysis Population Description

173 subjects received at least one treatment. The safety analysis set (subjects who received at least one dose of EXU treatment) were included in analysis. n = subjects who had outcome measure data available at particular time points. There was no imputation for missing data.

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Measure Participants	157
3 months (n=155)	-0.99 (1.37)
6 months (n=146)	-0.90 (1.58)
12 months (n=136)	-0.60 (1.72)
18 months (n=121)	-0.66 (1.61)
24 months (n=115)	-0.65 (1.67)
30 months (n=107)	-0.67 (1.72)
36 months (n=99)	-0.60 (1.73)
42 months (n=93)	-0.61 (1.72)
48 months (n=88)	-0.48 (1.64)
54 months (n=83)	-0.50 (1.61)
60 months (n=75)	-0.48 (1.56)
66 months (n=70)	-0.56 (1.82)
72 months (n=67)	-0.61 (1.87)
78 months (n=62)	-0.80 (1.47)
84 months (n=57)	-0.71 (1.26)
90 months (n=56)	-0.75 (1.51)
96 months (n=54)	-0.58 (1.46)
102 months (n=50)	-0.77 (1.52)
108 months (n=42)	-0.68 (1.51)
114 months (n=37)	-0.78 (1.60)
120 months (n=31)	-0.39 (1.46)
126 months (n=23)	-0.08 (1.22)

2. Secondary Outcome

Title	Hypoglycemic Event Rates by Interval of Exubera Treatment
Description	Number of hypoglycemic events per subject-month. Subject-month determined by time on treatment. Interval of treatment based on elapsed duration of treatment in the controlled & uncontrolled studies.Overall represents entire duration of treatment. Hypoglycemia: Characteristic symptoms of hypoglycemia with no blood glucose check. Clinical picture must include prompt resolution with food intake, subcutaneous glucagon or intravenous glucose.OR,Characteristic symptoms of hypoglycemia with blood glucose check showing glucose <=59 mg/dl.OR,Any glucose measurement <=49 mg/dl,with or without symptoms.
Time Frame	0 to 132 months

Outcome Measure Data

Analysis Population Description

173 subjects received at least one treatment. The safety analysis set (subjects who received at least one dose of EXU treatment) were included in analysis. n = subjects who had outcome measure data available at particular time points. There was no imputation for missing data.

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Measure Participants	159
0 to 4 weeks (n=159)	2.38
>4 to 8 weeks (n=158)	2.10
>8 to 12 weeks (n=157)	1.92
>12 weeks to 6 months (n=155)	1.88
>6 to12 months (n=149)	1.91
>12 to18 months (n=134)	1.63
>18 to 24 months (n=122)	1.96
>24 to 30 months (n=112)	1.99
>30 to 36 months (n=107)	1.78
>36 to 42 months (n=98)	1.54
>42 to 48 months (n=91)	1.47
>48 to 54 months (n=85)	1.36
>54 to 60 months (n=80)	1.38
>60 to 66 months (n=74)	1.32
>66 to 72 months (n=70)	1.42
>72 to 78 months (n=64)	1.47
>78 to 84 months (n=59)	1.74
>84 to 90 months (n=58)	1.63
>90 to 96 months (n=56)	1.67
>96 to 102 months (n=52)	1.52
>102 to 108 months (n=48)	1.16
>108 to 114 months (n=40)	1.51
>114 to 120 months (n=37)	1.41
>120 to 126 months (n=25)	1.13
>126 to 132 months (n=18)	0.92
Overall (n=159)	1.65

3. Secondary Outcome

Title	Severe Hypoglycemic Event Rates by Interval of Exubera Treatment
Description	Number of severe hypoglycemic events per 100 subject-months.Subject-month determined by time on treatment.Interval of treatment based on elapsed duration of treatment in controlled & uncontrolled studies.Overall represents entire duration of treatment.A severe hypoglycemic event must have met all 3of following:1.subject unable to treat self.2.subject exhibited 1 or more of neurological symptoms defined in protocol.3.blood glucose must be <=49 mg/dl if measured.If not measured,clinical manifestations must have been reversed by oral carbohydrates,subcutaneous glucagon,or intravenous glucose.
Time Frame	0-132 months

Outcome Measure Data

Analysis Population Description

173 subjects received at least one treatment. The safety analysis set (subjects who received at least one dose of EXU treatment) were included in analysis. n = subjects who had outcome measure data available at particular time points. There was no imputation for missing data.

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Measure Participants	159
0-4 weeks (n=159)	1.37
>4-8 weeks (n=158)	2.76
>8-12 weeks (n=157)	0.70
>12 weeks-6months (n=155)	2.64
>6-12 months (n=149)	1.07
>12-18 months (n=134)	0.93
>18-24 months (n=122)	0.85
>24-30 months (n=112)	1.07
>30-36 months (n=107)	0.97
>36-42 months (n=98)	0.18
>42-48 months (n=91)	0.19
>48-54 months (n=85)	0.60
>54-60 months (n=80)	0.87
>60-66 months (n=74)	0.47
>66-72 months (n=70)	0.75
>72-78 months (n=64)	0.27
>78-84 months (n=59)	1.14
>84-90 months (n=58)	1.47
>90-96 months (n=56)	0.31
>96-102 months (n=52)	1.32
>102-108 months (n=48)	0.39
>108-114 months (n=40)	0.44
>114-120 months (n=37)	0.54
>120-126 months (n=25)	0
>126-132 months (n=18)	0
Overall (n=159)	0.88

4. Secondary Outcome

Title	Insulin Antibodies (Percent Binding) by Time on Exubera Treatment - Subjects With Type 1 Diabetes
Description	Observed values by duration of treatment.
Time Frame	36 months to 126 months

Outcome Measure Data

Analysis Population Description

173 subjects received at least one treatment. The safety analysis set (subjects who received at least one dose of EXU treatment) were included in analysis. n = subjects who had outcome measure data available at particular time points. There was no imputation for missing data.

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Measure Participants	61
36 months (n=31)	26.00 (23.95)
42 months (n=4)	27.00 (15.44)
48 months (n=28)	19.00
54 months (n=27)	16.00
60 months (n=26)	14.00
66 months (n=23)	16.00
72 months (n=22)	13.00
78 months (n=24)	14.00
84 months (n=23)	16.00
90 months (n=21)	13.00
96 months (n=23)	18.00
102 months (n=21)	14.00
108 months (n=17)	18.00
114 months (n=15)	11.00
120 months (n=14)	8.50
126 months (n=14)	9.00

5. Secondary Outcome

Title	Insulin Antibodies (Percent Binding) by Time on Exubera Treatment - Subjects With Type 2 Diabetes (Using Insulin at Study Entry)
Description	observed values by duration of treatment.
Time Frame	36 to 126 months

Outcome Measure Data

Analysis Population Description

173 subjects received at least one treatment. The safety analysis set (subjects who received at least one dose of EXU treatment) were included in analysis. n = subjects who had outcome measure data available at particular time points. There was no imputation for missing data.

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Measure Participants	48
36 months (n=22)	2.75 (14.89)
42 months (n=9)	1.50 (12.69)
48 months (n=21)	1.50
54 months (n=20)	1.50
60 months (n=17)	1.50
66 months (n=16)	1.50
72 months (n=14)	1.50
78 months (n=14)	1.50
84 months (n=14)	1.50
90 months (n=12)	1.50
96 months (n=12)	1.50
102 months (n=11)	1.50
108 months (n=11)	4.00
114 months (n=11)	4.00
120 months (n=10)	1.50
126 months (n=8)	1.50

6. Primary Outcome

Title	Change in Forced Expiratory Volume in 1 Second (L) by Time on Exubera Treatment
Description	Change from Baseline: mean of (value of observed forced expiratory volume in 1 second (FEV1) (liters) at treatment duration minus baseline value). Duration of treatment is based on the elapsed duration of treatment in the controlled and uncontrolled studies. Baseline was based on pre-inhaled insulin measurements.
Time Frame	Baseline to 126 months

Outcome Measure Data

Analysis Population Description

173 subjects received at least one treatment. The safety analysis set (subjects who received at least one dose of EXU treatment) were included in analysis. n = subjects who had outcome measure data available at particular time points. There was no imputation for missing data.

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Measure Participants	156
3 months (n=154)	-0.077 (0.204)
6 months (n=149)	-0.101 (0.204)
12 months (n=138)	-0.137 (0.220)
18 months (n=123)	-0.141 (0.218)
24 months (n=116)	-0.184 (0.232)
30 months (n=108)	-0.210 (0.237)
36 months (n=101)	-0.253 (0.244)
42 months (n=92)	-0.288 (0.217)
48 months (n=88)	-0.307 (0.252)
54 months (n=83)	-0.291 (0.260)
60 months (n=75)	-0.312 (0.267)
66 months (n=70)	-0.344 (0.273)
72 months (n=67)	-0.363 (0.289)
78 months (n=61)	-0.376 (0.281)
84 months (n=57)	-0.421 (0.301)
90 months (n=56)	-0.446 (0.311)
96 months (n=54)	-0.455 (0.332)
102 months (n=50)	-0.469 (0.321)
108 months (n=42)	-0.496 (0.273)
114 months (n=35)	-0.510 (0.281)
120 months (n=23)	-0.490 (0.298)
126 months (n=11)	-0.634 (0.371)

7. Secondary Outcome

Title	Insulin Antibodies (Percent Binding) by Time on Exubera Treatment - Subjects With Type 2 Diabetes (Not Using Insulin at Study Entry)
Description	Observed values by duration of treatment.
Time Frame	6 to 120 months

Outcome Measure Data

Analysis Population Description

173 subjects received at least one treatment. The safety analysis set (subjects who received at least one dose of EXU treatment) were included in analysis. n = subjects who had outcome measure data available at particular time points. There was no imputation for missing data.

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Measure Participants	57
6 months (n=58)	1.50 (5.36)
12 months (n=48)	2.25
18 months (n=5)	10.00
24 months (n=41)	1.50
30 months (n=4)	7.25
36 months (n=37)	1.50
42 months (n=33)	1.50
48 months (n=32)	1.50
54 months (n=30)	1.50
60 months (n=25)	1.50
66 months (n=30)	1.50
72 months (n=24)	1.50
78 months (n=23)	1.50
84 months (n=20)	1.50
90 months (n=18)	1.50
96 months (n=18)	1.50
102 months (n=14)	1.50
108 months (n=13)	1.50
114 months (n=9)	1.50
120 months (n=6)	1.50

8. Secondary Outcome

Title	Number of Decliners in Either Forced Expiratory Volume in 1 Second (L) or Carbon Monoxide Diffusing Capacity (ml/Min/mm Hg), by Duration of Exubera Treatment
Description	Decliners = decline of ≥15% in forced expiratory volume or ≥20% in carbon monoxide diffusing capacity.
Time Frame	3 to >=108 months

Outcome Measure Data

Analysis Population Description

173 subjects received at least one treatment. The safety analysis set (subjects who received at least one dose of EXU treatment) were included in analysis. n = subjects who had outcome measure data available at particular time points. There was no imputation for missing data.

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Measure Participants	156
3 months (n=154)	2 1.2%
6 months (n=151)	19 11%
12 months (n=138)	14 8.1%
18 months (n=123)	15 8.7%
24 months (n=116)	26 15%
30 months (n=108)	26 15%
36 months (n=101)	30 17.3%
42 months (n=92)	30 17.3%
48 months (n=88)	24 13.9%
54 months (n=83)	22 12.7%
60 months (n=75)	28 16.2%
66 months (n=70)	25 14.5%
72 months (n=67)	19 11%
78 months (n=61)	21 12.1%
84 months (n=57)	26 15%
90 months (n=56)	25 14.5%
96 months (n=54)	21 12.1%
102 months (n=50)	25 14.5%
>=108 months (n=42)	29 16.8%

9. Secondary Outcome

Title	Number of Decliners in Forced Expiratory Volume in 1 Second (L) by Duration of Exubera Treatment
Description	Decliners at particular timepoint were defined as any decline of ≥15% in forced expiratory volume.
Time Frame	3 to >=108 months

Outcome Measure Data

Analysis Population Description

173 subjects received at least one treatment. The safety analysis set (subjects who received at least one dose of EXU treatment) were included in analysis. n = subjects who had outcome measure data available at particular time points. There was no imputation for missing data.

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Measure Participants	156
3 months (n=154)	2 1.2%
6 months (n=149)	5 2.9%
12 months (n=138)	6 3.5%
18 months (n=123)	5 2.9%
24 months (n=116)	9 5.2%
30 months (n=108)	14 8.1%
36 months (n=101)	18 10.4%
42 months (n=92)	18 10.4%
48 months (n=88)	19 11%
54 months (n=83)	14 8.1%
60 months (n=75)	21 12.1%
66 months (n=70)	19 11%
72 months (n=67)	17 9.8%
78 months (n=61)	17 9.8%
84 months (n=57)	21 12.1%
90 months (n=56)	24 13.9%
96 months (n=54)	19 11%
102 months (n=50)	24 13.9%
>=108 months (n=42)	27 15.6%

10. Secondary Outcome

Title	Number of Decliners in Carbon Monoxide Diffusing Capacity (ml/Min/mm Hg) by Duration of Exubera Treatment
Description	Decliners at particular timepoint were defined as any decline of ≥20% in carbon monoxide diffusing capacity.
Time Frame	6 to >=108 months

Outcome Measure Data

Analysis Population Description

173 subjects received at least one treatment. The safety analysis set (subjects who received at least one dose of EXU treatment) were included in analysis. n = subjects who had outcome measure data available at particular time points. There was no imputation for missing data.

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Measure Participants	152
6 months (n=149)	16 9.2%
12 months (n=130)	8 4.6%
18 months (n=115)	13 7.5%
24 months (n=113)	21 12.1%
30 months (n=100)	14 8.1%
36 months (n=95)	14 8.1%
42 months (n=86)	13 7.5%
48 months (n=82)	11 6.4%
54 months (n=80)	11 6.4%
60 months (n=70)	10 5.8%
66 months (n=64)	11 6.4%
72 months (n=62)	8 4.6%
78 months (n=59)	11 6.4%
84 months (n=57)	10 5.8%
90 months (n=50)	5 2.9%
96 months (n=52)	4 2.3%
102 months (n=42)	4 2.3%
>=108 months (n=41)	13 7.5%

11. Primary Outcome

Title	Change in Carbon Monoxide Diffusing Capacity (mL/Min/mm Hg) by Time on Exubera Treatment
Description	Change from Baseline: mean of (value of observed Carbon Monoxide Diffusing Capacity (mL/min/mm Hg) at treatment duration minus baseline value). Duration of treatment is based on the elapsed duration of treatment in the controlled and uncontrolled studies. Baseline was based on pre-inhaled insulin measurements.
Time Frame	baseline to 126 months

Outcome Measure Data

Analysis Population Description

173 subjects received at least one treatment. The safety analysis set (subjects who received at least one dose of EXU treatment) were included in analysis. n = subjects who had outcome measure data available at particular time points. There was no imputation for missing data.

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
Measure Participants	152
6 months (n=149)	-1.200 (4.358)
12 months (n=130)	-1.262 (4.446)
18 months (n=115)	-1.883 (4.690)
24 months (n=113)	-2.012 (4.821)
30 months (n=100)	-1.601 (5.816)
36 months (n=95)	-2.122 (5.030)
42 months (n=86)	-2.550 (5.307)
48 months (n=82)	-1.827 (3.623)
54 months (n=80)	-2.118 (3.485)
60 months (n=70)	-2.037 (4.325)
66 months (n=64)	-2.377 (4.168)
72 months (n=62)	-1.401 (5.061)
78 months (n=59)	-1.532 (5.764)
84 months (n=57)	-1.111 (4.672)
90 months (n=50)	-0.919 (4.043)
96 months (n=52)	-0.609 (4.763)
102 months (n=42)	-1.504 (3.514)
108 months (n=40)	-2.397 (4.496)
114 months (n=35)	-2.450 (4.471)
120 months (n=26)	-2.028 (3.403)
126 months (n=22)	-2.126 (3.984)

Adverse Events

Arm/Group Title	Inhaled Insulin
Arm/Group Description	Open label EXUBERA® (EXU; inhaled insulin), no comparator. At all times in the trial, each subject had an individualized recommended insulin dose for each of the dosing times. Initial recommended doses for EXU were based on the subject's weight, any previous responses to insulin, and other factors noted in the protocol.
All Cause Mortality
	Inhaled Insulin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Inhaled Insulin
	Affected / at Risk (%)	# Events
Total	63/ (NaN)
Blood and lymphatic system disorders
Anemia	2/173 (1.2%)
Cardiac disorders
Acute myocardial infarction	3/173 (1.7%)
Angina pectoris	2/173 (1.2%)
Angina unstable	1/173 (0.6%)
Arteriosclerosis coronary artery	1/173 (0.6%)
Bradycardia	2/173 (1.2%)
Cardiac failure congestive	3/173 (1.7%)
Cardio-respiratory arrest	1/173 (0.6%)
Coronary artery disease	10/173 (5.8%)
Coronary artery occlusion	2/173 (1.2%)
Coronary artery stenosis	1/173 (0.6%)
Myocardial infarction	5/173 (2.9%)
Myocardial ischaemia	1/173 (0.6%)
Tachycardia	1/173 (0.6%)
Ventricular extrasystoles	1/173 (0.6%)
Ear and labyrinth disorders
Vertigo	1/173 (0.6%)
Endocrine disorders
Goitre	1/173 (0.6%)
Eye disorders
Vitreous haemorrhage	1/173 (0.6%)
Gastrointestinal disorders
Impacted colon	1/173 (0.6%)
Duodenal ulcer	1/173 (0.6%)
Food poisoning	1/173 (0.6%)
Haemorrhagic ascites	1/173 (0.6%)
Nausea	1/173 (0.6%)
Upper gastrointestinal haemorrhage	1/173 (0.6%)
Vomiting	1/173 (0.6%)
General disorders
Chest pain	6/173 (3.5%)
Impaired healing	1/173 (0.6%)
Non-cardiac chest pain	1/173 (0.6%)
Pain	1/173 (0.6%)
Hepatobiliary disorders
Cholelithiasis	2/173 (1.2%)
Jaundice	1/173 (0.6%)
Infections and infestations
Abdominal wall abscess	1/173 (0.6%)
Bronchitis	1/173 (0.6%)
Cellulitis	1/173 (0.6%)
Cholecystitis infective	1/173 (0.6%)
Diverticulitis	1/173 (0.6%)
Gastroenteritis	1/173 (0.6%)
Localised infection	1/173 (0.6%)
Periorbital cellulitis	1/173 (0.6%)
Pneumonia	2/173 (1.2%)
Pyelonephritis	1/173 (0.6%)
Urosepsis	1/173 (0.6%)
Injury, poisoning and procedural complications
Ankle fracture	1/173 (0.6%)
Cervical vertebral fracture	1/173 (0.6%)
Clavicle fracture	1/173 (0.6%)
Foot fracture	1/173 (0.6%)
Humerus fracture	1/173 (0.6%)
Laceration	1/173 (0.6%)
Radius fracture	1/173 (0.6%)
Respiratory fume inhalation disorder	1/173 (0.6%)
Rib fracture	2/173 (1.2%)
Road traffic accident	4/173 (2.3%)
Upper limb fracture	1/173 (0.6%)
Investigations
Hepatic enzyme increased	1/173 (0.6%)
Oxygen saturation decreased	1/173 (0.6%)
Metabolism and nutrition disorders
Diabetic ketoacidosis	1/173 (0.6%)
Fluid overload	1/173 (0.6%)
Hyperkalaemia	1/173 (0.6%)
Hypoglycaemia	1/173 (0.6%)
Hypokalaemia	1/173 (0.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/173 (0.6%)
Back pain	2/173 (1.2%)
Osteoarthritis	2/173 (1.2%)
Spondylitis	1/173 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma	1/173 (0.6%)
Basal cell carcinoma	2/173 (1.2%)
Breast cancer female	2/173 (1.2%)
Central nervous system lympoma	1/173 (0.6%)
Prostate cancer	1/173 (0.6%)
Uterine leiomyoma	1/173 (0.6%)
Nervous system disorders
Cerebrovascular accident	2/173 (1.2%)
Haemorrhage intracranial	1/173 (0.6%)
Loss of consciousness	1/173 (0.6%)
Paraplegia	1/173 (0.6%)
Syncope	2/173 (1.2%)
Transient ischaemic attack	1/173 (0.6%)
Renal and urinary disorders
Dysuria	1/173 (0.6%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	2/173 (1.2%)
Erectile dysfunction	1/173 (0.6%)
Fallopian tube cyst	1/173 (0.6%)
Fallopian tube disorder	1/173 (0.6%)
Menorrhagia	1/173 (0.6%)
Ovarian cyst	2/173 (1.2%)
Pelvic peritoneal adhesions	1/173 (0.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/173 (0.6%)
Dyspnoea exertional	1/173 (0.6%)
Pulmonary embolism	1/173 (0.6%)
Respiratory failure	1/173 (0.6%)
Skin and subcutaneous tissue disorders
Skin ulcer	1/173 (0.6%)
Surgical and medical procedures
Cardiac pacemaker insertion	1/173 (0.6%)
Vascular disorders
Aortic stenosis	1/173 (0.6%)
Arterial thrombosis	1/173 (0.6%)
Arterial thrombosis limb	1/173 (0.6%)
Thrombosis	1/173 (0.6%)
Other (Not Including Serious) Adverse Events
	Inhaled Insulin
	Affected / at Risk (%)	# Events
Total	172/ (NaN)
Blood and lymphatic system disorders
Anaemia	7/173 (4%)
Lymphadenitis	1/173 (0.6%)
Lymphadenopathy	5/173 (2.9%)
Cardiac disorders
Acute myocardial infarction	3/173 (1.7%)
Angina pectoris	4/173 (2.3%)
Angina unstable	1/173 (0.6%)
Arteriosclerosis coronary artery	1/173 (0.6%)
Bradycardia	2/173 (1.2%)
Bundle branch block right	1/173 (0.6%)
Cardiac aneurysm	1/173 (0.6%)
Cardiac failure congestive	3/173 (1.7%)
Cardio-respiratory arrest	1/173 (0.6%)
Cardiomegaly	4/173 (2.3%)
Coronary artery disease	14/173 (8.1%)
Coronary artery occlusion	2/173 (1.2%)
Coronary artery stenosis	1/173 (0.6%)
Left atrial dilatation	1/173 (0.6%)
Myocardial infarction	5/173 (2.9%)
Myocardial ischaemia	1/173 (0.6%)
Palpitations	11/173 (6.4%)
Sinus arrhythmia	1/173 (0.6%)
Sinus tachycardia	1/173 (0.6%)
Supraventricular extrasystoles	1/173 (0.6%)
Supraventricular tachycardia	1/173 (0.6%)
Tachycardia	6/173 (3.5%)
Ventricular extrasystoles	2/173 (1.2%)
Congenital, familial and genetic disorders
Familial tremor	1/173 (0.6%)
Ear and labyrinth disorders
Auricular swelling	1/173 (0.6%)
Cerumen impaction	1/173 (0.6%)
Deafness	1/173 (0.6%)
Deafness unilateral	1/173 (0.6%)
Ear canal erythema	1/173 (0.6%)
Ear congestion	1/173 (0.6%)
Ear discomfort	7/173 (4%)
Ear disorder	3/173 (1.7%)
Ear pain	12/173 (6.9%)
Eustachian tube dysfunction	2/173 (1.2%)
Hypoacusis	2/173 (1.2%)
Meniere's disease	3/173 (1.7%)
Motion sickness	1/173 (0.6%)
Otorrhoea	2/173 (1.2%)
Tinnitus	4/173 (2.3%)
Tympanic membrane disorder	1/173 (0.6%)
Tympanic membrane perforation	1/173 (0.6%)
Vertigo	7/173 (4%)
Endocrine disorders
Androgen deficiency	1/173 (0.6%)
Goitre	3/173 (1.7%)
Hypothyroidism	5/173 (2.9%)
Thyroid pain	1/173 (0.6%)
Eye disorders
Cataract	9/173 (5.2%)
Cataract nuclear	2/173 (1.2%)
Conjunctival haemorrhage	1/173 (0.6%)
Conjunctivitis	4/173 (2.3%)
Diabetic retinopathy	15/173 (8.7%)
Diplopia	2/173 (1.2%)
Dry eye	2/173 (1.2%)
Eye allergy	1/173 (0.6%)
Eye discharge	2/173 (1.2%)
Eye haemorrhage	3/173 (1.7%)
Eye inflammation	1/173 (0.6%)
Eye irritation	2/173 (1.2%)
Eye movement disorder	2/173 (1.2%)
Eye pain	1/173 (0.6%)
Glaucoma	4/173 (2.3%)
Hyphaema	1/173 (0.6%)
Iridocyclitis	1/173 (0.6%)
Lacrimation increased	2/173 (1.2%)
Macular degeneration	1/173 (0.6%)
Macular oedema	2/173 (1.2%)
Myodesopsia	2/173 (1.2%)
Photopsia	2/173 (1.2%)
Retinal aneurysm	2/173 (1.2%)
Retinal detachment	1/173 (0.6%)
Retinal haemorrhage	1/173 (0.6%)
Retinopathy	6/173 (3.5%)
Scotoma	1/173 (0.6%)
Vision blurred	20/173 (11.6%)
Visual acuity reduced	1/173 (0.6%)
Visual impairment	2/173 (1.2%)
Vitreous haemorrhage	2/173 (1.2%)
LIGHT SENSITIVE VISION	1/173 (0.6%)
PROGRESSION OF PROLIFERATIVE DIABETIC RETINOPATHY OF LEFT EYE	1/173 (0.6%)
PROGRESSION OF PROLIFERATIVE DIABETIC RETINOPATHY RIGHT EYE	1/173 (0.6%)
Gastrointestinal disorders
Abdominal discomfort	9/173 (5.2%)
Abdominal distension	2/173 (1.2%)
Abdominal pain	19/173 (11%)
Abdominal pain lower	5/173 (2.9%)
Abdominal pain upper	19/173 (11%)
Breath odour	1/173 (0.6%)
Colitis	1/173 (0.6%)
Colonic Polyp	3/173 (1.7%)
Constipation	18/173 (10.4%)
Dental caries	6/173 (3.5%)
Diarrhoea	45/173 (26%)
Diverticulum	3/173 (1.7%)
Dry mouth	5/173 (2.9%)
Duodenal ulcer	1/173 (0.6%)
Duodenogastric reflux	2/173 (1.2%)
Dyspepsia	21/173 (12.1%)
Dysphagia	2/173 (1.2%)
Faecal incontinence	1/173 (0.6%)
Faeces discoloured	1/173 (0.6%)
Flatulence	2/173 (1.2%)
Food poisoning	6/173 (3.5%)
Frequent bowel movements	1/173 (0.6%)
Gastric ulcer	1/173 (0.6%)
Gastritis	2/173 (1.2%)
Gastrointestinal pain	1/173 (0.6%)
Gastrooesophageal reflux disease	17/173 (9.8%)
Gingival pain	3/173 (1.7%)
Gingival recession	1/173 (0.6%)
Gingival swelling	1/173 (0.6%)
Gingivitis	3/173 (1.7%)
Glossitis	1/173 (0.6%)
Haematochezia	1/173 (0.6%)
Haemorrhagic ascites	1/173 (0.6%)
Haemorrhoids	7/173 (4%)
Hiatus hernia	2/173 (1.2%)
Hypoaesthesia oral	4/173 (2.3%)
Impaired gastric emptying	3/173 (1.7%)
Inguinal hernia	1/173 (0.6%)
Irritable bowel syndrome	1/173 (0.6%)
Lip blister	2/173 (1.2%)
Lip disorder	1/173 (0.6%)
Mouth ulceration	1/173 (0.6%)
Nausea	48/173 (27.7%)
Paraesthesia oral	4/173 (2.3%)
Parotid gland enlargement	1/173 (0.6%)
Periodontal disease	3/173 (1.7%)
Rectal haemorrhage	1/173 (0.6%)
Rectal polyp	2/173 (1.2%)
Reflux oesophagitis	1/173 (0.6%)
Retching	2/173 (1.2%)
Stomach discomfort	7/173 (4%)
Swollen tongue	1/173 (0.6%)
Tongue discolouration	2/173 (1.2%)
Tongue disorder	2/173 (1.2%)
Tooth impacted	1/173 (0.6%)
Tooth loss	1/173 (0.6%)
Toothache	18/173 (10.4%)
Umbilical hernia	2/173 (1.2%)
Upper gastrointestinal haemorrhage	1/173 (0.6%)
Vomiting	24/173 (13.9%)
DRY, PEELING LIPS	1/173 (0.6%)
IMPACTED COLON	1/173 (0.6%)
General disorders
Asthenia	41/173 (23.7%)
Catheter site inflammation	1/173 (0.6%)
Chest discomfort	5/173 (2.9%)
Chest pain	23/173 (13.3%)
Chills	3/173 (1.7%)
Cyst	2/173 (1.2%)
Discomfort	1/173 (0.6%)
Face oedema	2/173 (1.2%)
Fatigue	38/173 (22%)
Feeling abnormal	3/173 (1.7%)
Feeling cold	3/173 (1.7%)
Feeling hot	3/173 (1.7%)
Feeling jittery	9/173 (5.2%)
Generalised oedema	7/173 (4%)
Hunger	24/173 (13.9%)
Ill-defined disorder	1/173 (0.6%)
Impaired healing	1/173 (0.6%)
Influenza like illness	3/173 (1.7%)
Injection site pain	1/173 (0.6%)
Injection site pruritus	1/173 (0.6%)
Irritability	5/173 (2.9%)
Malaise	8/173 (4.6%)
Non-cardiac chest pain	1/173 (0.6%)
Oedema	3/173 (1.7%)
Oedema peripheral	34/173 (19.7%)
Pain	14/173 (8.1%)
Peripheral coldness	1/173 (0.6%)
Pitting oedema	1/173 (0.6%)
Pyrexia	12/173 (6.9%)
Sensation of foreign body	2/173 (1.2%)
Sluggishness	3/173 (1.7%)
Temperature intolerance	1/173 (0.6%)
Thirst	4/173 (2.3%)
Hepatobiliary disorders
Cholelithiasis	3/173 (1.7%)
Hepatic steatosis	2/173 (1.2%)
Jaundice	1/173 (0.6%)
Liver disorder	1/173 (0.6%)
Immune system disorders
Anaphylactic reaction	1/173 (0.6%)
Drug hypersensitivity	1/173 (0.6%)
Hypersensitivity	8/173 (4.6%)
Latex allergy	1/173 (0.6%)
Seasonal allergy	20/173 (11.6%)
Infections and infestations
Abdominal wall abscess	1/173 (0.6%)
Abscess limb	2/173 (1.2%)
Acarodermatitis	1/173 (0.6%)
Acute sinusitis	1/173 (0.6%)
Breast abscess	1/173 (0.6%)
Bronchitis	30/173 (17.3%)
Candidiasis	1/173 (0.6%)
Catheter related infection	1/173 (0.6%)
Catheter site infection	1/173 (0.6%)
Cellulitis	7/173 (4%)
Cholecystitis infective	1/173 (0.6%)
Chronic sinusitis	1/173 (0.6%)
Conjunctivitis infective	1/173 (0.6%)
Cystitis	5/173 (2.9%)
Diverticulitis	2/173 (1.2%)
Ear infection	3/173 (1.7%)
Erythema infectiosum	1/173 (0.6%)
Eye infection	1/173 (0.6%)
Folliculitis	2/173 (1.2%)
Fungal infection	6/173 (3.5%)
Fungal skin infection	4/173 (2.3%)
Furuncle	7/173 (4%)
Gastric infection	1/173 (0.6%)
Gastroenteritis	16/173 (9.2%)
Gastroenteritis viral	32/173 (18.5%)
Genital infection fungal	1/173 (0.6%)
Groin Abscess	1/173 (0.6%)
Herpes simplex	1/173 (0.6%)
Herpes zosters	7/173 (4%)
Hordeolum	3/173 (1.7%)
Infected cyst	1/173 (0.6%)
Infected sebaceous cyst	2/173 (1.2%)
Infected skin ulcer	1/173 (0.6%)
Infection	4/173 (2.3%)
Infectious mononucleosis	1/173 (0.6%)
Influenza	50/173 (28.9%)
Kidney infection	2/173 (1.2%)
Labyrinthitis	4/173 (2.3%)
Laryngitis	7/173 (4%)
Localised infection	10/173 (5.8%)
Lower respiratory tract infection	6/173 (3.5%)
Lymph gland infection	1/173 (0.6%)
Gingival infection	5/173 (2.9%)
Nail bed infection	2/173 (1.2%)
Nasopharyngitis	34/173 (19.7%)
Onychomycosis	11/173 (6.4%)
Oral herpes	6/173 (3.5%)
Osteomyelitis	1/173 (0.6%)
Otitis externa	5/173 (2.9%)
Otitis media	11/173 (6.4%)
Paronychia	2/173 (1.2%)
Penile infection	1/173 (0.6%)
Periorbital cellulitis	1/173 (0.6%)
Pharyngitis	17/173 (9.8%)
Pharyngitis streptococcal	9/173 (5.2%)
Pneumonia	10/173 (5.8%)
Postoperative wound infection	2/173 (1.2%)
Pyelonephritis	2/173 (1.2%)
Recurring skin boils	1/173 (0.6%)
Respiratory tract infection	1/173 (0.6%)
Rhinitis	7/173 (4%)
Scrotal abscess	1/173 (0.6%)
Sinusitis	33/173 (19.1%)
Skin infection	1/173 (0.6%)
Soft tissue infection	1/173 (0.6%)
Subcutaneous abscess	1/173 (0.6%)
Tinea infection	1/173 (0.6%)
Tinea pedis	6/173 (3.5%)
Tonsillitis	2/173 (1.2%)
Tooth abscess	10/173 (5.8%)
Tooth infection	8/173 (4.6%)
Upper respiratory tract infection	102/173 (59%)
Urinary tract infection	26/173 (15%)
Urosepsis	1/173 (0.6%)
Vaginal infection	4/173 (2.3%)
Vaginitis bacterial	1/173 (0.6%)
Viral infection	9/173 (5.2%)
Viral pharyngitis	1/173 (0.6%)
Viral upper respiratory tract infection	1/173 (0.6%)
Vulval abscess	1/173 (0.6%)
Vulvovaginal mycotic infection	13/173 (7.5%)
Wound infection	3/173 (1.7%)
Gingival abscess	1/173 (0.6%)
Injury, poisoning and procedural complications
Animal bite	1/173 (0.6%)
Ankle fracture	3/173 (1.7%)
Arthropod bite	1/173 (0.6%)
Arthropod sting	1/173 (0.6%)
Back injury	6/173 (3.5%)
Barotitis media	1/173 (0.6%)
Burns second degree	2/173 (1.2%)
Burns third degree	1/173 (0.6%)
Cartilage injury	3/173 (1.7%)
Cervical vertebral fracture	2/173 (1.2%)
Clavicle fracture	2/173 (1.2%)
Contusion	16/173 (9.2%)
Device failure	1/173 (0.6%)
Epicondylitis	3/173 (1.7%)
Excoriation	19/173 (11%)
Eye injury	1/173 (0.6%)
Foot fracture	11/173 (6.4%)
Hand fracture	4/173 (2.3%)
Humerus fracture	1/173 (0.6%)
Incision site pain	3/173 (1.7%)
Injury	1/173 (0.6%)
Injury corneal	1/173 (0.6%)
Joint dislocation	1/173 (0.6%)
Joint injury	2/173 (1.2%)
Joint sprain	11/173 (6.4%)
Laceration	9/173 (5.2%)
Ligament rupture	1/173 (0.6%)
Limb injury	2/173 (1.2%)
Lung injury	1/173 (0.6%)
Meniscus lesion	2/173 (1.2%)
Muscle injury	3/173 (1.7%)
Muscle strain	12/173 (6.9%)
Open fracture	1/173 (0.6%)
Post procedural haemorrhage	1/173 (0.6%)
Procedural pain	8/173 (4.6%)
Radius fracture	1/173 (0.6%)
Respiratory fume inhalation disorder	1/173 (0.6%)
Rib fracture	6/173 (3.5%)
Road traffic accident	5/173 (2.9%)
Skeletal injury	6/173 (3.5%)
Skin laceration	8/173 (4.6%)
Stress fracture	1/173 (0.6%)
Sunburn	1/173 (0.6%)
Tendon injury	2/173 (1.2%)
Tendon rupture	1/173 (0.6%)
Thermal burn	8/173 (4.6%)
Tooth fracture	3/173 (1.7%)
Upper limb fracture	1/173 (0.6%)
Wound	3/173 (1.7%)
Wrist fracture	1/173 (0.6%)
Investigations
Aspartate aminotransferase increased	2/173 (1.2%)
Blood cholesterol increased	1/173 (0.6%)
Blood pressure increased	5/173 (2.9%)
Blood testosterone decreased	2/173 (1.2%)
Blood urine present	1/173 (0.6%)
Bone density decreased	1/173 (0.6%)
Cardiac murmur	1/173 (0.6%)
Cardiac stress test abnormal	1/173 (0.6%)
Carotid bruit	1/173 (0.6%)
Chest X-ray abnormal	1/173 (0.6%)
Culture	1/173 (0.6%)
Full blood count decreased	1/173 (0.6%)
Glycosylated haemoglobin	1/173 (0.6%)
Heart rate increased	6/173 (3.5%)
Heart rate irregular	2/173 (1.2%)
Hepatic enzyme increased	1/173 (0.6%)
Occult blood positive	2/173 (1.2%)
Oxygen saturation decreased	1/173 (0.6%)
Platelet count decreased	2/173 (1.2%)
Pulmonary function test decreased	2/173 (1.2%)
Pulse abnormal	1/173 (0.6%)
Smear cervix abnormal	1/173 (0.6%)
Urine analysis abnormal	1/173 (0.6%)
Vitamin B12 decreased	1/173 (0.6%)
Weight increased	2/173 (1.2%)
White blood cell count decreased	1/173 (0.6%)
Metabolism and nutrition disorders
Anorexia	1/173 (0.6%)
Dehydration	1/173 (0.6%)
Diabetic foot	2/173 (1.2%)
Diabetic ketoacidosis	1/173 (0.6%)
Dyslipidaemia	1/173 (0.6%)
Fluid overload	1/173 (0.6%)
Fluid retention	2/173 (1.2%)
Hypercalcaemia	1/173 (0.6%)
Hypercholesterolaemia	5/173 (2.9%)
Hyperglycaemia	6/173 (3.5%)
Hyperkalaemia	2/173 (1.2%)
Hyperlipidaemia	7/173 (4%)
Hypertriglyceridaemia	1/173 (0.6%)
Hypoglycaemia	125/173 (72.3%)
Hypokalaemia	4/173 (2.3%)
Ketosis	1/173 (0.6%)
Lactic acidosis	1/173 (0.6%)
Polydipsia	2/173 (1.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	52/173 (30.1%)
Arthritis	6/173 (3.5%)
Arthropathy	3/173 (1.7%)
Back pain	42/173 (24.3%)
Bone pain	2/173 (1.2%)
Bursitis	5/173 (2.9%)
Coccydynia	1/173 (0.6%)
Costochondritis	1/173 (0.6%)
Dupuytren's contracture	2/173 (1.2%)
Exostosis	7/173 (4%)
Fibromyalgia	1/173 (0.6%)
Flank pain	2/173 (1.2%)
Foot deformity	2/173 (1.2%)
Groin pain	1/173 (0.6%)
Intervertebral disc disorder	1/173 (0.6%)
Intervertebral disc protrusion	6/173 (3.5%)
Joint contracture	1/173 (0.6%)
Joint range of motion decreased	3/173 (1.7%)
Joint stiffness	3/173 (1.7%)
Joint swelling	4/173 (2.3%)
Limb discomfort	2/173 (1.2%)
Lumbar spinal stenosis	1/173 (0.6%)
Monarthritis	1/173 (0.6%)
Muscle disorder	1/173 (0.6%)
Muscle spasms	18/173 (10.4%)
Muscle tightness	1/173 (0.6%)
Muscular weakness	3/173 (1.7%)
Musculoskeletal chest pain	14/173 (8.1%)
Musculoskeletal discomfort	4/173 (2.3%)
Musculoskeletal disorder	2/173 (1.2%)
Musculoskeletal pain	23/173 (13.3%)
Musculoskeletal stiffness	4/173 (2.3%)
Myalgia	11/173 (6.4%)
Neck pain	8/173 (4.6%)
Nodule on extremity	1/173 (0.6%)
Osteitis	1/173 (0.6%)
Osteoarthritis	4/173 (2.3%)
Osteochondrosis	1/173 (0.6%)
Osteopenia	2/173 (1.2%)
Pain in extremity	48/173 (27.7%)
Pain in jaw	2/173 (1.2%)
Periarthritis	2/173 (1.2%)
Plantar fasciitis	1/173 (0.6%)
Polyarthritis	1/173 (0.6%)
Rotator cuff syndrome	2/173 (1.2%)
Sacroiliitis	1/173 (0.6%)
Spinal column stenosis	1/173 (0.6%)
Spinal osteoarthritis	1/173 (0.6%)
Spondylitis	2/173 (1.2%)
Synovial cyst	1/173 (0.6%)
Synovitis	1/173 (0.6%)
Tendon disorder	1/173 (0.6%)
Tendonitis	19/173 (11%)
Tenosynovitis	2/173 (1.2%)
Tenosynovitis stenosans	1/173 (0.6%)
Trigger finger	5/173 (2.9%)
Upper extremity mass	1/173 (0.6%)
Neuropathic arthropathy	1/173 (0.6%)
Pain in extremity	49/173 (28.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acrochordon	3/173 (1.7%)
B-cell lymphoma	1/173 (0.6%)
Basal cell carcinoma	3/173 (1.7%)
Breast cancer female	2/173 (1.2%)
Central nervous system lymphoma	1/173 (0.6%)
Colon adenoma	1/173 (0.6%)
Fibrous histiocytoma	1/173 (0.6%)
Lipoma	2/173 (1.2%)
Melanocytic naevus	3/173 (1.7%)
Prostate cancer	2/173 (1.2%)
Skin papilloma	3/173 (1.7%)
Squamous cell carcinoma	1/173 (0.6%)
Thyroid neoplasm	2/173 (1.2%)
Uterine leiomyoma	2/173 (1.2%)
Nervous system disorders
CARPAL TUNNEL SYNDROME - RIGHT WRIST	1/173 (0.6%)
Areflexia	1/173 (0.6%)
Burning sensation	4/173 (2.3%)
Carpal tunnel syndrome	10/173 (5.8%)
Cerebrovascular accident	2/173 (1.2%)
Cognitive disorder	1/173 (0.6%)
Coordination abnormal	1/173 (0.6%)
Diabetic neuropathy	2/173 (1.2%)
Disturbance in attention	5/173 (2.9%)
Dizziness	46/173 (26.6%)
Dizziness postural	1/173 (0.6%)
Dysgeusia	1/173 (0.6%)
Facial palsy	2/173 (1.2%)
Haemorrhage intracranial	1/173 (0.6%)
Head discomfort	1/173 (0.6%)
Headache	45/173 (26%)
Hyperaesthesia	1/173 (0.6%)
Hypoaesthesia	26/173 (15%)
IIIrd nerve paralysis	1/173 (0.6%)
Lethargy	9/173 (5.2%)
Loss of consciousness	2/173 (1.2%)
Lumbar radiculopathy	1/173 (0.6%)
Memory impairment	3/173 (1.7%)
Mental impairment	2/173 (1.2%)
Migraine	4/173 (2.3%)
Morton's neuralgia	1/173 (0.6%)
Nerve compression	3/173 (1.7%)
Neuralgia	3/173 (1.7%)
Paraesthesia	20/173 (11.6%)
Paraplegia	1/173 (0.6%)
Parkinson's disease	1/173 (0.6%)
Polyneuropathy	1/173 (0.6%)
Poor quality sleep	1/173 (0.6%)
Sciatic nerve neuropathy	1/173 (0.6%)
Sciatica	5/173 (2.9%)
Sinus headache	11/173 (6.4%)
Speech disorder	1/173 (0.6%)
Syncope	5/173 (2.9%)
Tension headache	2/173 (1.2%)
Tinel's sign	1/173 (0.6%)
Transient ischaemic attack	2/173 (1.2%)
Tremor	62/173 (35.8%)
VIth nerve paralysis	1/173 (0.6%)
Anxiety	23/173 (13.3%)
Intentional self-injury	1/173 (0.6%)
Somnolence	7/173 (4%)
Neuropathy peripheral	19/173 (11%)
Sensory Disturbance	2/173 (1.2%)
Psychiatric disorders
Abnormal dreams	1/173 (0.6%)
Agitation	2/173 (1.2%)
Attention deficit/hyperactivity disorder	1/173 (0.6%)
Bipolar disorder	1/173 (0.6%)
Confusional state	7/173 (4%)
Daydreaming	1/173 (0.6%)
Depression	20/173 (11.6%)
Disorientation	9/173 (5.2%)
Dissociation	1/173 (0.6%)
Emotional disorder	3/173 (1.7%)
Flat affect	1/173 (0.6%)
Mental status changes	1/173 (0.6%)
Mood altered	1/173 (0.6%)
Nervousness	17/173 (9.8%)
Nightmare	1/173 (0.6%)
Restlessness	3/173 (1.7%)
Sleep disorder	4/173 (2.3%)
Stress	20/173 (11.6%)
Thinking abnormal	1/173 (0.6%)
Insomnia	17/173 (9.8%)
Panic Disorder	1/173 (0.6%)
Renal and urinary disorders
Bladder spasm	1/173 (0.6%)
Dysuria	5/173 (2.9%)
Haematuria	3/173 (1.7%)
Hydronephrosis	1/173 (0.6%)
Hypercalciuria	1/173 (0.6%)
Microalbuminuria	7/173 (4%)
Micturition disorder	1/173 (0.6%)
Micturition urgency	3/173 (1.7%)
Nephrolithiasis	7/173 (4%)
Nephropathy	2/173 (1.2%)
Nephrotic syndrome	1/173 (0.6%)
Nocturia	2/173 (1.2%)
Pollakiuria	5/173 (2.9%)
Polyuria	5/173 (2.9%)
Proteinuria	3/173 (1.7%)
Renal cyst	1/173 (0.6%)
Renal failure	1/173 (0.6%)
Renal failure chronic	1/173 (0.6%)
Stress urinary incontinence	2/173 (1.2%)
Urinary incontinence	2/173 (1.2%)
Urinary tract obstruction	1/173 (0.6%)
Urine odour abnormal	1/173 (0.6%)
Reproductive system and breast disorders
Amenorrhoea	2/173 (1.2%)
Atrophic vulvovaginitis	1/173 (0.6%)
Benign prostatic hyperplasia	2/173 (1.2%)
Breast mass	1/173 (0.6%)
Breast pain	1/173 (0.6%)
Breast tenderness	1/173 (0.6%)
Cervical polyp	1/173 (0.6%)
Dysmenorrhoea	3/173 (1.7%)
Erectile dysfunction	14/173 (8.1%)
Fallopian tube cyst	1/173 (0.6%)
Fallopian tube disorder	1/173 (0.6%)
Menorrhagia	3/173 (1.7%)
Menstruation irregular	2/173 (1.2%)
Ovarian cyst	2/173 (1.2%)
Pelvic peritoneal adhesions	1/173 (0.6%)
Peyronie's disease	1/173 (0.6%)
Prostatomegaly	2/173 (1.2%)
Testicular cyst	1/173 (0.6%)
Testicular pain	1/173 (0.6%)
Uterine haemorrhage	1/173 (0.6%)
Vaginal haemorrhage	1/173 (0.6%)
Vulva cyst	1/173 (0.6%)
Vulvovaginal pruritus	1/173 (0.6%)
Respiratory, thoracic and mediastinal disorders
DECREASED BREATHING BILATERALLY	1/173 (0.6%)
Allergic sinusitis	1/173 (0.6%)
Asthma	7/173 (4%)
Atelectasis	1/173 (0.6%)
Bronchial hyperreactivity	2/173 (1.2%)
Bronchial irritation	1/173 (0.6%)
Chronic obstructive pulmonary disease	1/173 (0.6%)
Cough	70/173 (40.5%)
Dry throat	4/173 (2.3%)
Dysphonia	4/173 (2.3%)
Dyspnoea	16/173 (9.2%)
Dyspnoea exertional	4/173 (2.3%)
Epistaxis	4/173 (2.3%)
Hyperventilation	1/173 (0.6%)
Hypoventilation	1/173 (0.6%)
Increased upper airway secretion	1/173 (0.6%)
Lung disorder	3/173 (1.7%)
Mediastinal disorder	1/173 (0.6%)
Nasal congestion	23/173 (13.3%)
Nasal disorder	1/173 (0.6%)
Nasal dryness	1/173 (0.6%)
Nasal polyps	2/173 (1.2%)
Oropharyngeal pain	40/173 (23.1%)
Painful respiration	1/173 (0.6%)
Pharyngeal erythema	2/173 (1.2%)
Pharyngeal haemorrhage	1/173 (0.6%)
Pleural effusion	1/173 (0.6%)
Pleurisy	1/173 (0.6%)
Pleuritic pain	1/173 (0.6%)
Pneumonitis	1/173 (0.6%)
Postnasal drip	9/173 (5.2%)
Productive cough	12/173 (6.9%)
Pulmonary congestion	10/173 (5.8%)
Pulmonary embolism	1/173 (0.6%)
Pulmonary granuloma	1/173 (0.6%)
Pulmonary infarction	1/173 (0.6%)
Pulmonary oedema	1/173 (0.6%)
Rales	4/173 (2.3%)
Respiratory disorder	2/173 (1.2%)
Respiratory failure	1/173 (0.6%)
Respiratory gas exchange disorder	2/173 (1.2%)
Respiratory tract congestion	1/173 (0.6%)
Respiratory tract irritation	1/173 (0.6%)
Rhinalgia	1/173 (0.6%)
Rhinitis allergic	18/173 (10.4%)
Rhinitis seasonal	2/173 (1.2%)
Rhinorrhoea	9/173 (5.2%)
Sinus congestion	31/173 (17.9%)
Sinus polyp	1/173 (0.6%)
Sleep apnoea syndrome	7/173 (4%)
Sneezing	1/173 (0.6%)
Throat irritation	10/173 (5.8%)
Tonsillar hypertrophy	1/173 (0.6%)
Upper respiratory tract congestion	7/173 (4%)
Wheezing	7/173 (4%)
Skin and subcutaneous tissue disorders
Acrodermatitis	4/173 (2.3%)
Alopecia	2/173 (1.2%)
Blister	6/173 (3.5%)
Cold sweat	6/173 (3.5%)
Dandruff	1/173 (0.6%)
Dermal cyst	6/173 (3.5%)
Dermatitis	5/173 (2.9%)
Dermatitis atopic	1/173 (0.6%)
Dermatitis contact	2/173 (1.2%)
Dry skin	7/173 (4%)
Ecchymosis	1/173 (0.6%)
Eczema	2/173 (1.2%)
Erythema	3/173 (1.7%)
Granuloma annulare	1/173 (0.6%)
Hyperhidrosis	34/173 (19.7%)
Hyperkeratosis	6/173 (3.5%)
Hypoaesthesia facial	2/173 (1.2%)
Ingrowing nail	9/173 (5.2%)
Nail discomfort	1/173 (0.6%)
Nail disorder	1/173 (0.6%)
Night sweats	2/173 (1.2%)
Onychoclasis	1/173 (0.6%)
Onychogryphosis	1/173 (0.6%)
Onychomadesis	1/173 (0.6%)
Pain of skin	1/173 (0.6%)
Periorbital oedema	1/173 (0.6%)
Pruritus	3/173 (1.7%)
Pruritus generalised	2/173 (1.2%)
Psoriasis	2/173 (1.2%)
Purpura	1/173 (0.6%)
Rash	24/173 (13.9%)
Rash generalised	3/173 (1.7%)
Rash macular	3/173 (1.7%)
Rash papular	3/173 (1.7%)
Rash pruritic	1/173 (0.6%)
Rash vesicular	1/173 (0.6%)
Rosacea	2/173 (1.2%)
Seborrhoea	1/173 (0.6%)
Seborrhoeic dermatitis	1/173 (0.6%)
Skin discolouration	3/173 (1.7%)
Skin hyperpigmentation	2/173 (1.2%)
Skin irritation	3/173 (1.7%)
Skin lesion	9/173 (5.2%)
Skin nodule	2/173 (1.2%)
Skin ulcer	10/173 (5.8%)
Swelling face	1/173 (0.6%)
Urticaria	6/173 (3.5%)
Social circumstances
Family stress	2/173 (1.2%)
Menopause	1/173 (0.6%)
Surgical and medical procedures
Cardiac pacemaker insertion	1/173 (0.6%)
Female sterilisation	1/173 (0.6%)
Prophylaxis	1/173 (0.6%)
Sebaceous cyst excision	1/173 (0.6%)
Sinus operation	5/173 (2.9%)
Vascular disorders
Aneurysm	2/173 (1.2%)
Aortic stenosis	1/173 (0.6%)
Arterial thrombosis	1/173 (0.6%)
Arterial thrombosis limb	1/173 (0.6%)
Flushing	3/173 (1.7%)
Haematoma	5/173 (2.9%)
Hot flush	5/173 (2.9%)
Hypertension	27/173 (15.6%)
Intermittent claudication	1/173 (0.6%)
Pallor	1/173 (0.6%)
Peripheral vascular disorder	1/173 (0.6%)
Raynaud's phenomenon	2/173 (1.2%)
Thrombosis	1/173 (0.6%)
Vein disorder	1/173 (0.6%)

Limitations/Caveats

Study terminated early due to business and operational issues. All subjects who were treated with inhaled insulin in parent protocols(217-102,-103,or-104) or in extension protocols (217-102E,-103E,-104E,or A2171036)are included in safety evaluation.

More Information

Certain Agreements

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

Pfizer has the right to review disclosures, requesting a delay of <60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), <12 mo from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential info other than study results.