Efficacy and Safety of Inhaled Insulin Compared With Subcutaneous Human Insulin Therapy in Adults With Type 2 Diabetes

• Sponsor: Pfizer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00136916
• Collaborator: (none)
• Enrollment: 635
• Locations: 92
• Arms: 2
• Duration (Months): 78
• Patients Per Site: 6.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is being done to find out the good and bad effects of inhaled insulin that is used by oral inhalation, to adult males and females with type 2 diabetes mellitus. The other name for this inhaled insulin is Exubera®.

This study included a 2-year comparative treatment period followed by a 6-month follow-up period during which inhaled insulin-treated subjects were switched back to subcutaneous short-acting insulin. After this follow-up period, all eligible subjects entered a comparative extension period that was to last for 5 years. When the comparative portion of the study was terminated, all subjects were requested to return for a final extension follow-up month 3 visit.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: Inhaled Insulin; Drug: Subcutaneous insulin	Phase 3

Detailed Description

Pfizer announced in October 2007 that it would stop marketing Exubera. Nektar, the company from which Pfizer licensed Exubera, announced on April 9, 2008 that it had stopped its search for a new marketing partner. Accordingly, there will be no commercial availability of Exubera. As a result, study A2171029 was terminated on June 9, 2008. Neither safety nor efficacy reasons were the cause of the study termination.

Study Design

• Study Type: Interventional
• Actual Enrollment: 635 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Exubera® (Inhaled Insulin) Compared With Subcutaneous Human Insulin Therapy in Adult Subjects With Type 2 Diabetes Mellitus: A Long-Term, Outpatient, Open-Label, Parallel-Group Comparative Trial
• Study Start Date: Jun 1, 2002
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Inhaled Insulin Inhalable short-acting insulin	Drug: Inhaled Insulin; Inhaled insulin with dose adjusted according to premeal blood glucose; Other Names: Exubera
Active Comparator: Subcutaneous insulin	Drug: Subcutaneous insulin; Subcutaneous insulin with dose adjusted according to premeal blood glucose

Outcome Measures

Primary Outcome Measures

1. Change From Month 3 in Forced Expiratory Volume in 1 Second (FEV1) [Month 3 through extension Month 60]

   Change from Month 3: mean of (value of observed FEV1 [forced expiratory volume in the first second of forced exhalation] in liters [L] at treatment observation minus Month 3 value).

2. Change From Baseline in FEV1 [Baseline through extension follow up Month 3]

   Change from baseline: mean of (value of observed FEV1 [L] at treatment observation minus baseline value).

3. Annual Rate of Change in FEV1 [Week -2 through extension follow up Month 3 or end of study]

   Annual rate of change in FEV1 calculated as slope over time [visit] for forced expiratory volume in 1 second measured as liters per year (L/yr).

4. Summary of ≥ 15 % Decliners in FEV1 [Month 3 through extension follow up Month 3]

   Number of subjects with a post-baseline FEV1 decrease of ≥ 15 % [(baseline observed value - visit observed value)/(baseline observed value) * 100]; in the absence of an obvious intercurrrent illness, a repeat FEV1 was performed.

5. Annual Rate of Change in Carbon Monoxide Diffusion Capacity (DLco) [Week -2 through extension follow up Month 3 or end of study]

   Annual rate of change in DLco calculated as slope over time (visit) measured as milliliters per minute per millimeters of mercury per year (ml/min/mmHg/yr).

6. Change From Baseline in Carbon Monoxide Diffusion Capacity (DLco) [Baseline through extension follow up Month 3]

   Change from baseline: mean of (value of observed DLco [milliliters per minute per millimeters of mercury (ml/min/mmHg)] at treatment observation minus baseline value).

7. Summary of ≥ 20 % Decliners in DLco [Month 3 through extension follow up Month 3]

   Number of subjects with a post-baseline DLco decrease of ≥ 20 % [(baseline observed value - visit observed value)/(baseline observed value) * 100]; in the absence of an obvious intercurrrent illness, a repeat DLco was performed.

Secondary Outcome Measures

1. Forced Vital Capacity (FVC) [Week -3 through extension follow up Month 3 or end of study]

   Forced Vital Capacity (FVC) measured in liters (L).

2. Total Lung Capacity (TLC) [Baseline through extension follow up Month 3]

   Total Lung Capacity measured in liters (L).

3. Change From Baseline in Glycosylated Hemoglobin (HbA1c) [Baseline through extension follow up Month 3]

   Change from baseline: mean of (value of observed HbA1c [%] at treatment observation minus baseline value).

4. Change From Baseline in Fasting Plasma Glucose (FPG) [Baseline through extension follow up Month 3]

   Change from baseline: mean of (value of observed FPG [milligrams per deciliter (mg/dL)] at treatment observation minus baseline value).

5. Change From Baseline in Body Weight [Baseline through extension follow up Month 3]

   Change from baseline: mean of (value of observed body weight [kilograms (kg)] at treatment observation minus baseline value).

6. Total Daily Long-acting Insulin Dose (Unadjusted for Body Weight) [Month 3 through extension Month 36]

   Total daily long-acting insulin dose unadjusted for body weight. Long-acting (units) insulin for inhaled insulin and subcutaneous treatment groups included NPH insulin, Ultralente®, and insulin glargine.

7. Total Daily Long-acting Insulin (Adjusted for Body Weight) [Month 3 through extension Month 36]

   Total daily dose of long-acting insulin adjusted for body weight (units per kilogram [kg]). Long-acting (units) insulin for inhaled insulin and subcutaneous treatment groups included NPH insulin, Ultralente®, and insulin glargine.

8. Total Daily Short-acting Insulin Dose (Unadjusted for Body Weight) [Month 3 through extension Month 36]

   Total daily dose of short-acting insulin unadjusted for body weight. Short-acting insulin (milligrams [mg]) for the inhaled insulin treatment group was inhaled insulin; short-acting insulin (units) for the subcutaneous insulin treatment group included insulin lispro, insulin aspart, and regular insulin.

9. Total Daily Short-acting Insulin Dose (Adjusted for Body Weight) [Month 3 through extension Month 36]

   Total daily dose of short-acting insulin adjusted for body weight. Short-acting insulin (mg) for the inhaled insulin treatment group was inhaled insulin (mg divided by kg); short-acting insulin (units) for the subcutaneous insulin treatment group included insulin lispro, insulin aspart, and regular insulin (units divided by kg).

10. Lipid Panel: Total Cholesterol, High Density Lipoprotein, Low Density Lipoprotein, and Triglycerides [Week -4 through Month 24]

    Lipid values for total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides measured as milligrams per deciliter (mg/dL).

11. Hypoglycemic Event Rates [Month 1 through extension Month 36]

    Hypoglycemic event rate; hypoglycemic event identified by characteristic symptoms of hypoglycemia with no blood glucose (BG) check with prompt resolution with food intake, SC glucagon, or intravenous (IV) glucose; characteristic symptoms with BG of 59 mg/dL (3.2 mmol/L) or less with or without symptoms. Crude event rate = total events divided by subject months (elapsed number of months a subject was in the study at each time interval).

12. Severe Hypoglycemic Event Rates [Month 1 through extension Month 36]

    Severe hypoglycemic event rate; all 3 criteria were met: subject unable to treat self, exhibited at least 1 neurological symptom (memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty awakening, suspected seizure, loss of consciousness); BG measurement ≤49 mg/dL, or not measured but clinical manifestations reversed by oral carbohydrates, SC glucagon, or IV glucose. Crude event rate: total events divided by subject months multiplied by 100 ([total events/subject months]*100). Subjects months: elapsed number of months subject was in study in each time interval.

13. Cough Questionnaire [Week 0 and if indicated through extension follow up Month 3]

    Clinician administered 6 question instrument to measure cough frequency (night, day), severity, timing in relation to short-acting insulin dosing, severity related to insulin dosing (SC or inhaled), and productivity of cough; range 0 (indicates no symptoms) to 4 (indicates severe symptoms). Questionnaire administered at Week 0 then if and only if, cough is identified as an adverse event not explained by a concomitant condition, such as an upper respiratory tract infection.

14. Baseline Dyspnea Index (BDI) [Week -1]

    Clinician administered instrument to measure the baseline severity of breathlessness (shortness of breath) in symptomatic patients with 3 domains: functional impairment, magnitude of task, and magnitude of effort. BDI score range 0 (very severe impairment) to 4 (no impairment) scaled to a BDI focal score (0-12). Lower score indicates greater impairment.

15. Transition Dyspnea Index (TDI) [Week 4 through extension follow up Month 3 or end of study]

    Clinician administered instrument to measure the baseline severity of breathlessness (shortness of breath) in symptomatic patients with 3 domains: functional impairment, magnitude of task, and magnitude of effort. TDI score range -3 (major deterioration) to +3 (major improvement); sum of all domains yields the TDI focal score (-9 to +9); lower score indicates greater deterioration. Compared to previous scoring to determine deterioration or improvement.

16. High Resolution Computerized Tomography (HRCT) Scan: Within Normal Limits (Yes or No) at Observation When Baseline HRCT Was Within Normal Limits [Baseline, M12, M24, Ext M6, Ext M18, Ext M36]

    Number of subjects with Yes or No responses (within normal limits at specified time points = Yes or not within normal limits at specified time points = No) at observation when HRCT of thorax was within normal limits at baseline.

17. High Resolution Computerized Tomography (HRCT) Scan: Within Normal Limits (Yes or No) at Observation When Baseline HRCT Was Not Within Normal Limits [Baseline, M12, M24, Ext M6, Ext M18, Ext M36]

    Number of subjects with Yes or No responses (within normal limits at specified time points = Yes or not within normal limits at specified time points = No) at observation when HRCT of thorax was not within normal limits at baseline. "No" response at observation further categorized as no significant change (NSC), more abnormal (> Abn), or less abnormal (< Abn).

18. Insulin Antibodies [Baseline through extension Month 36]

    Observed values for insulin antibodies measured as micro units per milliliter (microU/mL).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 35 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 2 diabetes mellitus

Exclusion Criteria:

• COPD

• Asthma

• Smoking Pregnancy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Phoenix	Arizona	United States	85016
2	Pfizer Investigational Site	Tucson	Arizona	United States	85715
3	Pfizer Investigational Site	Fresno	California	United States	93720
4	Pfizer Investigational Site	Greenbrae	California	United States	94904
5	Pfizer Investigational Site	Los Angeles	California	United States	90073
6	Pfizer Investigational Site	Sacramento	California	United States	95816
7	Pfizer Investigational Site	San Diego	California	United States	92103
8	Pfizer Investigational Site	San Diego	California	United States	92108
9	Pfizer Investigational Site	San Luis Obispo	California	United States	93401
10	Pfizer Investigational Site	Tustin	California	United States	92780
11	Pfizer Investigational Site	Walnut Creek	California	United States	94598
12	Pfizer Investigational Site	Denver	Colorado	United States	80209
13	Pfizer Investigational Site	Hamden	Connecticut	United States	06518
14	Pfizer Investigational Site	Madison	Connecticut	United States	06443
15	Pfizer Investigational Site	New Britain	Connecticut	United States	06050
16	Pfizer Investigational Site	Waterbury	Connecticut	United States	06708
17	Pfizer Investigational Site	Chiefland	Florida	United States	32626
18	Pfizer Investigational Site	Clearwater	Florida	United States	33761
19	Pfizer Investigational Site	Fort Myers	Florida	United States	33901
20	Pfizer Investigational Site	Hollywood	Florida	United States	33021
21	Pfizer Investigational Site	Miami	Florida	United States	33156
22	Pfizer Investigational Site	Ocala	Florida	United States	34471
23	Pfizer Investigational Site	Palm Harbor	Florida	United States	34684
24	Pfizer Investigational Site	Tallahassee	Florida	United States	32308
25	Pfizer Investigational Site	West Palm Beach	Florida	United States	33401
26	Pfizer Investigational Site	Honolulu	Hawaii	United States	96813
27	Pfizer Investigational Site	Honolulu	Hawaii	United States	96814
28	Pfizer Investigational Site	Chicago	Illinois	United States	60602
29	Pfizer Investigational Site	Chicago	Illinois	United States	60607
30	Pfizer Investigational Site	Chicago	Illinois	United States	60610
31	Pfizer Investigational Site	Springfield	Illinois	United States	62704
32	Pfizer Investigational Site	Wilmette	Illinois	United States	60091
33	Pfizer Investigational Site	New Orleans	Louisiana	United States	70112
34	Pfizer Investigational Site	Bethesda	Maryland	United States	20817
35	Pfizer Investigational Site	Boston	Massachusetts	United States	02215
36	Pfizer Investigational Site	Ann Arbor	Michigan	United States	48106
37	Pfizer Investigational Site	Bloomfield Hills	Michigan	United States	48302
38	Pfizer Investigational Site	Plymouth	Michigan	United States	48170
39	Pfizer Investigational Site	Royal Oak	Michigan	United States	48073
40	Pfizer Investigational Site	Southfield	Michigan	United States	48034
41	Pfizer Investigational Site	Chesterfield	Missouri	United States	63017
42	Pfizer Investigational Site	St. Louis	Missouri	United States	63141
43	Pfizer Investigational Site	Butte	Montana	United States	59701
44	Pfizer Investigational Site	Lincoln	Nebraska	United States	68521
45	Pfizer Investigational Site	Henderson	Nevada	United States	89014
46	Pfizer Investigational Site	Albuquerque	New Mexico	United States	87108
47	Pfizer Investigational Site	Albuquerque	New Mexico	United States	87109
48	Pfizer Investigational Site	Mineola	New York	United States	11501
49	Pfizer Investigational Site	New Hyde Park	New York	United States	11042
50	Pfizer Investigational Site	Rochester	New York	United States	14609
51	Pfizer Investigational Site	Durham	North Carolina	United States	27713
52	Pfizer Investigational Site	Winston-Salem	North Carolina	United States	27103
53	Pfizer Investigational Site	Mansfield	Ohio	United States	44903
54	Pfizer Investigational Site	Tulsa	Oklahoma	United States	74104
55	Pfizer Investigational Site	Warwick	Rhode Island	United States	02886
56	Pfizer Investigational Site	Beaumont	Texas	United States	77701
57	Pfizer Investigational Site	Beaumont	Texas	United States	77706
58	Pfizer Investigational Site	Corpus Christi	Texas	United States	78411
59	Pfizer Investigational Site	Corpus Christi	Texas	United States	78412
60	Pfizer Investigational Site	Dallas	Texas	United States	75230
61	Pfizer Investigational Site	Dallas	Texas	United States	75231
62	Pfizer Investigational Site	Dallas	Texas	United States	75246
63	Pfizer Investigational Site	Houston	Texas	United States	77079
64	Pfizer Investigational Site	Irving	Texas	United States	75061
65	Pfizer Investigational Site	San Antonio	Texas	United States	78229
66	Pfizer Investigational Site	Burlington	Vermont	United States	05401
67	Pfizer Investigational Site	Richmond	Virginia	United States	23225
68	Pfizer Investigational Site	Renton	Washington	United States	98055
69	Pfizer Investigational Site	Milwaukee	Wisconsin	United States	53209
70	Pfizer Investigational Site	Porto Alegre	RS	Brazil	90035-170
71	Pfizer Investigational Site	Sao Paulo	SP	Brazil	01244-030
72	Pfizer Investigational Site	Calgary	Alberta	Canada	T2T 5C7
73	Pfizer Investigational Site	Calgary	Alberta	Canada	T3B 0M3
74	Pfizer Investigational Site	Red Deer	Alberta	Canada	T4N 6V7
75	Pfizer Investigational Site	Victoria	British Columbia	Canada	V8R 1J8
76	Pfizer Investigational Site	Winnepeg	Manitoba	Canada	R3A 1R9
77	Pfizer Investigational Site	Winnipeg	Manitoba	Canada	R3E 3P4
78	Pfizer Investigational Site	Halifax	Nova Scotia	Canada	B3H 1V7
79	Pfizer Investigational Site	Halifax	Nova Scotia	Canada	B3H 2Y9
80	Pfizer Investigational Site	London	Ontario	Canada	N6A 4V2
81	Pfizer Investigational Site	Ottawa	Ontario	Canada	K1H 1A2
82	Pfizer Investigational Site	Toronto	Ontario	Canada	M4N-3M5
83	Pfizer Investigational Site	Toronto	Ontario	Canada	M5G 1X5
84	Pfizer Investigational Site	Laval	Quebec	Canada	H7T 2P5
85	Pfizer Investigational Site	Montreal	Quebec	Canada	H1T 2M4
86	Pfizer Investigational Site	Montreal	Quebec	Canada	H3A 1A1
87	Pfizer Investigational Site	Saskatoon	Saskatchewan	Canada	S7N 0W8
88	Pfizer Investigational Site	Aguas Buenas		Puerto Rico	00703
89	Pfizer Investigational Site	Anasco		Puerto Rico	00610
90	Pfizer Investigational Site	Cabo Rojo		Puerto Rico	00623
91	Pfizer Investigational Site	San Juan		Puerto Rico	00909
92	Pfizer Investigational Site	San Juan		Puerto Rico	00921

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: NCT00136916
• Other Study ID Numbers: A2171029
• First Posted: Aug 29, 2005
• Last Update Posted: Feb 18, 2010
• Last Verified: Dec 1, 2009

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

Study Results

Participant Flow

Pre-assignment Detail	At screening visit and during the 4-week run-in phase subjects received subcutaneous insulin regime of 2 to 3 daily doses (QD) of regular insulin-/short-acting insulin analog (lispro or aspart) and 1 or 2 doses QD of intermediate or long-acting insulin (neutral protamine hagedorn [NPH] insulin or Ultralente®) or insulin glargine QD at bedtime.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Period Title: Overall Study
STARTED	319	316
Received Treatment	316	311
COMPLETED	194	212
NOT COMPLETED	125	104

Baseline Characteristics

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin	Total
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.	Total of all reporting groups
Overall Participants	316	311	627
Age, Customized (participants) [Number]
Between 26 and 35 years	2 0.6%	7 2.3%	9 1.4%
Between 36 and 45 years	36 11.4%	49 15.8%	85 13.6%
Between 46 and 55 years	100 31.6%	93 29.9%	193 30.8%
Between 56 and 65 years	117 37%	101 32.5%	218 34.8%
Between 66 and 75 years	61 19.3%	61 19.6%	122 19.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.7 (9.2)	55.5 (9.9)	56.1 (9.6)
Sex: Female, Male (Count of Participants)
Female	111 35.1%	118 37.9%	229 36.5%
Male	205 64.9%	193 62.1%	398 63.5%

Outcome Measures

1. Primary Outcome

Title	Change From Month 3 in Forced Expiratory Volume in 1 Second (FEV1)
Description	Change from Month 3: mean of (value of observed FEV1 [forced expiratory volume in the first second of forced exhalation] in liters [L] at treatment observation minus Month 3 value).
Time Frame	Month 3 through extension Month 60

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) FEV1: received at least 1 dose treatment, had baseline and at least 1 post-baseline FEV1. Due to study termination, originally planned inferential analysis for change from Month 3 through extension Month 60 was not done. Cross reference outcome measure: change from baseline in FEV1.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	0	0

2. Primary Outcome

Title	Change From Baseline in FEV1
Description	Change from baseline: mean of (value of observed FEV1 [L] at treatment observation minus baseline value).
Time Frame	Baseline through extension follow up Month 3

Outcome Measure Data

Analysis Population Description

FAS FEV1; extension Month 36 (M36) Last Observation Carried Forward (LOCF) based on data in the extension phase only; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively. Cross reference outcome measure: change from Month 3 in forced expiratory volume in 1 second.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	311	304
Baseline (n=311, 304)	2.91 (0.68)	2.93 (0.71)
Month 3 (M3) (n=290, 291)	-0.06 (0.13)	-0.01 (0.15)
M6 (n=281, 280)	-0.05 (0.16)	-0.05 (0.17)
M9 (n=266, 276)	-0.08 (0.17)	-0.07 (0.16)
M12 (n=259, 263)	-0.09 (0.17)	-0.07 (0.16)
M15 (n=247, 250)	-0.12 (0.18)	-0.09 (0.17)
M18 (n=237, 236)	-0.12 (0.18)	-0.10 (0.18)
M21 (n=232, 233)	-0.13 (0.18)	-0.11 (0.18)
M24 (n=223, 226)	-0.15 (0.19)	-0.13 (0.18)
Follow-up (FU) M1 (n=249, 221)	-0.14 (0.18)	-0.14 (0.19)
FU M3 (n=248, 231)	-0.13 (0.21)	-0.14 (0.20)
FU M6 (n=242, 220)	-0.12 (0.20)	-0.15 (0.18)
Extension (Ext) M1 (n=161, 163)	-0.16 (0.20)	-0.16 (0.20)
Ext M3 (n=157, 158)	-0.19 (0.21)	-0.16 (0.19)
Ext M6 (n=148, 159)	-0.20 (0.21)	-0.17 (0.20)
Ext M9 (n=144, 157)	-0.19 (0.21)	-0.16 (0.21)
Ext M12 (n=144, 157)	-0.20 (0.21)	-0.18 (0.22)
Ext M15 (n=141, 145)	-0.22 (0.23)	-0.21 (0.20)
Ext M18 (n=135, 139)	-0.22 (0.23)	-0.21 (0.22)
Ext M21 (n=132, 143)	-0.23 (0.24)	-0.21 (0.21)
Ext M24 (n=125, 131)	-0.24 (0.24)	-0.23 (0.22)
Ext M27 (n=124, 125)	-0.25 (0.23)	-0.24 (0.22)
Ext M30 (n=125, 126)	-0.24 (0.22)	-0.23 (0.23)
Ext M33 (n=98, 113)	-0.24 (0.24)	-0.24 (0.22)
Ext M36 (n=54, 60)	-0.25 (0.18)	-0.28 (0.17)
Ext M36 [LOCF] (n=171, 169)	-0.24 (0.24)	-0.24 (0.21)
Ext FU M3 (n=119, 115)	-0.24 (0.21)	-0.25 (0.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M3
	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	-0.045
	Confidence Interval	() 90%; -0.064 to -0.026
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.011
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline pulmonary function tests (PFTs), center, age, sex, and height.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M6
	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	-0.003
	Confidence Interval	() 90%; -0.025 to 0.020
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.014
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M9
	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	-0.010
	Confidence Interval	() 90%; -0.033 to 0.013
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.014
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline pulmonary function tests (PFTs), center, age, sex, and height.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M12
	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	-0.020
	Confidence Interval	() 90%; -0.044 to 0.004
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.014
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M15
	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	-0.023
	Confidence Interval	() 90%; -0.048 to 0.003
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.015
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline pulmonary function tests (PFTs), center, age, sex, and height.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M18
	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	-0.023
	Confidence Interval	() 90%; -0.050 to 0.004
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.016
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline pulmonary function tests (PFTs), center, age, sex, and height.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M21
	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	-0.020
	Confidence Interval	() 90%; -0.047 to 0.007
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline pulmonary function tests (PFTs), center, age, sex, and height.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M24
	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	-0.026
	Confidence Interval	() 90%; -0.054 to 0.002
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	FU M1
	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	0.007
	Confidence Interval	() 90%; -0.021 to 0.034
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	FU M3
	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	0.014
	Confidence Interval	() 90%; -0.016 to 0.044
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.018
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	FU M6
	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	0.027
	Confidence Interval	() 90%; -0.002 to 0.055
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.017
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M1
	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	-0.004
	Confidence Interval	() 90%; -0.040 to 0.032
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.022
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M3
	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	-0.033
	Confidence Interval	() 90%; -0.070 to 0.004
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.023
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M6
	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	-0.039
	Confidence Interval	() 90%; -0.077 to -0.002
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.023
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M9
	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	-0.036
	Confidence Interval	() 90%; -0.075 to 0.003
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline pulmonary function tests (PFTs), center, age, sex, and height.

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M12
	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	-0.018
	Confidence Interval	() 90%; -0.058 to 0.022
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.024
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M15
	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	0.007
	Confidence Interval	() 90%; -0.034 to 0.048
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.025
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline pulmonary function tests (PFTs), center, age, sex, and height.

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M18
	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	-0.011
	Confidence Interval	() 90%; -0.055 to 0.033
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M21
	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	-0.015
	Confidence Interval	() 90%; -0.058 to 0.029
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline pulmonary function tests (PFTs), center, age, sex, and height.

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M24
	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	-0.015
	Confidence Interval	() 90%; -0.061 to 0.030
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.028
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M27
	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	-0.000
	Confidence Interval	() 90%; -0.044 to 0.043
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline pulmonary function tests (PFTs), center, age, sex, and height.

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M30
	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	-0.005
	Confidence Interval	() 90%; -0.051 to 0.040
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M33
	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	0.008
	Confidence Interval	() 90%; -0.042 to 0.058
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.030
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline pulmonary function tests (PFTs), center, age, sex, and height.

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M36
	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	0.024
	Confidence Interval	() 90%; -0.030 to 0.077
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.032
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M36 LOCF
	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	-0.003
	Confidence Interval	() 90%; -0.042 to 0.035
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.023
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height. Ext M36 (LOCF) based on data in the extension phase only.

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext FU M3
	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	0.019
	Confidence Interval	() 90%; -0.023 to 0.062
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.026
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

3. Primary Outcome

Title	Annual Rate of Change in FEV1
Description	Annual rate of change in FEV1 calculated as slope over time [visit] for forced expiratory volume in 1 second measured as liters per year (L/yr).
Time Frame	Week -2 through extension follow up Month 3 or end of study

Outcome Measure Data

Analysis Population Description

FAS FEV1. Due to early termination of study a limited set of analyses were undertaken and results of Annual rate of change in FEV1 were not summarized as planned.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	0	0

4. Primary Outcome

Title	Summary of ≥ 15 % Decliners in FEV1
Description	Number of subjects with a post-baseline FEV1 decrease of ≥ 15 % [(baseline observed value - visit observed value)/(baseline observed value) * 100]; in the absence of an obvious intercurrrent illness, a repeat FEV1 was performed.
Time Frame	Month 3 through extension follow up Month 3

Outcome Measure Data

Analysis Population Description

FAS FEV1; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	311	304
M3 (n=290, 291)	2 0.6%	2 0.6%
M6 (n=281, 280)	3 0.9%	4 1.3%
M9 (n=266, 276)	7 2.2%	5 1.6%
M12 (n=259, 263)	7 2.2%	4 1.3%
M15 (n=247, 250)	13 4.1%	6 1.9%
M18 (n=237, 236)	10 3.2%	8 2.6%
M21 (n=232, 233)	12 3.8%	8 2.6%
M24 (n=223, 226)	14 4.4%	13 4.2%
FU M1 (n=249, 221)	11 3.5%	7 2.3%
FU M3 (n=248, 231)	16 5.1%	15 4.8%
FU M6 (n=242, 220)	13 4.1%	11 3.5%
Ext M1 (n=161, 163)	12 3.8%	6 1.9%
Ext M3 (n=157, 158)	12 3.8%	5 1.6%
Ext M6 (n=148, 159)	14 4.4%	8 2.6%
Ext M9 (n=144, 157)	11 3.5%	10 3.2%
Ext M12 (n=144, 157)	19 6%	13 4.2%
Ext M15 (n=141, 145)	15 4.7%	11 3.5%
Ext M18 (n=135, 139)	17 5.4%	18 5.8%
Ext M21 (n=132, 143)	22 7%	11 3.5%
Ext M24 (n=125, 131)	22 7%	16 5.1%
Ext M27 (n=124, 125)	18 5.7%	14 4.5%
Ext M30 (n=125, 126)	20 6.3%	18 5.8%
Ext M33 (n=98, 113)	10 3.2%	12 3.9%
Ext M36 (n=54, 60)	5 1.6%	6 1.9%
Ext FU M3 (n=119, 115)	14 4.4%	19 6.1%

5. Primary Outcome

Title	Annual Rate of Change in Carbon Monoxide Diffusion Capacity (DLco)
Description	Annual rate of change in DLco calculated as slope over time (visit) measured as milliliters per minute per millimeters of mercury per year (ml/min/mmHg/yr).
Time Frame	Week -2 through extension follow up Month 3 or end of study

Outcome Measure Data

Analysis Population Description

FAS FEV1. Due to early termination of study a limited set of analyses were undertaken and results of Annual rate of change in DLco were not summarized as planned. Cross reference outcome measure: change from baseline in Carbon Monoxide Diffusion Capacity (DLco).

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	0	0

6. Secondary Outcome

Title	Forced Vital Capacity (FVC)
Description	Forced Vital Capacity (FVC) measured in liters (L).
Time Frame	Week -3 through extension follow up Month 3 or end of study

Outcome Measure Data

Analysis Population Description

FAS FEV1. Due to early termination of study a limited set of analyses were undertaken and results of FVC were not summarized as planned.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	0	0

7. Secondary Outcome

Title	Total Lung Capacity (TLC)
Description	Total Lung Capacity measured in liters (L).
Time Frame	Baseline through extension follow up Month 3

Outcome Measure Data

Analysis Population Description

FAS FEV1. Due to early termination of study a limited set of analyses were undertaken and results of TLC were not summarized as planned.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	0	0

8. Secondary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (HbA1c)
Description	Change from baseline: mean of (value of observed HbA1c [%] at treatment observation minus baseline value).
Time Frame	Baseline through extension follow up Month 3

Outcome Measure Data

Analysis Population Description

FAS HbA1c: received at least 1 dose of study treatment, had baseline HbA1c and at least 1 post-baseline HbA1c; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	315	303
Baseline (n=315, 303)	7.66 (1.12)	7.77 (1.12)
Week 6 (W6) (n=291, 280)	-0.64 (0.67)	-0.60 (0.70)
M3 (n=296, 291)	-0.80 (0.86)	-0.73 (0.89)
M6 (n=284, 287)	-0.67 (0.94)	-0.68 (1.00)
M9 (n=270, 280)	-0.56 (0.98)	-0.61 (0.93)
M12 (n=261, 263)	-0.45 (0.94)	-0.58 (1.00)
M15(n=252, 258)	-0.43 (1.00)	-0.51 (1.00)
M18(n=244, 241)	-0.42 (1.02)	-0.53 (1.06)
M21 (n=236, 238)	-0.43 (1.04)	-0.52 (1.02)
M24 (n=226, 234)	-0.35 (1.09)	-0.48 (1.13)
FU M3 (n=225, 226)	-0.41 (1.04)	-0.44 (1.06)
FU M6 (n=230, 230)	-0.27 (1.12)	-0.31 (1.06)
Ext M1 (n=167, 162)	-0.41 (1.16)	-0.40 (1.05)
Ext M3 (n=164, 162)	-0.33 (1.19)	-0.42 (1.05)
Ext M6 (n=157, 163)	-0.26 (1.11)	-0.40 (1.10)
Ext M9 (n=152, 157)	-0.11 (1.15)	-0.26 (1.13)
Ext M12 (n=150, 157)	-0.08 (1.19)	-0.17 (1.16)
Ext M15(n=146, 151)	-0.17 (1.30)	-0.25 (1.15)
Ext M18 (n=145, 145)	-0.20 (1.19)	-0.29 (1.17)
Ext M21(n=137, 147)	-0.13 (1.16)	-0.20 (1.20)
Ext M24 (n=131, 137)	-0.18 (1.21)	-0.23 (1.11)
Ext M27(n=129, 132)	-0.18 (1.13)	-0.28 (1.20)
Ext M30 (n=129, 129)	-0.20 (1.19)	-0.30 (1.19)
Ext M33(n=104, 116)	8.54 (88.44)	-0.18 (1.17)
Ext M36 (n=55, 64)	-0.20 (1.15)	-0.30 (1.18)
Ext FU M3 (n=117, 116)	-0.11 (1.40)	-0.17 (1.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M3
	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	-0.119
	Confidence Interval	() 90%; -0.215 to -0.023
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.058
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M6
	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	-0.023
	Confidence Interval	() 90%; -0.133 to 0.087
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.067
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M9
	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	0.010
	Confidence Interval	() 90%; -0.104 to 0.124
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.069
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M12
	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	0.091
	Confidence Interval	() 90%; -0.033 to 0.214
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.075
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M15
	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	0.052
	Confidence Interval	() 90%; -0.081 to 0.185
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.081
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M18
	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	0.090
	Confidence Interval	() 90%; -0.054 to 0.234
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.087
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M21
	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	0.068
	Confidence Interval	() 90%; -0.073 to 0.208
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.085
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M24
	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	0.100
	Confidence Interval	() 90%; -0.058 to 0.257
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.096
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	FU M3
	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	0.006
	Confidence Interval	() 90%; -0.143 to 0.154
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.090
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	FU M6
	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	0.036
	Confidence Interval	() 90%; -0.119 to 0.190
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.094
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M1
	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	-0.019
	Confidence Interval	() 90%; -0.200 to 0.161
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.110
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M3
	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	0.081
	Confidence Interval	() 90%; -0.101 to 0.263
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.110
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M6
	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	0.141
	Confidence Interval	() 90%; -0.038 to 0.320
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.108
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M9
	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	0.150
	Confidence Interval	() 90%; -0.041 to 0.342
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.116
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M12
	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	0.104
	Confidence Interval	() 90%; -0.090 to 0.298
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.118
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M15
	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	0.074
	Confidence Interval	() 90%; -0.132 to 0.279
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.125
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M18
	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	0.087
	Confidence Interval	() 90%; -0.111 to 0.284
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.120
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M21
	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	0.064
	Confidence Interval	() 90%; -0.141 to 0.270
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.124
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M24
	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	0.047
	Confidence Interval	() 90%; -0.156 to 0.249
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.123
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M27
	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	0.067
	Confidence Interval	() 90%; -0.138 to 0.272
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.124
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M30
	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	0.046
	Confidence Interval	() 90%; -0.171 to 0.264
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.132
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M33
	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	9.824
	Confidence Interval	() 90%; -3.920 to 23.569
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.319
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M36
	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	0.011
	Confidence Interval	() 90%; -0.316 to 0.337
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.197
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext FU M3
	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	0.024
	Confidence Interval	() 90%; -0.245 to 0.292
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.163
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline HbA1c, and center.

9. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG)
Description	Change from baseline: mean of (value of observed FPG [milligrams per deciliter (mg/dL)] at treatment observation minus baseline value).
Time Frame	Baseline through extension follow up Month 3

Outcome Measure Data

Analysis Population Description

FAS HbA1c; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	315	303
Baseline (n=315, 303)	158.13 (42.71)	154.53 (41.51)
W6 (n=282, 276)	-23.36 (51.69)	-12.55 (50.46)
M3 (n=294, 290)	-26.38 (52.72)	-12.77 (54.93)
M6 (n=281, 285)	-25.21 (53.48)	-9.05 (68.42)
M9 (n=267, 279)	-26.68 (54.95)	-10.41 (56.42)
M12 (n=260, 263)	-20.55 (59.68)	-7.60 (60.03)
M15(n=253, 255)	-21.37 (54.53)	-8.82 (55.57)
M18(n=242, 238)	-24.52 (54.50)	-7.69 (58.47)
M21(n=232, 237)	-25.95 (53.06)	-13.14 (54.66)
M24 (n=226, 232)	-24.02 (54.45)	-8.91 (65.24)
FU M3 (n=5, 4)	-22.60 (44.65)	-4.08 (32.08)
FU M6 (n=161, 156)	-2.85 (66.18)	-1.56 (71.72)
Ext M1 (n=165, 162)	-17.91 (60.96)	-7.34 (60.98)
Ext M3 (n=162, 159)	-18.16 (66.59)	-9.29 (62.50)
Ext M6 (n=152, 161)	-15.65 (67.18)	-4.34 (61.96)
Ext M9 (n=149, 155)	-13.99 (61.68)	-6.06 (60.86)
Ext M12 (n=148, 155)	-12.53 (72.25)	-4.98 (62.92)
Ext M15(n=143, 143)	-6.88 (68.85)	-4.23 (65.21)
Ext M18 (n=136, 138)	-17.23 (65.97)	-10.32 (63.11)
Ext M21(n=132, 144)	-12.86 (63.98)	-6.53 (64.09)
Ext M24 (n=129, 136)	-14.45 (61.65)	-3.47 (68.57)
Ext M27 (n=128, 129)	-21.68 (58.35)	-3.76 (63.31)
Ext M30 (n=127, 130)	-11.80 (62.82)	-6.40 (61.47)
Ext M33(n=103, 115)	-16.26 (63.44)	-7.35 (66.21)
Ext M36 (n=55, 64)	-28.61 (65.99)	-13.35 (53.97)
Ext FU M3 (n=115, 118)	-2.87 (81.19)	1.88 (64.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M3
	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	-12.39
	Confidence Interval	() 90%; -19.07 to -5.710
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.054
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M6
	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	-14.21
	Confidence Interval	() 90%; -22.11 to -6.312
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.795
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M12
	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	-10.96
	Confidence Interval	() 90%; -19.07 to -2.852
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.920
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M24
	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	-12.56
	Confidence Interval	() 90%; -20.89 to -4.232
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.052
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	FU M3
	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	-16.83
	Confidence Interval	() 90%; -80.69 to 47.019
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.867
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	FU M6
	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	2.578
	Confidence Interval	() 90%; -9.257 to 14.412
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.173
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M1
	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	-9.460
	Confidence Interval	() 90%; -19.37 to 0.450
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.007
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M3
	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	-9.481
	Confidence Interval	() 90%; -20.11 to 1.153
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.446
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M6
	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	-10.76
	Confidence Interval	() 90%; -21.95 to 0.438
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.785
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M9
	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	-6.827
	Confidence Interval	() 90%; -16.98 to 3.328
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.154
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M12
	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	-7.287
	Confidence Interval	() 90%; -19.15 to 4.579
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.192
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M15
	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	-1.848
	Confidence Interval	() 90%; -13.76 to 10.066
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.219
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M18
	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	-9.022
	Confidence Interval	() 90%; -20.83 to 2.790
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.156
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M21
	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	-7.078
	Confidence Interval	() 90%; -18.99 to 4.834
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.217
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M24
	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	-12.53
	Confidence Interval	() 90%; -24.63 to -0.429
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.329
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M27
	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	-19.07
	Confidence Interval	() 90%; -30.45 to -7.685
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 6.895
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M30
	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	-3.220
	Confidence Interval	() 90%; -15.15 to 8.705
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.223
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M33
	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	-8.490
	Confidence Interval	() 90%; -21.09 to 4.107
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.625
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M36
	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	-21.88
	Confidence Interval	() 90%; -36.66 to -7.105
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.906
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext FU M3
	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	-4.673
	Confidence Interval	() 90%; -19.16 to 9.812
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.770
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline fasting plasma glucose, and center.

10. Secondary Outcome

Title	Change From Baseline in Body Weight
Description	Change from baseline: mean of (value of observed body weight [kilograms (kg)] at treatment observation minus baseline value).
Time Frame	Baseline through extension follow up Month 3

Outcome Measure Data

Analysis Population Description

FAS HbA1c; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	314	302
Baseline (n=314, 302)	87.18 (14.75)	88.31 (15.50)
W4 (n=280, 270)	0.63 (2.11)	0.83 (1.86)
W8 (n=289, 281)	1.07 (2.41)	1.00 (2.31)
M3 (n=288, 290)	1.08 (2.75)	1.13 (2.55)
W18(n=280, 285)	1.33 (3.13)	1.76 (3.03)
M6 (n=276, 277)	1.15 (3.59)	1.89 (3.53)
M9 (n=269, 274)	1.50 (3.95)	2.15 (3.90)
M12 (n=259, 264)	1.75 (4.29)	2.37 (4.34)
M15(n=247, 249)	1.88 (4.33)	2.62 (4.49)
M18(n=237, 235)	1.79 (4.53)	2.93 (4.85)
M21(n=232, 232)	1.99 (4.56)	3.04 (5.04)
M24 (n=223, 226)	2.04 (4.86)	3.36 (5.16)
FU M3 (n=249, 231)	2.32 (5.25)	3.63 (5.34)
FU M6 (n=243, 218)	2.38 (5.34)	4.09 (7.70)
Ext M1 (n=161, 162)	2.87 (5.48)	3.75 (5.58)
Ext M3 (n=157, 157)	2.83 (4.78)	4.14 (5.69)
Ext M6 (n=148, 159)	3.15 (5.70)	4.01 (6.07)
Ext M9 (n=144, 156)	2.95 (5.95)	3.89 (5.87)
Ext M12 (n=144, 156)	2.96 (6.00)	4.19 (6.12)
Ext M15 (n=142, 145)	3.12 (5.91)	4.54 (6.26)
Ext M18 (n=135, 139)	3.33 (9.20)	4.46 (6.12)
Ext M21(n=132, 143)	2.79 (6.90)	5.01 (8.37)
Ext M24 (n=126, 131)	2.94 (6.98)	4.57 (6.37)
Ext M27(n=125, 125)	2.99 (6.94)	5.58 (9.62)
Ext M30 (n=125, 126)	3.39 (6.43)	4.78 (6.96)
Ext M33(n=99, 113)	2.77 (6.33)	5.22 (7.21)
Ext M36 (n=54, 60)	2.48 (6.61)	5.28 (7.09)
Ext FU M3 (n=119, 115)	2.74 (6.90)	4.44 (6.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M3
	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	-0.059
	Confidence Interval	() 90%; -0.416 to 0.299
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.217
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M6
	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	-0.735
	Confidence Interval	() 90%; -1.224 to -0.246
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.297
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M12
	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	-0.642
	Confidence Interval	() 90%; -1.251 to -0.032
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.370
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M24
	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	-1.355
	Confidence Interval	() 90%; -2.120 to -0.589
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.464
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	FU M3
	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	-1.303
	Confidence Interval	() 90%; -2.086 to -0.520
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.475
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	FU M6
	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	-1.557
	Confidence Interval	() 90%; -2.539 to -0.575
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.596
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M1
	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	-0.904
	Confidence Interval	() 90%; -1.898 to 0.090
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.603
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M3
	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	-1.280
	Confidence Interval	() 90%; -2.225 to -0.334
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.573
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M6
	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	-0.834
	Confidence Interval	() 90%; -1.909 to 0.241
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.652
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M9
	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	-1.001
	Confidence Interval	() 90%; -2.080 to 0.078
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.654
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M12
	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	-1.316
	Confidence Interval	() 90%; -2.431 to -0.200
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.676
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M15
	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	-1.512
	Confidence Interval	() 90%; -2.661 to -0.363
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.696
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M18
	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	-1.313
	Confidence Interval	() 90%; -2.824 to 0.198
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.916
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M21
	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	-2.399
	Confidence Interval	() 90%; -3.891 to -0.907
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.904
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M24
	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	-1.566
	Confidence Interval	() 90%; -2.867 to -0.265
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.788
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M27
	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	-2.720
	Confidence Interval	() 90%; -4.439 to -1.001
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.041
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M30
	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	-1.401
	Confidence Interval	() 90%; -2.755 to -0.047
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.820
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M33
	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	-2.281
	Confidence Interval	() 90%; -3.781 to -0.782
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.908
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M36
	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	-2.766
	Confidence Interval	() 90%; -4.932 to -0.599
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.305
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext FU M3
	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	-1.637
	Confidence Interval	() 90%; -3.120 to -0.153
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.898
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline weight, and center.

11. Secondary Outcome

Title	Total Daily Long-acting Insulin Dose (Unadjusted for Body Weight)
Description	Total daily long-acting insulin dose unadjusted for body weight. Long-acting (units) insulin for inhaled insulin and subcutaneous treatment groups included NPH insulin, Ultralente®, and insulin glargine.
Time Frame	Month 3 through extension Month 36

Outcome Measure Data

Analysis Population Description

FAS HbA1c; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	315	303
M3 (n=301, 298)	44.10 (25.60)	47.98 (25.06)
M6 (n=289, 291)	44.03 (26.27)	47.31 (25.47)
M9 (n=275, 284)	43.64 (26.17)	48.11 (26.02)
M12 (n=266, 270)	44.62 (27.43)	48.01 (26.02)
M15 (n=258, 260)	45.02 (27.76)	48.37 (26.48)
M18 (n=243, 242)	46.07 (27.77)	48.93 (27.60)
M21 (n=240, 240)	46.67 (29.06)	49.84 (28.73)
M24 (n=229, 237)	46.62 (28.55)	50.34 (29.31)
Ext M1 (n=167, 164)	45.29 (28.00)	51.29 (28.45)
Ext M3 (n=165, 162)	45.76 (28.61)	51.62 (28.71)
Ext M6 (n=159, 164)	45.89 (28.61)	52.18 (28.85)
Ext M9 (n=156, 158)	46.51 (29.34)	52.32 (28.89)
Ext M12 (n=151, 158)	46.52 (29.84)	51.72 (29.06)
Ext M15 (n=148, 149)	46.39 (30.12)	52.92 (29.83)
Ext M18 (n=145, 145)	46.31 (31.17)	52.37 (29.78)
Ext M21 (n=137, 148)	46.49 (31.17)	52.68 (29.40)
Ext M24 (n=131, 137)	47.21 (32.42)	52.18 (30.33)
Ext M27 (n=132, 133)	48.13 (32.76)	52.42 (29.87)
Ext M30 (n=131, 130)	48.13 (33.41)	53.22 (29.85)
Ext M33 (n=104, 116)	48.38 (32.47)	51.93 (30.65)
Ext M36 (n=56, 65)	46.42 (31.91)	53.47 (28.96)

12. Secondary Outcome

Title	Total Daily Long-acting Insulin (Adjusted for Body Weight)
Description	Total daily dose of long-acting insulin adjusted for body weight (units per kilogram [kg]). Long-acting (units) insulin for inhaled insulin and subcutaneous treatment groups included NPH insulin, Ultralente®, and insulin glargine.
Time Frame	Month 3 through extension Month 36

Outcome Measure Data

Analysis Population Description

FAS HbA1c; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	315	303
M3 (n=301, 298)	0.51 (0.29)	0.54 (0.27)
M6 (n=289, 291)	0.50 (0.29)	0.54 (0.28)
M9 (n=275, 284)	0.50 (0.29)	0.55 (0.29)
M12 (n=266, 270)	0.51 (0.30)	0.55 (0.29)
M15 (n=258, 260)	0.52 (0.31)	0.56 (0.30)
M18 (n=243, 242)	0.53 (0.31)	0.57 (0.31)
M21 (n=240, 240)	0.53 (0.32)	0.57 (0.32)
M24 (n=229, 237)	0.54 (0.32)	0.58 (0.32)
Ext M1 (n=167, 164)	0.53 (0.33)	0.59 (0.31)
Ext M3 (n=165, 162)	0.53 (0.34)	0.59 (0.31)
Ext M6 (n=159, 164)	0.54 (0.34)	0.60 (0.31)
Ext M9 (n=156, 158)	0.54 (0.35)	0.60 (0.31)
Ext M12 (n=151, 158)	0.54 (0.36)	0.60 (0.32)
Ext M15 (n=148, 149)	0.54 (0.36)	0.61 (0.32)
Ext M18 (n=145, 145)	0.54 (0.37)	0.61 (0.32)
Ext M21 (n=137, 148)	0.54 (0.37)	0.61 (0.32)
Ext M24 (n=131, 137)	0.55 (0.39)	0.61 (0.34)
Ext M27 (n=132, 133)	0.56 (0.39)	0.61 (0.33)
Ext M30 (n=131, 130)	0.56 (0.41)	0.62 (0.33)
Ext M33 (n=104, 116)	0.56 (0.37)	0.61 (0.34)
Ext M36 (n=56, 65)	0.53 (0.37)	0.61 (0.31)

13. Secondary Outcome

Title	Total Daily Short-acting Insulin Dose (Unadjusted for Body Weight)
Description	Total daily dose of short-acting insulin unadjusted for body weight. Short-acting insulin (milligrams [mg]) for the inhaled insulin treatment group was inhaled insulin; short-acting insulin (units) for the subcutaneous insulin treatment group included insulin lispro, insulin aspart, and regular insulin.
Time Frame	Month 3 through extension Month 36

Outcome Measure Data

Analysis Population Description

FAS HbA1c; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively.

Arm/Group Title	Inhaled Insulin (Exubera®) (mg)	Subcutaneous Insulin (Units)
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	315	303
M3 (n=302, 299)	12.66 (6.80)	31.15 (18.75)
M6 (n=290, 292)	13.18 (6.90)	31.73 (19.08)
M9 (n=275, 285)	13.57 (7.57)	31.58 (18.89)
M12 (n=266, 270)	14.40 (7.90)	31.94 (19.29)
M15 (n=258, 261)	14.70 (8.06)	31.88 (19.37)
M18 (n=245, 242)	14.91 (8.41)	32.79 (20.70)
M21 (n=240, 242)	15.09 (8.55)	33.18 (20.92)
M24 (n=229, 238)	15.43 (8.65)	34.04 (21.84)
Ext M1 (n=167, 164)	13.89 (8.47)	34.52 (24.52)
Ext M3 (n=165, 163)	14.62 (9.18)	35.29 (23.19)
Ext M6 (n=159, 165)	14.62 (9.16)	35.43 (24.80)
Ext M9 (n=156, 161)	14.82 (9.10)	35.68 (24.72)
Ext M12 (n=151, 160)	15.42 (9.81)	36.56 (26.34)
Ext M15 (n=148, 151)	15.48 (9.90)	36.27 (25.51)
Ext M18 (n=145, 146)	15.57 (9.93)	37.37 (26.29)
Ext M21 (n=138, 149)	15.94 (10.41)	36.80 (27.09)
Ext M24 (n=131, 138)	15.46 (9.70)	38.51 (29.06)
Ext M27 (n=132, 134)	16.25 (10.30)	38.54 (28.13)
Ext M30 (n=131, 131)	16.56 (10.63)	39.01 (28.66)
Ext M33 (n=105, 117)	16.51 (10.43)	40.33 (30.81)
Ext M36 (n=56, 66)	17.25 (11.30)	42.34 (28.72)

14. Secondary Outcome

Title	Total Daily Short-acting Insulin Dose (Adjusted for Body Weight)
Description	Total daily dose of short-acting insulin adjusted for body weight. Short-acting insulin (mg) for the inhaled insulin treatment group was inhaled insulin (mg divided by kg); short-acting insulin (units) for the subcutaneous insulin treatment group included insulin lispro, insulin aspart, and regular insulin (units divided by kg).
Time Frame	Month 3 through extension Month 36

Outcome Measure Data

Analysis Population Description

FAS HbA1c; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively.

Arm/Group Title	Inhaled Insulin (Exubera®) (mg)	Subcutaneous Insulin (Units)
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	315	303
M3 (n=302, 299)	0.15 (0.07)	0.36 (0.22)
M6 (n=290, 292)	0.15 (0.08)	0.36 (0.22)
M9 (n=275, 285)	0.16 (0.08)	0.36 (0.22)
M12 (n=266, 270)	0.17 (0.09)	0.37 (0.23)
M15 (n=258, 261)	0.17 (0.09)	0.37 (0.24)
M18 (n=245, 242)	0.17 (0.09)	0.38 (0.25)
M21 (n=240, 242)	0.17 (0.09)	0.39 (0.26)
M24 (n=229, 238)	0.18 (0.10)	0.40 (0.27)
Ext M1 (n=167, 164)	0.16 (0.09)	0.40 (0.30)
Ext M3 (n=165, 163)	0.17 (0.10)	0.41 (0.26)
Ext M6 (n=159, 165)	0.17 (0.10)	0.41 (0.30)
Ext M9 (n=156, 161)	0.17 (0.10)	0.42 (0.30)
Ext M12 (n=151, 160)	0.18 (0.11)	0.43 (0.32)
Ext M15 (n=148, 151)	0.18 (0.11)	0.42 (0.31)
Ext M18 (n=145, 146)	0.18 (0.11)	0.44 (0.32)
Ext M21 (n=138, 149)	0.18 (0.11)	0.43 (0.33)
Ext M24 (n=131, 138)	0.18 (0.10)	0.45 (0.35)
Ext M27 (n=132, 134)	0.19 (0.11)	0.45 (0.34)
Ext M30 (n=131, 131)	0.19 (0.12)	0.46 (0.34)
Ext M33 (n=105, 117)	0.19 (0.11)	0.47 (0.36)
Ext M36 (n=56, 66)	0.19 (0.12)	0.48 (0.31)

15. Secondary Outcome

Title	Lipid Panel: Total Cholesterol, High Density Lipoprotein, Low Density Lipoprotein, and Triglycerides
Description	Lipid values for total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides measured as milligrams per deciliter (mg/dL).
Time Frame	Week -4 through Month 24

Outcome Measure Data

Analysis Population Description

FAS: received at least 1 dose of study treatment. Due to early termination of study a limited set of analyses were undertaken and results of Lipids were not summarized as planned.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	0	0

16. Primary Outcome

Title	Change From Baseline in Carbon Monoxide Diffusion Capacity (DLco)
Description	Change from baseline: mean of (value of observed DLco [milliliters per minute per millimeters of mercury (ml/min/mmHg)] at treatment observation minus baseline value).
Time Frame	Baseline through extension follow up Month 3

Outcome Measure Data

Analysis Population Description

FAS FEV1; extension M36 LOCF based on data in the extension phase only; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively. Cross reference outcome measure Annual rate of change in Carbon Monoxide Diffusion Capacity (DLco).

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	308	303
Baseline (n=308, 303)	24.13 (5.54)	23.97 (5.72)
M3 (n=289, 290)	-0.57 (1.60)	-0.32 (1.62)
M6 (n=278, 280)	-0.56 (1.62)	-0.44 (1.73)
M9 (n=266, 272)	-0.67 (1.78)	-0.72 (1.77)
M12 (n=258, 263)	-0.72 (1.86)	-0.41 (1.87)
M15 (n=246, 248)	-0.81 (1.83)	-0.56 (1.96)
M18 (n=237, 232)	-0.86 (1.95)	-0.65 (1.92)
M21 (n=231, 231)	-0.89 (1.98)	-0.67 (1.92)
M24 (n=221, 223)	-0.74 (2.10)	-0.81 (2.06)
FU M1 (n=247, 220)	-0.46 (2.05)	-1.02 (2.01)
FU M3 (n=247, 231)	-0.58 (2.07)	-0.90 (2.15)
FU M6 (n=241, 219)	-0.64 (2.15)	-0.95 (2.11)
Ext M1 (n=159, 161)	-1.01 (2.08)	-1.09 (2.15)
Ext M3 (n=157, 157)	-1.07 (2.10)	-1.16 (2.45)
Ext M6 (n=148, 157)	-1.48 (1.87)	-1.26 (2.38)
Ext M9 (n=143, 155)	-1.15 (2.31)	-1.36 (2.54)
Ext M12 (n=141, 155)	-1.49 (2.22)	-1.59 (2.38)
Ext M15 (n=141, 142)	-1.49 (2.25)	-1.46 (2.41)
Ext M18 (n=132, 138)	-1.54 (2.25)	-1.63 (2.21)
Ext M21 (n=129, 142)	-1.33 (2.45)	-1.64 (2.45)
Ext M24 (n=124, 130)	-1.39 (2.27)	-1.46 (2.43)
Ext M27 (n=123, 124)	-1.35 (2.48)	-1.44 (2.41)
Ext M30 (n=124, 125)	-1.75 (2.13)	-1.62 (2.55)
Ext M33 (n=98, 113)	-1.47 (2.05)	-1.61 (2.25)
Ext M36 (n=52, 60)	-1.22 (2.16)	-1.87 (2.23)
Ext M36 [LOCF] (n=171, 169)	-1.39 (2.31)	-1.77 (2.46)
Ext FU M3 (n=118, 114)	-1.12 (2.15)	-1.69 (2.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M3
	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	-0.251
	Confidence Interval	() 90%; -0.466 to -0.037
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.130
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M6
	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	-0.095
	Confidence Interval	() 90%; -0.323 to 0.134
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.139
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M9
	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	0.084
	Confidence Interval	() 90%; -0.158 to 0.325
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.146
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M12
	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	-0.266
	Confidence Interval	() 90%; -0.524 to -0.009
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.156
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M15
	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	-0.181
	Confidence Interval	() 90%; -0.453 to 0.091
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.165
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M18
	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	-0.141
	Confidence Interval	() 90%; -0.427 to 0.145
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.173
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M21
	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	-0.155
	Confidence Interval	() 90%; -0.445 to 0.134
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.176
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	M24
	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	0.119
	Confidence Interval	() 90%; -0.193 to 0.431
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.189
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	FU M1
	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	0.617
	Confidence Interval	() 90%; 0.322 to 0.911
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.179
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	FU M3
	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	0.354
	Confidence Interval	() 90%; 0.051 to 0.657
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.184
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	FU M6
	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	0.318
	Confidence Interval	() 90%; 0.011 to 0.626
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.186
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M1
	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	0.136
	Confidence Interval	() 90%; -0.227 to 0.500
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.220
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M3
	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	0.098
	Confidence Interval	() 90%; -0.289 to 0.485
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.235
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M6
	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	-0.202
	Confidence Interval	() 90%; -0.576 to 0.172
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.226
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M9
	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	0.245
	Confidence Interval	() 90%; -0.180 to 0.669
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.257
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M12
	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	0.126
	Confidence Interval	() 90%; -0.284 to 0.535
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.248
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M15
	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	0.023
	Confidence Interval	() 90%; -0.395 to 0.441
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.253
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M18
	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	0.146
	Confidence Interval	() 90%; -0.262 to 0.554
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.247
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M21
	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	0.321
	Confidence Interval	() 90%; -0.138 to 0.780
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.278
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M24
	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	0.043
	Confidence Interval	() 90%; -0.419 to 0.506
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.280
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M27
	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	0.190
	Confidence Interval	() 90%; -0.279 to 0.659
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.284
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M30
	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	-0.117
	Confidence Interval	() 90%; -0.579 to 0.346
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.280
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M33
	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	0.262
	Confidence Interval	() 90%; -0.189 to 0.714
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.273
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M36
	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	0.267
	Confidence Interval	() 90%; -0.370 to 0.904
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.383
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext M36 LOCF
	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	0.399
	Confidence Interval	() 90%; -0.003 to 0.802
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.244
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height. Ext M36 (LOCF) based on data in the extension phase only.

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Inhaled Insulin (Exubera®), Subcutaneous Insulin
	Comments	Ext FU M3
	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	0.619
	Confidence Interval	() 90%; 0.137 to 1.102
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.292
	Estimation Comments	Adjusted Primary Analysis Model includes terms of treatment, baseline PFTs, center, age, sex, and height.

17. Primary Outcome

Title	Summary of ≥ 20 % Decliners in DLco
Description	Number of subjects with a post-baseline DLco decrease of ≥ 20 % [(baseline observed value - visit observed value)/(baseline observed value) * 100]; in the absence of an obvious intercurrrent illness, a repeat DLco was performed.
Time Frame	Month 3 through extension follow up Month 3

Outcome Measure Data

Analysis Population Description

FAS FEV1; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	308	303
M3 (n=289, 290)	0 0%	2 0.6%
M6 (n=278, 280)	1 0.3%	2 0.6%
M9 (n=266, 272)	0 0%	3 1%
M12 (n=258, 263)	4 1.3%	3 1%
M15 (n=246, 248)	1 0.3%	2 0.6%
M18(n=237, 232)	2 0.6%	5 1.6%
M21 (n=231, 231)	0 0%	3 1%
M24 (n=221, 223)	4 1.3%	5 1.6%
FU M1 (n=247, 220)	2 0.6%	4 1.3%
FU M3 (n=247, 231)	3 0.9%	6 1.9%
FU M6 (n=241, 219)	5 1.6%	5 1.6%
Ext M1 (n=159, 161)	3 0.9%	3 1%
Ext M3 (n=157, 157)	3 0.9%	8 2.6%
Ext M6 (n=148, 157)	4 1.3%	6 1.9%
Ext M9 (n=143, 155)	4 1.3%	7 2.3%
Ext M12 (n=141, 155)	8 2.5%	9 2.9%
Ext M15(n=141, 142)	4 1.3%	6 1.9%
Ext M18 (n=132, 138)	6 1.9%	7 2.3%
Ext M21(n=129, 142)	4 1.3%	8 2.6%
Ext M24 (n=124, 130)	5 1.6%	7 2.3%
Ext M27(n=123, 124)	7 2.2%	8 2.6%
Ext M30 (n=124, 125)	7 2.2%	11 3.5%
Ext M33(n=98, 113)	1 0.3%	4 1.3%
Ext M36 (n=52, 60)	2 0.6%	3 1%
Ext FU M3 (n=118, 114)	6 1.9%	10 3.2%

18. Secondary Outcome

Title	Hypoglycemic Event Rates
Description	Hypoglycemic event rate; hypoglycemic event identified by characteristic symptoms of hypoglycemia with no blood glucose (BG) check with prompt resolution with food intake, SC glucagon, or intravenous (IV) glucose; characteristic symptoms with BG of 59 mg/dL (3.2 mmol/L) or less with or without symptoms. Crude event rate = total events divided by subject months (elapsed number of months a subject was in the study at each time interval).
Time Frame	Month 1 through extension Month 36

Outcome Measure Data

Analysis Population Description

FAS HbA1c; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	315	303
M1 (n=315, 303)	1.63	1.80
M2 (n=307, 302)	1.40	1.60
M3 (n=297, 298)	1.22	1.65
M4 (n=289, 295)	1.10	1.64
M5 (n=284, 293)	0.95	1.28
M6 (n=283, 290)	0.98	1.09
M7 (n=280, 289)	0.80	1.12
M8 (n=276, 288)	0.82	0.94
M9 (n=275, 287)	0.71	0.86
M10 (n=273, 285)	0.72	0.93
M11 (n=267, 274)	0.68	0.79
M12 (n=264, 274)	0.72	0.94
M13 (n=263, 269)	0.71	0.82
M14 (n=260, 265)	0.62	0.87
M15 (n=256, 265)	0.64	0.78
M16 (n=254, 261)	0.68	0.97
M17 (n=252, 257)	0.53	0.82
M18 (n=246, 253)	0.61	0.95
M19 (n=245, 252)	0.59	0.78
M20 (n=242, 249)	0.62	0.73
M21 (n=241, 246)	0.57	0.65
M22 (n=236, 244)	0.44	0.72
M23 (n=236, 241)	0.41	0.82
M24 (n=229, 232)	0.45	0.66
Ext M1 (n=172, 169)	1.16	1.16
Ext M2 (n=171, 169)	1.10	1.33
Ext M3 (n=169, 169)	1.02	1.12
Ext M4 (n=167, 169)	0.87	1.44
Ext M5 (n=165, 168)	0.91	1.18
Ext M6 (n=162, 167)	0.87	1.20
Ext M7 (n=161, 167)	1.10	1.41
Ext M8 (n=158, 164)	0.82	1.34
Ext M9 (n=158, 164)	0.56	1.25
Ext M10 (n=156, 164)	0.99	1.11
Ext M11 (n=153, 164)	0.70	0.92
Ext M12 (n=152, 162)	1.26	1.25
Ext M13 (n=152, 160)	1.07	1.14
Ext M14 (n=151, 159)	0.95	1.01
Ext M15 (n=149, 156)	0.86	1.25
Ext M16 (n=149, 156)	0.99	1.23
Ext M17 (n=148, 154)	1.20	1.01
Ext M18 (n=146, 154)	1.08	1.05
Ext M19 (n=143, 152)	1.25	1.21
Ext M20 (n=142, 152)	1.20	1.08
Ext M21 (n=141, 151)	0.78	1.15
Ext M22 (n=141, 149)	0.79	1.08
Ext M23 (n=139, 149)	0.82	1.06
Ext M24 (n=138, 147)	0.88	1.11
Ext M25 (n=137, 146)	0.73	1.22
Ext M26 (n=137, 145)	0.68	1.25
Ext M27 (n=137, 141)	0.62	1.04
Ext M28 (n=135, 137)	0.68	0.87
Ext M29 (n=135, 137)	0.81	0.91
Ext M30 (n=133, 137)	0.64	0.87
Ext M31 (n=124, 133)	0.67	1.32
Ext M32 (n=117, 125)	0.82	0.81
Ext M33 (n=100, 117)	0.55	0.89
Ext M34 (n=84, 90)	0.64	0.57
Ext M35 (n=66, 78)	0.63	0.80
Ext M36 (n=51, 60)	0.72	0.47
Overall comparative (n=315, 303)	0.95	1.19
Overall extension (n=172, 169)	0.89	1.10

19. Secondary Outcome

Title	Severe Hypoglycemic Event Rates
Description	Severe hypoglycemic event rate; all 3 criteria were met: subject unable to treat self, exhibited at least 1 neurological symptom (memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty awakening, suspected seizure, loss of consciousness); BG measurement ≤49 mg/dL, or not measured but clinical manifestations reversed by oral carbohydrates, SC glucagon, or IV glucose. Crude event rate: total events divided by subject months multiplied by 100 ([total events/subject months]*100). Subjects months: elapsed number of months subject was in study in each time interval.
Time Frame	Month 1 through extension Month 36

Outcome Measure Data

Analysis Population Description

FAS HbA1c; (n) = number of subjects with analyzable data at observation for inhaled insulin and SC insulin, respectively.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	315	303
M1 (n=315, 303)	0.98	0.67
M2 (n=307, 302)	0.34	0.34
M3 (n=297, 298)	0.69	0.34
M4 (n=289, 295)	0.35	1.38
M5 (n=284, 293)	0.36	1.74
M6 (n=283, 290)	0.72	2.10
M7 (n=280, 289)	0.00	0.70
M8 (n=276, 288)	0.37	0.70
M9 (n=275, 287)	0.74	0.35
M10 (n=273, 285)	0.00	0.36
M11 (n=267, 274)	0.38	0.37
M12 (n=264, 274)	0.76	0.37
M13 (n=263, 269)	0.77	0.76
M14 (n=260, 265)	0.78	0.38
M15 (n=256, 265)	0.79	0.77
M16 (n=254, 261)	0.00	0.00
M17 (n=252, 257)	0.00	0.40
M18 (n=246, 253)	0.00	0.40
M19 (n=245, 252)	0.41	0.00
M20 (n=242, 249)	0.42	0.00
M21 (n=241, 246)	0.00	0.00
M22 (n=236, 244)	0.00	0.00
M23 (n=236, 241)	0.00	0.85
M24 (n=229, 232)	0.00	0.00
Ext M1 (n=172, 169	0.95	0.93
Ext M2 (n=171, 169)	0.00	1.87
Ext M3 (n=169, 169)	1.92	0.94
Ext M4 (n=167, 169)	1.92	0.00
Ext M5 (n=165, 168)	0.00	0.00
Ext M6 (n=162, 167)	0.00	0.94
Ext M7 (n=161, 167)	0.00	1.90
Ext M8 (n=158, 164)	0.00	0.00
Ext M9 (n=158, 164)	0.00	2.86
Ext M10 (n=156, 164)	0.00	3.81
Ext M11 (n=153, 164)	0.00	3.86
Ext M12 (n=152, 162)	0.98	3.91
Ext M13 (n=152, 160)	0.00	0.98
Ext M14 (n=151, 159)	0.00	1.96
Ext M15 (n=149, 156)	1.00	0.00
Ext M16 (n=149, 156)	1.00	1.96
Ext M17 (n=148, 154)	1.00	0.99
Ext M18 (n=146, 154)	1.01	0.00
Ext M19 (n=143, 152)	1.03	0.99
Ext M20 (n=142, 152)	4.16	0.99
Ext M21 (n=141, 151)	0.00	0.00
Ext M22 (n=141, 149)	0.00	1.00
Ext M23 (n=139, 149)	0.00	0.00
Ext M24 (n=138, 147)	1.06	2.02
Ext M25 (n=137, 146)	0.00	1.01
Ext M26 (n=137, 145)	0.00	0.00
Ext M27 (n=137, 141)	1.07	0.00
Ext M28 (n=135, 137)	0.00	0.00
Ext M29 (n=135, 137)	0.00	1.06
Ext M30 (n=133, 137)	0.00	0.00
Ext M31 (n=124, 133)	0.00	1.15
Ext M32 (n=117, 125)	0.00	3.58
Ext M33 (n=100, 117)	0.00	0.00
Ext M34 (n=84, 90)	0.00	1.89
Ext M35 (n=66, 78)	0.00	0.00
Ext M36 (n=51, 60)	0.00	0.82
Overall comparative (n=315, 303)	0.45	0.65
Overall extension (n=172, 169)	0.50	1.17

20. Secondary Outcome

Title	Cough Questionnaire
Description	Clinician administered 6 question instrument to measure cough frequency (night, day), severity, timing in relation to short-acting insulin dosing, severity related to insulin dosing (SC or inhaled), and productivity of cough; range 0 (indicates no symptoms) to 4 (indicates severe symptoms). Questionnaire administered at Week 0 then if and only if, cough is identified as an adverse event not explained by a concomitant condition, such as an upper respiratory tract infection.
Time Frame	Week 0 and if indicated through extension follow up Month 3

Outcome Measure Data

Analysis Population Description

FAS. Due to early termination of study a limited set of analyses were undertaken and results of Cough Questionnaire were not summarized as planned.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	0	0

21. Secondary Outcome

Title	Baseline Dyspnea Index (BDI)
Description	Clinician administered instrument to measure the baseline severity of breathlessness (shortness of breath) in symptomatic patients with 3 domains: functional impairment, magnitude of task, and magnitude of effort. BDI score range 0 (very severe impairment) to 4 (no impairment) scaled to a BDI focal score (0-12). Lower score indicates greater impairment.
Time Frame	Week -1

Outcome Measure Data

Analysis Population Description

FAS FEV1. Due to early termination of study a limited set of analyses were undertaken and results of BDI were not summarized as planned.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	0	0

22. Secondary Outcome

Title	Transition Dyspnea Index (TDI)
Description	Clinician administered instrument to measure the baseline severity of breathlessness (shortness of breath) in symptomatic patients with 3 domains: functional impairment, magnitude of task, and magnitude of effort. TDI score range -3 (major deterioration) to +3 (major improvement); sum of all domains yields the TDI focal score (-9 to +9); lower score indicates greater deterioration. Compared to previous scoring to determine deterioration or improvement.
Time Frame	Week 4 through extension follow up Month 3 or end of study

Outcome Measure Data

Analysis Population Description

FAS FEV1. Due to early termination of study a limited set of analyses were undertaken and results of TDI were not summarized as planned.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	0	0

23. Secondary Outcome

Title	High Resolution Computerized Tomography (HRCT) Scan: Within Normal Limits (Yes or No) at Observation When Baseline HRCT Was Within Normal Limits
Description	Number of subjects with Yes or No responses (within normal limits at specified time points = Yes or not within normal limits at specified time points = No) at observation when HRCT of thorax was within normal limits at baseline.
Time Frame	Baseline, M12, M24, Ext M6, Ext M18, Ext M36

Outcome Measure Data

Analysis Population Description

All subjects analysis substudy population: subjects from participating sites with a baseline and subsequent post-baseline HRCT measurement. Subjects were recruited prior to randomization; substudy enrollment continued until at least 50 subjects randomized to inhaled insulin were enrolled or until enrollment in the study was complete.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	71	76
M12 = Yes	67 21.2%	64 20.6%
M12 = No	4 1.3%	12 3.9%
M24 = Yes	38 12%	51 16.4%
M24 = No	8 2.5%	10 3.2%
Ext M6 = Yes	32 10.1%	37 11.9%
Ext M6 = No	8 2.5%	8 2.6%
Ext M18 = Yes	28 8.9%	33 10.6%
Ext M18 = No	8 2.5%	6 1.9%
Ext M36 = Yes	22 7%	27 8.7%
Ext M36 = No	6 1.9%	4 1.3%

24. Secondary Outcome

Title	High Resolution Computerized Tomography (HRCT) Scan: Within Normal Limits (Yes or No) at Observation When Baseline HRCT Was Not Within Normal Limits
Description	Number of subjects with Yes or No responses (within normal limits at specified time points = Yes or not within normal limits at specified time points = No) at observation when HRCT of thorax was not within normal limits at baseline. "No" response at observation further categorized as no significant change (NSC), more abnormal (> Abn), or less abnormal (< Abn).
Time Frame	Baseline, M12, M24, Ext M6, Ext M18, Ext M36

Outcome Measure Data

Analysis Population Description

All subjects analysis substudy population: subjects from participating sites with a baseline and subsequent post-baseline HRCT measurement. Subjects were recruited prior to randomization; substudy enrollment continued until at least 50 subjects randomized to inhaled insulin were enrolled or until enrollment in the study was complete.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	26	21
M12 = Yes	6 1.9%	5 1.6%
M12 = No	20 6.3%	16 5.1%
M12 = No (NSC)	19 6%	11 3.5%
M12 = No (> Abn)	0 0%	2 0.6%
M12 = No (< Abn)	1 0.3%	3 1%
M24 = Yes	4 1.3%	6 1.9%
M24 = No	17 5.4%	9 2.9%
M24 = No (NSC)	17 5.4%	8 2.6%
M24 = No (> Abn)	0 0%	1 0.3%
M24 = No (< Abn)	0 0%	0 0%
Ext M6 = Yes	3 0.9%	3 1%
Ext M6 = No	16 5.1%	9 2.9%
Ext M6 = No (NSC)	15 4.7%	8 2.6%
Ext M6 = No (> Abn)	1 0.3%	1 0.3%
Ext M6 = No (< Abn)	0 0%	0 0%
Ext M18 = Yes	3 0.9%	2 0.6%
Ext M18 = No	14 4.4%	7 2.3%
Ext M18 = No (NSC)	12 3.8%	7 2.3%
Ext M18 = No (> Abn)	1 0.3%	0 0%
Ext M18 = No (< Abn)	1 0.3%	0 0%
Ext M24 = Yes	5 1.6%	2 0.6%
Ext M24 = No	9 2.8%	8 2.6%
Ext M24 = No (NSC)	8 2.5%	8 2.6%
Ext M24 = No (> Abn)	1 0.3%	0 0%
Ext M24 = No (< Abn)	0 0%	0 0%

25. Secondary Outcome

Title	Insulin Antibodies
Description	Observed values for insulin antibodies measured as micro units per milliliter (microU/mL).
Time Frame	Baseline through extension Month 36

Outcome Measure Data

Analysis Population Description

FAS; (n)=number of subjects with analyzable data at observation: inhaled insulin/SC insulin, respectively. Insulin antibody levels increased in Exubera®-treated compared to control subjects; results are included to establish there were no safety consequences due to these elevations although this was not an originally specified protocol endpoint.

Arm/Group Title	Inhaled Insulin (Exubera®)	Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.	Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
Measure Participants	312	300
Baseline (n=312, 300)	1.05	1.05
W3 (n=270, 264)	1.05	1.05
W6 (n=289, 282)	4.40	1.05
M3 (n=293, 289)	12.00	1.05
W18 (n=275, 280)	18.00	1.05
M6 (n=276, 279)	20.00	1.05
M9 (n=267, 277)	22.00	1.05
M12 (n=263, 263)	19.00	1.05
M15 (n=252, 253)	20.00	1.05
M18 (n=241, 239)	20.00	1.05
M21 (n=234, 233)	19.00	1.05
M24 (n=226, 233)	20.00	1.05
FU M1 (n=247, 226)	14.00	1.05
FU M3 (n=249, 229)	8.50	1.05
FU M6 (n=250, 227)	6.55	1.05
Ext M1 (n=165, 160)	13.00	1.05
Ext M3 (n=159, 158)	15.00	1.05
Ext M6 (n=157, 156)	12.00	1.05
Ext M9 (n=150, 157)	11.50	1.05
Ext M12 (n=148, 154)	13.00	1.05
Ext M15 (n=144, 147)	10.50	1.05
Ext M18 (n=140, 144)	13.00	1.05
Ext M21 (n=136, 145)	12.00	1.05
Ext M24 (n=130, 135)	10.50	1.05
Ext M27 (n=129, 131)	12.00	2.50
Ext M30 (n=125, 127)	8.40	1.05
Ext M33 (n=103, 114)	9.20	1.05
Ext M36 (n=56, 63)	5.75	1.05

Adverse Events

Adverse Event Reporting Description	Adverse events for this study are reported using MedDRA in Basic Results but are reported using COSTART in the Clinical Study Report (CSR) and PhRMA Web Synopsis (PWS) for consistency with earlier studies. Consequently, subtle differences may be observed.
Arm/Group Title	Inhaled Insulin (Exubera®)		Subcutaneous Insulin
Arm/Group Description	Pre-prandial inhalable short-acting insulin (INH) regime (packaged as 1 mg and 3 mg inhalation blister packs) plus a single bedtime dose or 2 daily doses of either Ultralene® or NPH insulin, or insulin glargine once daily (QD) at bedtime.		Subcutaneous (SC) insulin: 2 to 3 daily doses of regular insulin or short-acting insulin analog (lispro or aspart) plus 1 or 2 daily doses of an intermediate to long-acting insulin (NPH insulin or Ultralene®), or insulin glargine QD at bedtime.
All Cause Mortality
	Inhaled Insulin (Exubera®)		Subcutaneous Insulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Inhaled Insulin (Exubera®)		Subcutaneous Insulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	76/316 (24.1%)		76/311 (24.4%)
Blood and lymphatic system disorders
Anaemia	0/316 (0%)		2/311 (0.6%)
Pancytopenia	0/316 (0%)		1/311 (0.3%)
Cardiac disorders
Acute myocardial infarctionAcute myocardial infarction	1/316 (0.3%)		0/311 (0%)
Angina pectoris	1/316 (0.3%)		2/311 (0.6%)
Angina unstable	1/316 (0.3%)		3/311 (1%)
Aortic valve incompetence	0/316 (0%)		1/311 (0.3%)
Arrhythmia	1/316 (0.3%)		0/311 (0%)
Atrial fibrillation	0/316 (0%)		2/311 (0.6%)
Bradycardia	1/316 (0.3%)		0/311 (0%)
Cardiac arrest	0/316 (0%)		1/311 (0.3%)
Cardiac failure congestive	1/316 (0.3%)		0/311 (0%)
Coronary artery disease	5/316 (1.6%)		3/311 (1%)
Coronary artery insufficiency	0/316 (0%)		1/311 (0.3%)
Coronary artery occlusion	1/316 (0.3%)		1/311 (0.3%)
Coronary artery stenosis	0/316 (0%)		1/311 (0.3%)
Myocardial infarction	4/316 (1.3%)		5/311 (1.6%)
Myocardial ischaemia	0/316 (0%)		1/311 (0.3%)
Ear and labyrinth disorders
Vertigo	1/316 (0.3%)		0/311 (0%)
Gastrointestinal disorders
Abdominal adhesions	1/316 (0.3%)		0/311 (0%)
Abdominal pain	0/316 (0%)		4/311 (1.3%)
Abdominal pain lower	1/316 (0.3%)		0/311 (0%)
Abdominal pain upper	0/316 (0%)		1/311 (0.3%)
Diabetic gastroparesis	0/316 (0%)		1/311 (0.3%)
Duodenal ulcer haemorrhage	1/316 (0.3%)		0/311 (0%)
Gastric ulcer	0/316 (0%)		1/311 (0.3%)
Gastric volvulus	0/316 (0%)		1/311 (0.3%)
Gastrointestinal haemorrhage	0/316 (0%)		1/311 (0.3%)
Inguinal hernia	0/316 (0%)		1/311 (0.3%)
Lip swelling	1/316 (0.3%)		0/311 (0%)
Melaena	1/316 (0.3%)		0/311 (0%)
Oesophageal spasm	1/316 (0.3%)		0/311 (0%)
Oesophageal varices haemorrhage	0/316 (0%)		1/311 (0.3%)
Pancreatitis acute	0/316 (0%)		1/311 (0.3%)
Reflux gastritis	0/316 (0%)		1/311 (0.3%)
Small intestinal obstruction	1/316 (0.3%)		1/311 (0.3%)
Vomiting	0/316 (0%)		2/311 (0.6%)
General disorders
Chest discomfort	0/316 (0%)		1/311 (0.3%)
Chest pain	2/316 (0.6%)		5/311 (1.6%)
Non-cardiac chest pain	1/316 (0.3%)		0/311 (0%)
Pyrexia	0/316 (0%)		1/311 (0.3%)
Hepatobiliary disorders
Bile duct obstruction	1/316 (0.3%)		0/311 (0%)
Cholecystitis	0/316 (0%)		1/311 (0.3%)
Cholecystitis acute	1/316 (0.3%)		0/311 (0%)
Cholelithiasis	1/316 (0.3%)		2/311 (0.6%)
Infections and infestations
Appendicitis	3/316 (0.9%)		0/311 (0%)
Arthritis infective	0/316 (0%)		1/311 (0.3%)
Bronchitis	2/316 (0.6%)		0/311 (0%)
Cellulitis	7/316 (2.2%)		5/311 (1.6%)
Dengue fever	0/316 (0%)		1/311 (0.3%)
Diverticulitis	1/316 (0.3%)		1/311 (0.3%)
Gastritis viral	0/316 (0%)		1/311 (0.3%)
Herpes zoster	0/316 (0%)		1/311 (0.3%)
Incision site infection	0/316 (0%)		1/311 (0.3%)
Infected skin ulcer	0/316 (0%)		2/311 (0.6%)
Lobar pneumonia	1/316 (0.3%)		0/311 (0%)
Meningitis viral	0/316 (0%)		1/311 (0.3%)
Osteomyelitis	3/316 (0.9%)		1/311 (0.3%)
Peritonsillar abscess	1/316 (0.3%)		0/311 (0%)
Pneumonia	2/316 (0.6%)		3/311 (1%)
Post procedural infection	1/316 (0.3%)		0/311 (0%)
Sepsis syndrome	1/316 (0.3%)		0/311 (0%)
Skin infection	1/316 (0.3%)		0/311 (0%)
Staphylococcal infection	0/316 (0%)		1/311 (0.3%)
Tooth abscess	0/316 (0%)		1/311 (0.3%)
Urinary tract infection	2/316 (0.6%)		0/311 (0%)
Wound infection	0/316 (0%)		1/311 (0.3%)
Injury, poisoning and procedural complications
Ankle fracture	0/316 (0%)		1/311 (0.3%)
Device migration	1/316 (0.3%)		0/311 (0%)
Face injury	1/316 (0.3%)		0/311 (0%)
Failure of implant	1/316 (0.3%)		0/311 (0%)
Fall	0/316 (0%)		2/311 (0.6%)
Femoral neck fracture	0/316 (0%)		1/311 (0.3%)
Hip fracture	0/316 (0%)		1/311 (0.3%)
Humerus fracture	0/316 (0%)		1/311 (0.3%)
Incisional hernia, obstructive	0/316 (0%)		1/311 (0.3%)
Joint injury	0/316 (0%)		1/311 (0.3%)
Lower limb fracture	1/316 (0.3%)		0/311 (0%)
Rib fracture	0/316 (0%)		1/311 (0.3%)
Tendon rupture	1/316 (0.3%)		1/311 (0.3%)
Traumatic haemorrhage	1/316 (0.3%)		0/311 (0%)
Vascular graft occlusion	0/316 (0%)		1/311 (0.3%)
Investigations
Heart rate irregular	0/316 (0%)		1/311 (0.3%)
Metabolism and nutrition disorders
Diabetic ketoacidosis	0/316 (0%)		1/311 (0.3%)
Hypercholesterolaemia	0/316 (0%)		1/311 (0.3%)
Hyperkalaemia	0/316 (0%)		1/311 (0.3%)
Hypoglycaemia	4/316 (1.3%)		12/311 (3.9%)
Hypokalaemia	0/316 (0%)		1/311 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/316 (0.3%)		2/311 (0.6%)
Back pain	2/316 (0.6%)		1/311 (0.3%)
Cervical spinal stenosis	1/316 (0.3%)		0/311 (0%)
Intervertebral disc protrusion	0/316 (0%)		3/311 (1%)
Lumbar spinal stenosis	1/316 (0.3%)		1/311 (0.3%)
Musculoskeletal pain	1/316 (0.3%)		0/311 (0%)
Myalgia	1/316 (0.3%)		0/311 (0%)
Neck pain	1/316 (0.3%)		0/311 (0%)
Osteoarthritis	1/316 (0.3%)		1/311 (0.3%)
Pain in extremity	1/316 (0.3%)		1/311 (0.3%)
Rotator cuff syndrome	1/316 (0.3%)		0/311 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of the cervix	0/316 (0%)		1/311 (0.3%)
Colon cancer	0/316 (0%)		1/311 (0.3%)
Colon cancer metastatic	1/316 (0.3%)		0/311 (0%)
Endometrial cancer	0/316 (0%)		1/311 (0.3%)
Gastric neoplasm	0/316 (0%)		1/311 (0.3%)
Lung neoplasm	1/316 (0.3%)		0/311 (0%)
Oesophageal carcinoma	1/316 (0.3%)		0/311 (0%)
Ovarian cancer metastatic	0/316 (0%)		1/311 (0.3%)
Prostate cancer	4/316 (1.3%)		1/311 (0.3%)
Rectal cancer	0/316 (0%)		1/311 (0.3%)
Renal cell carcinoma	0/316 (0%)		1/311 (0.3%)
Thyroid neoplasm	0/316 (0%)		1/311 (0.3%)
Nervous system disorders
Cataplexy	0/316 (0%)		1/311 (0.3%)
Cerebral ischaemia	1/316 (0.3%)		0/311 (0%)
Cerebrovascular accident	2/316 (0.6%)		1/311 (0.3%)
Dizziness	1/316 (0.3%)		0/311 (0%)
Facial palsy	1/316 (0.3%)		0/311 (0%)
Global amnesia	1/316 (0.3%)		0/311 (0%)
Hypoaesthesia	0/316 (0%)		1/311 (0.3%)
Lumbar radiculopathy	1/316 (0.3%)		0/311 (0%)
Migraine	1/316 (0.3%)		1/311 (0.3%)
Multiple sclerosis	0/316 (0%)		1/311 (0.3%)
Radiculopathy	1/316 (0.3%)		0/311 (0%)
Syncope	1/316 (0.3%)		0/311 (0%)
Transient ischaemic attack	1/316 (0.3%)		1/311 (0.3%)
Psychiatric disorders
Anxiety	0/316 (0%)		1/311 (0.3%)
Bipolar II disorder	1/316 (0.3%)		0/311 (0%)
Bipolar disorder	0/316 (0%)		2/311 (0.6%)
Confusional state	0/316 (0%)		1/311 (0.3%)
Depression	0/316 (0%)		1/311 (0.3%)
Panic attack	0/316 (0%)		1/311 (0.3%)
Panic disorder	0/316 (0%)		1/311 (0.3%)
Renal and urinary disorders
Haematuria	0/316 (0%)		1/311 (0.3%)
Renal cyst	1/316 (0.3%)		0/311 (0%)
Renal failure	0/316 (0%)		1/311 (0.3%)
Renal failure chronic	0/316 (0%)		1/311 (0.3%)
Reproductive system and breast disorders
Prostatomegaly	1/316 (0.3%)		0/311 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/316 (0.3%)		0/311 (0%)
Asthma	1/316 (0.3%)		0/311 (0%)
Bronchospasm	1/316 (0.3%)		0/311 (0%)
Dyspnoea	0/316 (0%)		2/311 (0.6%)
Dyspnoea exertional	1/316 (0.3%)		0/311 (0%)
Lung infiltration	0/316 (0%)		1/311 (0.3%)
Pleuritic pain	0/316 (0%)		1/311 (0.3%)
Pneumothorax	0/316 (0%)		1/311 (0.3%)
Pulmonary granuloma	1/316 (0.3%)		0/311 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	0/316 (0%)		2/311 (0.6%)
Surgical and medical procedures
Foot amputation	0/316 (0%)		1/311 (0.3%)
Hip arthroplasty	0/316 (0%)		1/311 (0.3%)
Hysterectomy	1/316 (0.3%)		0/311 (0%)
Knee arthroplasty	1/316 (0.3%)		0/311 (0%)
Leg amputation	0/316 (0%)		1/311 (0.3%)
Shoulder operation	0/316 (0%)		1/311 (0.3%)
Vascular operation	0/316 (0%)		1/311 (0.3%)
Vascular disorders
Angiopathy	0/316 (0%)		1/311 (0.3%)
Arterial occlusive disease	2/316 (0.6%)		1/311 (0.3%)
Deep vein thrombosis	0/316 (0%)		1/311 (0.3%)
Hypertension	1/316 (0.3%)		0/311 (0%)
Hypotension	1/316 (0.3%)		0/311 (0%)
Peripheral arterial occlusive disease	0/316 (0%)		1/311 (0.3%)
Peripheral vascular disorder	1/316 (0.3%)		2/311 (0.6%)
Thrombosis	0/316 (0%)		1/311 (0.3%)
Other (Not Including Serious) Adverse Events
	Inhaled Insulin (Exubera®)		Subcutaneous Insulin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	308/316 (97.5%)		301/311 (96.8%)
Gastrointestinal disorders
Abdominal pain	13/316 (4.1%)		16/311 (5.1%)
Diarrhoea	49/316 (15.5%)		27/311 (8.7%)
Gastrooesophageal reflux disease	19/316 (6%)		15/311 (4.8%)
Nausea	24/316 (7.6%)		29/311 (9.3%)
Vomiting	15/316 (4.7%)		17/311 (5.5%)
General disorders
Asthenia	23/316 (7.3%)		21/311 (6.8%)
Chest pain	20/316 (6.3%)		20/311 (6.4%)
Fatigue	19/316 (6%)		30/311 (9.6%)
Oedema peripheral	38/316 (12%)		42/311 (13.5%)
Immune system disorders
Seasonal allergy	12/316 (3.8%)		21/311 (6.8%)
Infections and infestations
Bronchitis	45/316 (14.2%)		22/311 (7.1%)
Cellulitis	18/316 (5.7%)		8/311 (2.6%)
Gastroenteritis	14/316 (4.4%)		17/311 (5.5%)
Gastroenteritis viral	23/316 (7.3%)		17/311 (5.5%)
Influenza	63/316 (19.9%)		76/311 (24.4%)
Lower respiratory tract infection	22/316 (7%)		14/311 (4.5%)
Nasopharyngitis	83/316 (26.3%)		94/311 (30.2%)
Sinusitis	41/316 (13%)		46/311 (14.8%)
Upper respiratory tract infection	104/316 (32.9%)		101/311 (32.5%)
Urinary tract infection	29/316 (9.2%)		30/311 (9.6%)
Metabolism and nutrition disorders
Hyperlipidaemia	18/316 (5.7%)		18/311 (5.8%)
Hypoglycaemia	245/316 (77.5%)		247/311 (79.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	51/316 (16.1%)		43/311 (13.8%)
Back pain	43/316 (13.6%)		52/311 (16.7%)
Muscle spasms	14/316 (4.4%)		16/311 (5.1%)
Musculoskeletal pain	21/316 (6.6%)		21/311 (6.8%)
Myalgia	16/316 (5.1%)		16/311 (5.1%)
Neck pain	15/316 (4.7%)		16/311 (5.1%)
Pain in extremity	41/316 (13%)		43/311 (13.8%)
Nervous system disorders
Dizziness	37/316 (11.7%)		45/311 (14.5%)
Headache	43/316 (13.6%)		28/311 (9%)
Hypoaesthesia	19/316 (6%)		20/311 (6.4%)
Tremor	37/316 (11.7%)		50/311 (16.1%)
Psychiatric disorders
Depression	21/316 (6.6%)		40/311 (12.9%)
Respiratory, thoracic and mediastinal disorders
Cough	142/316 (44.9%)		70/311 (22.5%)
Dyspnoea	24/316 (7.6%)		17/311 (5.5%)
Nasal congestion	11/316 (3.5%)		21/311 (6.8%)
Oropharyngeal pain	29/316 (9.2%)		29/311 (9.3%)
Productive cough	16/316 (5.1%)		5/311 (1.6%)
Sinus congestion	20/316 (6.3%)		27/311 (8.7%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	21/316 (6.6%)		30/311 (9.6%)
Rash	17/316 (5.4%)		16/311 (5.1%)
Vascular disorders
Hypertension	52/316 (16.5%)		62/311 (19.9%)

Limitations/Caveats

Due to early termination of study, none of the subjects completed the study as planned. Subjects active at the time of study termination completed an end-of-study assessment and a 3-month follow-up visit.

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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 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.