A One Year Clinical Trial Assessing the Usefulness and Safety of Inhaled Insulin in Diabetics With Asthma

Annualized rates of change (slope throughout time from baseline to end of study\[visit\]) for forced expiratory volume in 1 second (FEV1) (liters per year \[L/yr\]) measured 30 minutes following the administration of albuterol.

Time frame: Weeks -3, -2, -1, 1, 2, 3, 4, 6, 12, 18, 26, 39, and 52

Population: Primary analysis set (PAS): all subjects who were randomized, had no significant protocol violations, had baseline (BL) post-albuterol pulmonary function test (PFT) measurement, had at least 2 post-BL, post-albuterol PFT measurements with 1 measurement at least 6 months post-BL, and received study drug for at least 50% (154 days) of study duration.

Annualized rates of change (slope throughout time from baseline to end of study\[visit\]) for hemoglobin-adjusted carbon monoxide diffusion capacity (DLco)in milliliters per minute/millimeters of mercury/year (ml/min/mmHg/yr) measured 30 minutes following the administration of albuterol.

Time frame: Weeks -3, -2, -1, 1, 2, 3, 4, 6, 12, 18, 26, 39, and 52

Population: Primary analysis set (PAS).

Carbon Monoxide Diffusing Capacity (DLco) measured in milliters/minutes/millimeters of mercury (mL/min/mmHg) 30 minutes following the administration of albuterol. Change from Baseline: mean DLco (mL/min/mmHg) at observation minus baseline value.

Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 12, Week 18, Week 26, Week 39, Week 52, Week 52 Last Observation Carried Forward (LOCF)

Population: Full analysis set (FAS); LOCF: last observation carried forward.

Change from Baseline at each visit in post-bronchodilator forced expiratory volume in one second (FEV1). FEV1 was measured in liters (L) 30 minutes following the administration of albuterol. Change from baseline: mean FEV1 (L) at observation minus baseline value.

Time frame: Baseline through Week 52 Last Observation Carried Forward (LOCF)

Population: Full analysis set (FAS): all subjects who were randomized, had a baseline post-albuterol pulmonary function test (PFT) measurement, and had at least two post-baseline, post-albuterol PFT measurements. LOCF: last observation carried forward.

Asthma Control Questionnaire©: 6 self-administered questions that assess asthma control over the past week covering nocturnal waking, morning symptoms, activity limitations, shortness of breath, wheezing, and short-acting bronchodilator use; 7-point ordinal rating scale from 0 (good control) to 6 (poor control). A seventh question was completed by a health professional on forced expiratory volume in 1 second (FEV1) % predicted using a one-week recall period; scale: 0 (\>95% predicted) to 6 (\<50% predicted). Overall score = mean of questions 1 - 7.

Time frame: Baseline, Weeks 4, 12, 26, 39, 52

Population: FAS; abbreviations: Eval = evaluations, BL = Baseline.

Total score = the sum of the numeric grades from the three dyspnea index questions. Functional Impairment rating scale: Grade 4 (no impairment) to Grade 0 (very severe impairment); Magnitude of Task rating scale: Grade 4 (extraordinary) to Grade 0 (no task); and Magnitude of Effort rating scale: Grade 4 (extraordinary) to grade 0 (no effort).

Time frame: run-in period

Population: Full analysis set (FAS)

Body weight: mean Baseline and change from Baseline in kilograms (kg). Change from baseline = mean body weight in kilograms (kg) at observation minus baseline value.

Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 11, Week 12, Week 18, Wek 26, Week 39, Week 50, Week 51, Week 52, Week 52 Last Observation Carried Forward (LOCF)

Population: Primary analysis set (PAS)

Responsiveness was the percent change from the forced expiratory volume in 1 second (FEV1) value before bronchodilator use to the FEV1 value 30 minutes after bronchodilator use, operationally defined as \[(post-bronchodilator FEV1 minus pre-bronchodilator FEV1 divided by pre-bronchodilator FEV1\] multiplied by 100.

Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 12, Week 18, Week 26, Week 39, Week 52

Population: Full analysis set (FAS)

Carbon Monoxide Diffusing Capacity (DLco) dose responsivness 10 and 60 minutes after insulin. DLco dose-responsiveness to insulin was defined as the difference between the DLco value following a dose of insulin and DLco value before a dose of insulin, operationally defined as the post-dose DLco value minus pre-dose DLco value.

Time frame: Baseline, Week 9, Week 51

Population: Full analysis set (FAS)

Change from Baseline in Insulin Dose Responsiveness for Forced Expiratory Volume in one second (FEV1) measured 10 and 60 minutes after the first daily dose of insulin. Insulin dose responsiveness = the difference between FEV1 value following a dose of insulin and FEV1 value before a dose of insulin, operationally defined as the post dose FEV1 value minus predose FEV1 value.

Time frame: Baseline, Week 9, Week 51

Population: Full analysis set (FAS)

Change from baseline in Post-bronchodilator Forced Vital Capacity (FVC) measured in liters (L) 30 minutes following the administration of albuterol: change = FVC at observation minus FVC at Baseline.

Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 12, Week 18, Week 26, Week 39, Week 52, Week 52 Last Observation Carried Forward (LOCF)

Population: Full analysis set (FAS); LOCF: last observation carried forward.

Change From Baseline in Pre-Bronchodilator Carbon Monoxide Diffusing Capacity (DLco) measured in milliters/minutes/millimeters of mercury (mL/min/mmHg): change = DLco at observation minus DLco at Baseline.

Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 12, Week 18, Week 26, Week 39, Week 52, Week 52 Last Observation carried Forward (LOCF)

Population: Full analysis set (FAS); LOCF: last observation carried forward.

Change from Baseline in Pre-Bronchodilator Forced Expiratory Volume in One Second (FEV1) at each visit. FEV1 was measured in liters (L) before the administration of albuterol. Change from baseline: mean FEV1 (L) at observation minus mean baseline value.

Time frame: Week 1, Week 2, Week 3, Week 4, Week 6, Week 12, Week 18, Week 26, Week 39, Week 52, Week 52 Last Observation Carried Forward (LOCF)

Population: Full analysis set (FAS); LOCF: last observation carried forward.

Change From Baseline in Pre-Insulin Carbon Monoxide Diffusing Capacity (DLco) measured in milliters/minutes/millimeters of mercury (mL/min/mmHg): change = DLco at observation minus DLco at Baseline.

Time frame: Baseline, Week 9, Week 51, Week 51 Last Observation Carried Forward (LOCF)

Population: Full analysis set (FAS); LOCF: last observation carried forward.

Change from Baseline in Pre-Insulin Forced Expiratory Volume in one second (FEV1) measured in liters (L): change = FEV1 at observation minus FEV1 at Baseline.

Time frame: Baseline, Week 9, Week 51, Week 51 Last Observation Carried Forward

Population: Full analysis set (FAS); LOCF: last observation carried forward.

Fasting plasma glucose (milligrams per deciliter \[mg/dL\]) at Baseline, and change from Baseline. Change from baseline: mean of value of fasting plasma glucose in mg/dL at observation minus baseline value.

Time frame: Baseline, Week 6, Week 12, Week 26, Week 39, Week 52, Week 52 Last Observation Carried Forward (LOCF)

Population: Primary analysis set (PAS); Last Observation Carried Forward: if the end of study value was missing the last available observation for that subject was used..

Glycosylated Hemoglobin (HbA1c): observed mean values at Baseline and each observation, and change from Baseline. Change from Baseline = mean HbA1c at observation minus mean HbA1c at Baseline.

Time frame: Baseline, Week 6, Week 12, Week 26, Week 39, Week 52, Week 52 Last Observation Carried Forward (LOCF)

Population: Full analysis set (FAS)

A Hypoglycemic event was identified by characteristic symptoms of hypoglycemia with no blood glucose check with prompt resolution with food intake, subcutaneous glucagon, or intravenouus glucose; characteristic symptoms with blood glucose of 59 milligrams per deciliter (mg/dL) (3.2 mmol/L) or less with blood glucose check; or any glucose measurement of 49 mg/dL (2.7 mmol/L) or less, with or without symptoms. Crude event rate = total events divided by subject months. Subject months = elapsed number of months a subject was in the study in each time interval.

Time frame: 0 to 1 month to 11 to 12 months, and Overall

Population: Full analysis set (FAS)

Non-severe asthma exacerbation = one of the following: any home monitored morning (4:45 am - 10:15 am) forced expiratory volume in 1 second (FEV1) \<80% of the morning baseline for 2 or more consecutive days; or home monitored FEV1 \<60% of Baseline at any time. Percent of Baseline = 100\*(daily FEV1)/Baseline weekly FEV1. Subject-months=elapsed number of months a subject was in the study in each time interval. Crude event rate = total events divided by subject-months.

Time frame: 0 to 1 week to > 12 months

Population: FAS; review of source data for this endpoint showed excessive data variability for home-monitored FEV1 with outliers ranging from 0.01 to \>100, and many subjects with random peaks and dips of 100% or more of their baseline. It is unlikely that the protocol definition is robust enough to provide real information about exacerbation frequencies.

Severe asthma exacerbation was defined as one of the following: subject received oral (systemic) corticosteriods for the treatment of asthma; or subject had an unscheduled visit to a physician, emergency room, or hospital for the treatment of asthma. Subject-months=elapsed number of months a subject was in the study in each time interval. Crude event rate = total events divided by subject-months \* 100.

Time frame: 0 to 1 Week to > 12 Months

Population: Full analysis set (FAS); due to inconsistencies in data entry for systemic steroids, the protocol definition for severe asthma exacerbations, which was based on systemic corticosteroid use for asthma, could not be accurately assessed. Due the small number of events the incidence of severe asthma exacerbations was assessed per 100 months.

Lipids: median changes (milligrams per deciliter \[mg/dL\]) from Baseline median to last observation in cholesterol (random), triglycerides (random), high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol. Normalized data was used in the computations. Last observation = last observation while on study drug or during the lag. Measures of dispersion for median changes in lipids were not determined.

Time frame: Baseline to Last Observation

Population: Primary analysis set (PAS); median change from Baseline to last observation. Last observation was defined as last observation while on study drug or during the lag. Full range (-999 to 999) was not calculated.

Mean weekly asthma symptom scores: subjects recorded their asthma symptom scores in an electronic symptom diary twice daily throughout the study, immediately upon awakening (5-10 AM) and in the evening or at bedtime (7-12 PM). Questions included extent of albuterol use, symptoms of wheezing, coughing, activity limitations and sleep; scale 0 (none/fine) to 3 (severe/ continuous/bad night).

Time frame: Baseline through end of study

Population: Data for mean weekly asthma symptom scores were not presented due to lack of resource resulting from scaling down of Exubera® (inhaled insulin) development.

Subjects measured peak expiratory flow rate (PEFR) and forced expiratory volume in 1 second (FEV1) twice daily and entered the results in an electronic diary. Daily data were used to calculate the mean PEFR and FEV1 for each week (observed weekly mean and change from baseline in weekly mean). For each subject, the mean weekly morning (and evening) PEFR and FEV1 was defined as the sum of the daily morning (and evening) PEFR (and FEV1) measurements during the week divided by the number of non-missing PEFR (and FEV1) measurements during the week.

Time frame: Week -3 through Week 52

Population: Mean weekly morning and evening peak expiratory flow rate (PEFR) and forced expiratory volume in 1 second (FEV1) were not presented due to lack of resource resulting from scaling down of Exubera® (inhaled insulin) development.

All subjects used an electronic symptom diary to record their daily use of short-acting bronchodilators. Subjects recorded the sum of their short-acting bronchodilator use (puffs of albuterol) daily, immediately upon arising, and again in the evening or before bed.

Time frame: Daily: Baseline to end of study

Population: Mean weekly number of puffs of albuterol was not presented due to lack of resource resulting from scaling down of Exubera® (inhaled insulin) development.

Methacholine Challange: performed on a subset of subjects using the 5-breath dosimeter method. Subjects were challenged with ascending doses of nebulized methacholine; dosing schedule: 0.03, 0.06, 0.12, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 16.0, 32.0 milligrams per milliliter (mg/ml) administered in 5-minute intervals. Forced expiratory volume in 1 second (FEV1) was measured 1-3 minutes after each inhalation of methacholine solution. Testing continued until highest FEV1 decreased by ≥20% from the challenge (post-diluent) reference, or until completion all doses.

Time frame: 1 to 2 days following Weeks -3 and -1 visits, and at Week 11, Week 50, and Week 52 (+5)

Population: There were no methacholine challenges performed in subjects using inhaled insulin due to protocol-defined exclusion criteria for methacholine challenge testing, and methacholine provocative concentration \[of methacholine\] causing a 20% fall in FEV1 (PC20) data were not analyzed.

All asthma medication changes during the study were classified as step-up or step-down according to treatment guidelines. Step 1: Intermittant Asthma; Step 2: Mild Persistent Asthma; Step 3: Moderate Persistent Asthma; Step 4: Severe Persistent Asthma. The number of subjects in each step classification of asthma severity were provided at each assessment timepoint for each treatment group, with a shift table indicating the number of subjects moving from each step classification at each timepoint.

Time frame: Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12, Week 18, Week 26, Week 39, Week 52, Week 54, Week 58

Population: Data for the number of step-up and step-down changes in classification of asthma severity by medication usage were not tabulated or analyzed as accurate dose information data for all concomitant medications were not available due to inconsistencies in the way concomitant medication data were collected.

Number of subjects who used a systemic corticosteroid at any time during the study, and the total number of systemic corticosteroid rescues. New rescue event = \>=2 consecutive days between the end of one event and the start of another event.

Time frame: Baseline through Week 52

Population: Full analysis set (FAS); number of subjects with systemic corticosteroid rescues = inhaled insulin: 12, and subcutaneous insulin: 14. Due to inconsistencies in data entry, the numbers of systemic corticosteroid rescues were not considered entirely accurate.

Percent predicted change from Baseline in 10 Minute and 60 Minute post-insulin forced expiratory volume in one second (FEV1) measured in liters (L): National Health and Nutrition Examination Survey (NHANES III) reference standard. Percent change from Baseline in FEV1 measured in liters (L) 10 and 60 Minutes post-insulin. Percent change = (value at observation minus Baseline value) divided by Baseline value \*100%.

Time frame: Baseline, Week 9, Week 51, Week 51 Last Observation Carried Forward (LOCF)

Population: Full analysis set (FAS); LOCF: last observation carried forward.

Percent predicted change from Baseline in post-bronchodilator forced expiratory volume in one second (FEV1) measured in liters (L): National Health and Nutrition Examination Survey (NHANES III) reference standard. Percent change from Baseline in post-bronchdilator FEV1 measured in liters (L): (observed value minus Baseline value) divided by Baseline value \*100%.

Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 12, Week 18, Week 26, Week 39, Week 52, Week 52 Last Observation Carried Forward (LOCF)

Population: Full analysis set (FAS); LOCF: last observation carried forward.

Severe hypoglycemic event = all 3 of the following criteria were met: subject unable to treat self, exhbited at least 1 neurological symptom (memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, loss of consciousness); blood glucose measurement was ≤ 49 mg/dL, or not measured but clinical manifestations reversed by oral carbohydrates, subcutaneous glucagon, or i.v. glucose. Crude event rate = number of events divided by 100 subject-months. Subject months = elapsed number of months subject was in study in each time interval.

Time frame: 0 to 1 month to 11 to 12 months, and Overall

Population: Full analysis set (FAS). Due the small number of events severe hypoglycemic event rates were assessed per 100 months.

Step classification of asthma severity by medication usage. Subjects were classified at each visit according to the medication used on the day of the particular time-point; Step 1: intermittent asthma, Step 2: mild persistent asthma, Step 3: moderate persistent asthma, Step 4: severe persistent asthma. The number (%) of subjects in each step classification were provided at each assessment timepoint with a shift table indicating the number (%) of subjects moving from each step classification at each time-point.

Time frame: Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12, Week 18, Week 26, Week 39, Week 52, Week 54, Week 58

Population: Data for step classification of asthma severity by medication usage were not tabulated or analyzed as accurate dose information data for all concomitant medications were not available due to inconsistencies in the way concomitant medication data were collected.

Total daily dose of long-acting insulin adjusted for body weight (units per kilogram \[kg\]). Long-acting insulin included Insulin NPH, Ultralente, and Insulin Glargine for both groups. Inhaled Insulin reported in mg/kg. Subcutaneous Insulin reported in units/kg.

Time frame: Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12, Week 18, Week 26, Week 39, Week 52

Population: Primary analysis set (PAS)

Total Daily Long-Acting Insulin Dose Unadjusted for Body Weight: long-acting insulin included Insulin NPH, Ultralente, and Insulin Glargine for both groups. Inhaled Insulin reported in mg. Subcutaneous Insulin reported in units.

Time frame: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12, Week 18, Week 26, Week 39, Week 52

Population: Primary analysis set (PAS)

Total Daily Short-Acting Insulin Dose adjusted for body weight (units divided by kg). Short-acting insulin (mg) for the Inhaled Insulin group was Inhaled Insulin. Short-acting insulin (unit) for the Subcutaneous Insulin group included Insulin Lispro, Insulin Aspart, and Regular Insulin.

Time frame: Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12, Week 18, Week 26, Week 39, Week 52

Population: Primary analysis set (PAS)

Average Total Daily Insulin Dose: short-acting insulin (milligrams \[mg\]). Short-acting insulin (mg) for the Inhaled Insulin group was Inhaled Insulin. Short-acting insulin (unit) for the Subcutaneous Insulin group included Insulin Lispro, Insulin Aspart, and Regular Insulin.

Time frame: Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12, Week 18, Week 26, Week 39, Week 52

Population: Primary analysis set (PAS)

Transition Dyspnea Index total score = sum of the numeric grades from the three dyspnea index questions: Change in Functional Impairment, Change in Magnitude of Task, and Change in Magnitude of Effort. Rating scale: -3 (major deterioration), -2 (moderate deterioration), -1 (minor deterioration, 0 (no change), +1 (minor improvement), +2 (moderate improvement), +3 (major improvement).

Time frame: Week 4, Week 12, Week 26, Week 39, Week 52

Population: Full analysis set (FAS)