Efficacy and Safety of Inhaled Insulin Compared With Subcutaneous Human Insulin Therapy in Adults With Type 1 Diabetes

Study Overview
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Brief Summary
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This study is being done to find out the good and bad effects of a drug that is not approved for sale and the effects if any on measures of pulmonary function in adult males and females with type 1 diabetes mellitus. The drug is called EXUBERA (inhaled insulin). 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.

Detailed Description
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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 A2171022 was terminated on June 9, 2008. Neither safety nor efficacy reasons were the cause of the study termination.

Official Title
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Efficacy and Safety of Exubera (Inhaled Insulin) Compared With Subcutaneous Human Insulin Therapy in Adult Subjects With Type 1 Diabetes Mellitus: A Long-Term, Outpatient, Open-Label, Parallel-Group Comparative Trial

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Subcutaneous Insulin
* Drug: Inhaled Insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes mellitus Exclusion Criteria: severe asthma or COPD smoking brittle diabetes

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Subcutaneous Insulin<br> | Drug: Subcutaneous Insulin<br>* Subcutaneous insulin with dose adjusted according to premeal blood glucose<br>|
| Experimental: Inhaled Insulin<br> | Drug: Inhaled Insulin<br>* Inhaled insulin with dose adjusted according to premeal blood glucose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Forced Expiratory Volume in One Second (FEV1) | Change from Baseline: mean of (value of observed forced expiratory volume in the first second of forced exhalation [FEV1] in liters [L] at observation minus Baseline value). | Baseline through Extension Follow-up Month 3 | 
| Summary of ≥ 15% Decliners in Forced Expiratory Volume in One Second (FEV1) | Number of subjects with a post-baseline Forced Expiratory Volume in One Second (FEV1) decrease of ≥ 15 % [(baseline observed value minus visit observed value)/(baseline observed value) * 100]; in the absence of an obvious intercurrent illness, a repeat FEV1 was performed. | Month 3 through Extension Follow-up 3 | 
| Change From Baseline in Carbon Monoxide Diffusion Capacity (DLco) | Change from Baseline: mean of (value of Carbon Monoxide Diffusing Capacity [DLco] measured in milliters/minutes/millimeters of mercury [mL/min/mmHg] at observation minus Baseline value). | Baseline through Extension Follow-up Month 3 | 
| Summary of ≥ 20% Decliners in Carbon Monoxide Diffusing Capacity (DLco). | Number of subjects with a post-baseline Carbon Monoxide Diffusing Capacity (DLco) decrease of ≥ 20% [(baseline observed value minus visit observed value)/(baseline observed value) * 100]; in the absence of an obvious intercurrent illness, a repeat DLco was performed. | Month 3 through Extension Follow-up Month 3 | 
| Annual Rate of Change in Forced Expiratory Volume in 1 Second (FEV1) | 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). | Week -2 through Extension Follow-up Month 6 or end of study | 
| Annual Rate of Change in Carbon Monoxide Diffusion Capacity (DLco) | Annual rate of change in DLco calculated as slope over time (visit) measured as milliliters per minute per millimeters of hemoglobin per year (ml/min/mmHg/yr). | Week -2 through Extension Follow-up Month 6 or end of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change from Baseline: mean of (value of Glycosylated Hemoglobin [HbA1c] at observation minus Baseline value). | Baseline through Extension Follow-up Month 3 | 
| Hypoglycemic Event Rates | 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. Subject months = elapsed number of months a subject was in the study in each time interval. Crude event rate = total events divided by subject month of treatment. | Month 1 through Extension Month 39 | 
| Severe Hypoglycemic Event Rates | 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); and blood glucose measurement was ≤49 mg/dL, or not measured but clinical manifestations reversed by oral carbohydrates, subcutaneous glucagon, or i.v. glucose. Subject months = elapsed number of months subject was in study in each time interval. Crude event rate = total events divided by subject months * 100. | Month 1 through Extension Month 39 | 
| Change From Baseline in Fasting Plasma Glucose | Change from Baseline: mean of (value of fasting plasma glucose [milligrams per deciliter (mg/dL)] at observation minus Baseline value). | Baseline through Extension Follow-up Month 3 | 
| Change From Baseline Body Weight | Body weight: mean Baseline and change from Baseline in kilograms (kg). Change from baseline = mean body weight in kilograms (kg) at observation minus mean baseline body weight. | Baseline through Extension Follow-up Month 3 | 
| Total Daily Long-Acting Insulin Dose (Unadjusted for Body Weight) | Total Daily Long-Acting Insulin Dose Unadjusted for Body Weight; long-acting insulin included NPH Insulin, Ultralente, and Insulin Glargine for both groups. | Month 3 through Extension Month 39 | 
| Total Daily Long-Acting Insulin Dose Adjusted for Body Weight | Total daily dose of long-acting insulin adjusted for body weight (units per kilogram [kg]). Long-acting insulin included NPH Insulin, Ultralente, and Insulin Glargine for both groups. | Month 3 through Extension Month 39 | 
| Total Daily Short-Acting Insulin Dose (Unadjusted for Body Weight) | Total daily dose of short-acting insulin unadjusted for body weight. 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. | Month 3 through Extension Month 39 | 
| Total Daily Short-Acting Insulin Dose Adjusted for Body Weight | Total Daily Short-Acting Insulin Dose adjusted for body weight (milligrams [mg] or units divided by kilograms [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. | Month 3 through Extension Month 39 | 
| Baseline Dyspnea Index (BDI) | 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. | Week - 1 | 
| Transition Dyspnea Index (TDI) | 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. | Week 4 through ,Extension Follow-up Month 6 and every 6 months thereafter or end of study | 
| Lipids | Total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides measured as milligrams per deciliter (mg/dL). | Week -4 through Month 24 | 
| Cough Questionnaire | Subject completed cough questionnaire with reference to the past 4 weeks. Six question instrument to measure cough frequency (night, day), severity, timing in relation to short-acting insulin dosing, severity related to insulin dosing (subcutaneous [SC] or inhaled), and productivity of cough; range 0 (no symptoms) to 4 (severe symptoms). Questionnaire was administered at Week 0 and then at subsequent visits only if cough was identified as an adverse event not explained by a concomitant condition, such as an upper respiratory tract infection. | Week 0 and if indicated through Extension Follow up Month 3 | 
| Forced Vital Capacity (FVC) | Forced Vital Capacity (FVC) measured in liters (L). | Week -3 through Extension Follow-up Month 6 or End of Study | 
| Total Lung Capacity (TLC) | Total Lung Capacity measured in liters (L). | Week -3 through Extension Follow-up Month 6 or End of Study | 
| Insulin Antibodies | Median insulin antibodies at each visit measured in micro units per milliliter (microU/mL). | Baseline through Extension Month 39 |