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

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 A2171029 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 2 Diabetes Mellitus: A Long-Term, Outpatient, Open-Label, Parallel-Group Comparative Trial

Conditions
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Diabetes Mellitus

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes mellitus Exclusion Criteria: COPD Asthma Smoking Pregnancy

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 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 |
| --- | --- |
| Experimental: Inhaled Insulin<br>Inhalable short-acting insulin | Drug: Inhaled Insulin<br>* Inhaled insulin with dose adjusted according to premeal blood glucose<br>* Other names: Exubera;|
| Active Comparator: Subcutaneous insulin<br> | Drug: Subcutaneous insulin<br>* Subcutaneous 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 Month 3 in Forced Expiratory Volume in 1 Second (FEV1) | 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). | Month 3 through extension Month 60 | 
| Change From Baseline in FEV1 | Change from baseline: mean of (value of observed FEV1 [L] at treatment observation minus baseline value). | Baseline through extension follow up Month 3 | 
| Annual Rate of Change in 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 3 or end of study | 
| Summary of ≥ 15 % Decliners in FEV1 | 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. | Month 3 through extension follow up Month 3 | 
| 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 mercury per year (ml/min/mmHg/yr). | Week -2 through extension follow up Month 3 or end of study | 
| Change From Baseline in Carbon Monoxide Diffusion Capacity (DLco) | 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). | Baseline through extension follow up Month 3 | 
| Summary of ≥ 20 % Decliners in DLco | 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. | Month 3 through extension follow up Month 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Vital Capacity (FVC) | Forced Vital Capacity (FVC) measured in liters (L). | Week -3 through extension follow up Month 3 or end of study | 
| Total Lung Capacity (TLC) | Total Lung Capacity measured in liters (L). | Baseline through extension follow up Month 3 | 
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change from baseline: mean of (value of observed HbA1c [%] at treatment observation minus baseline value). | Baseline through extension follow up Month 3 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) | Change from baseline: mean of (value of observed FPG [milligrams per deciliter (mg/dL)] at treatment observation minus baseline value). | Baseline through extension follow up Month 3 | 
| Change From Baseline in Body Weight | Change from baseline: mean of (value of observed body weight [kilograms (kg)] at treatment observation minus baseline value). | 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 (units) insulin for inhaled insulin and subcutaneous treatment groups included NPH insulin, Ultralente®, and insulin glargine. | Month 3 through extension Month 36 | 
| Total Daily Long-acting Insulin (Adjusted for Body Weight) | 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. | Month 3 through extension Month 36 | 
| Total Daily Short-acting Insulin Dose (Unadjusted for Body Weight) | 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. | Month 3 through extension Month 36 | 
| Total Daily Short-acting Insulin Dose (Adjusted for Body Weight) | 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). | Month 3 through extension Month 36 | 
| Lipid Panel: Total Cholesterol, High Density Lipoprotein, Low Density Lipoprotein, and Triglycerides | Lipid values for total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides measured as milligrams per deciliter (mg/dL). | Week -4 through Month 24 | 
| Hypoglycemic Event Rates | 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). | Month 1 through extension Month 36 | 
| Severe Hypoglycemic Event Rates | 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. | Month 1 through extension Month 36 | 
| Cough Questionnaire | 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. | Week 0 and if indicated through extension follow up Month 3 | 
| 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 3 or end of study | 
| High Resolution Computerized Tomography (HRCT) Scan: Within Normal Limits (Yes or No) at Observation When Baseline HRCT Was Within Normal Limits | 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. | Baseline, M12, M24, Ext M6, Ext M18, Ext M36 | 
| High Resolution Computerized Tomography (HRCT) Scan: Within Normal Limits (Yes or No) at Observation When Baseline HRCT Was Not Within Normal Limits | 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). | Baseline, M12, M24, Ext M6, Ext M18, Ext M36 | 
| Insulin Antibodies | Observed values for insulin antibodies measured as micro units per milliliter (microU/mL). | Baseline through extension Month 36 |