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

Study Overview
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Brief Summary
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A One Year Clinical Trial Assessing the Usefulness and Safety of Inhaled Insulin in Diabetics with Chronic Obstructive Pulmonary Disease.

Detailed Description
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Pfizer announced in October 2007 that it would stop marketing Exubera. At that time recruitment for study A2171030 was placed on hold. 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 A2171030 was terminated on June 17, 2008. Neither safety nor efficacy reasons were the cause of the study termination.

Official Title
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Efficacy and Safety of Inhaled Human Insulin (Exubera) Compared With Subcutaneous Human Insulin in the Therapy of Adult Subjects With Type 1 or Type 2 Diabetes Mellitus and Chronic Obstructive Pulmonary Disease: A One-Year, Multicenter, Randomized, Outpatient, Open-Label, Parallel-Group Comparative Trial

Conditions
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Diabetes Mellitus, Chronic Obstructive Pulmonary Disease

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: Diabetes Mellitus (Type 1 or Type 2) currently controlled with injected insulin Prior smokers with a fixed airflow obstruction at screening (FEV1/FVC < 70%) and FEV1 < 80% predicted and/or a history of chronic productive cough. Exclusion Criteria: Poorly controlled, unstable or steroid-dependent COPD, insulin pump therapy, active smoking

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 77 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 short-acting insulin with dose adjusted according to premeal blood glucose plus oral antidiabetic agent(s) and/or either once or twice daily doses of either Ultralente or neutral protamine hagedorn (NPH) insulin, or a single bedtime dose of insulin glargine.<br>|
| Experimental: Inhaled Insulin<br> | Drug: Inhaled Insulin<br>* Inhaled insulin with dose adjusted according to premeal blood glucose plus oral antidiabetic agent(s) and/or either once or twice daily doses of either Ultralente or NPH insulin, or a single bedtime dose of insulin glargine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) | FEV1 was measured in liters (L) 30 minutes following the administration of ipratropium. Change from baseline: mean of (value of observed FEV1 (L) at treatment duration minus baseline value). | Baseline, Weeks 1, 2, 3, 4, 6, 12, 18, 26, 39, 52 | 
| Change From Baseline in Post-Bronchodilator Carbon Monoxide Diffusion Capacity (DLco) | DLco measured in milliters/minutes/millimeters of mercury (mL/min/mmHg) 30 minutes following the administration of ipratropium. Change from baseline: mean of (value of observed DLco (mL/min/mmHg) at treatment duration minus baseline value). | Baseline, Weeks 1, 2, 3, 4, 6, 12, 18, 26, 39, 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Full Pulmonary Function Tests (PFTs) (Spirometry, Pre-Ipratropium and Pre-Insulin PFTs) | Full PFTs included spirometry pre- and 30-minutes post-ipratropium and were completed between the hours of 6 AM and 10 AM with subjects in the fasting state. Full PFT data were collected, but not analyzed. | Duration of the study | 
| Full PFTs (DLco, Pre-Ipratropium and Pre- Insulin PFTs) | Full PFTs included DLco pre- and 30-minutes post-ipratropium and were completed between the hours of 6 AM and 10 AM with subjects in the fasting state. Full PFT data were collected, but not analyzed. | Duration of the study | 
| Other PFTs (Besides FEV1 and DLco) | Other PFTs (besides FEV1 and DLco) were measured 30 minutes following the administration of ipratropium. Other PFTs included forced vital capacity (FVC), peak expiratory flow rate (maximal forced expiratory flow) (PEFR[FEFmax]), and forced expiratory flow from 25% to 75% of vital capacity (FEF25%-75%). Other PFT data were collected, but not analyzed. | Duration of the study | 
| Bronchodilator Responsiveness as Determined by the Change in FEV1 | Responsiveness was the percent change from the 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. | Weeks 1, 2, 3, 4, 6, 12, 18, 26, 39, 52 | 
| Insulin Dose Responsiveness for FEV1 | FEV1 dose responsiveness 10 and 60 minutes after insulin. FEV1 dose-responsiveness to insulin (defined as the difference between the FEV1 value following a dose of insulin and FEV1 value before a dose of insulin, operationally defined as the post-dose FEV1 value minus pre-dose FEV1 value). | Baseline, Week 9, Week 51 | 
| Insulin Dose Responsiveness for DLco | DLco dose responsivness 10 and 60 minutes after insulin. DLco dose-responsiveness to insulin (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). | Baseline, Week 9, Week 51 | 
| Methacholine PC20 | Methacholine challenge testing was conducted at selected sites at visits which did not occur at other sites (Weeks -2.9, -0.9, 11, 50 and 52+5). Methacholine challenge was not analyzed as there was only 1 test performed, which was a baseline test, and no methacholine tests performed in subjects using inhaled insulin. | Duration of the study | 
| Mean Weekly Number of Puffs of Short-Acting Bronchodilator Used | All subjects used diary cards to record their daily use of short-acting bronchodilators. Subjects recorded the sum of their short-acting bronchodilator use (puffs of albuterol plus ipratropium plus Combivent®, as applicable) daily, immediately upon arising, and again in the evening or before bed. Mean weekly number of puffs of short-acting bronchodilator used data were collected, but not analyzed. | Duration of the study | 
| Incidence of Non-Severe Chronic Obstructive Pulmonary Disease (COPD) Exacerbations | Non-severe COPD exacerbation = additional therapy (systemic corticosteroids, antibiotics, oxygen) needed for worsening respiratory symptoms and/or lung function, not needing hospitalization > 24 hours. 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. | 0 to 1 week to > 9 months | 
| Incidence of Severe COPD Exacerbations | Severe COPD exacerbation = a COPD-related hospitalization > 24 hours. 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. | 0 to 1 week to > 9 months | 
| Baseline Dyspnea Index (BDI) and Transition Dyspnea Index (TDI) Questionnaires | The BDI and TDI measured or quantitated the severity of breathlessness (shortness of breath) in symptomatic subjects. BDI and TDI data were collected, but not analyzed. | Duration of the study | 
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Change from baseline: mean of (value of observed HbA1c at treatment duration minus baseline value). | Baseline, Weeks 6, 12, 26, 39, and 52 | 
| Change From Baseline in Fasting Plasma Glucose | Change from baseline: mean of (value of observed fasting plasma glucose in milligrams/deciliters (mg/dL) at treatment duration minus baseline value). | Baseline, Weeks 6, 12, 26, 39, 52 | 
| Change From Baseline in Body Weight | Change from baseline: mean of (value of observed body weight in kilograms (kg) at treatment duration minus baseline value). | Baseline, Weeks 1, 2, 3, 4, 6, 9, 11, 12, 18, 26, 39, 50, 51, 52 | 
| Mean Total Daily Intermediate-/Long-Acting Insulin Dose (Unadjusted for Body Weight) | Intermediate-/long-acting insulin included Insulin NPH, Ultralente, and Insulin Glargine for both groups. | Weeks 1, 2, 3, 4, 6, 9, 12, 18, 26, 39, 52 | 
| Mean Total Daily Short-Acting Insulin Dose (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. | Weeks 1, 2, 3, 4, 6, 9, 12, 18, 26, 39, 52 | 
| Mean Total Daily Intermediate-/Long-Acting Insulin Dose (Adjusted for Body Weight) | Intermediate/long-acting insulin included Insulin NPH, Ultralente, and Insulin Glargine for both groups. Dose was adjusted for body weight (units divided by kg). | Weeks 1, 2, 3, 4, 6, 9, 12, 18, 26, 39, 52 | 
| Mean Total Daily Short-Acting Insulin Dose (Adjusted 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. Dose was adjusted for body weight (mg divided by kg or units divided by kg). | Weeks 1, 2, 3, 4, 6, 9, 12, 18, 26, 39, 52 | 
| Lipids | Lipids collected: Total cholesterol, high-density lipoprotein, low-density lipoptrotein, and triglycerides. Lipids data were collected, but not analyzed. | Duration of the study | 
| Hypoglycemic Event Rates | A hypoglycemic event was identified by characteristic symptoms; blood glucose levels at 59 mg/dL (3.2 mmol/L) or less with a glucose check; or any glucose measurement 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. | 0 to1 month to > 11 months | 
| Severe Hypoglcyemic Event Rates | An event was severe if the subject was unable to treat him/herself; had at least 1 neurological symptom; or blood glucose of < = 49 mg/dL or the blood glucose was not measured, but the clinical manifestations were reversed by oral carbohydrates, subcutaneous glucagon, or intravenous glucose. Crude event rate=total events/100 subject-months. Subject-months=elapsed number of months a subject was in the study in each time interval. | 0 to 1 month to > 11 months |