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

Phase 3

Terminated

Conditions: Diabetes Mellitus, Type 1

Interventions: Drug: Subcutaneous Insulin
Drug: Inhaled Insulin

Registration Number: NCT00137046

Lead Sponsor: Pfizer

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 582

Inclusion Criteria

Type 1 diabetes mellitus

Exclusion Criteria

severe asthma or COPD
smoking
brittle diabetes

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Subcutaneous Insulin	Subcutaneous Insulin	-
Inhaled Insulin	Inhaled Insulin	-

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Forced Expiratory Volume in One Second (FEV1)	Baseline through Extension Follow-up Month 3	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).
Summary of ≥ 15% Decliners in Forced Expiratory Volume in One Second (FEV1)	Month 3 through Extension Follow-up 3	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.
Change From Baseline in Carbon Monoxide Diffusion Capacity (DLco)	Baseline through Extension Follow-up Month 3	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).
Summary of ≥ 20% Decliners in Carbon Monoxide Diffusing Capacity (DLco).	Month 3 through Extension Follow-up Month 3	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.
Annual Rate of Change in Forced Expiratory Volume in 1 Second (FEV1)	Week -2 through Extension Follow-up Month 6 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).
Annual Rate of Change in Carbon Monoxide Diffusion Capacity (DLco)	Week -2 through Extension Follow-up Month 6 or end of study	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).

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Glycosylated Hemoglobin (HbA1c)	Baseline through Extension Follow-up Month 3	Change from Baseline: mean of (value of Glycosylated Hemoglobin \[HbA1c\] at observation minus Baseline value).
Hypoglycemic Event Rates	Month 1 through Extension Month 39	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.
Severe Hypoglycemic Event Rates	Month 1 through Extension Month 39	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.
Change From Baseline in Fasting Plasma Glucose	Baseline through Extension Follow-up Month 3	Change from Baseline: mean of (value of fasting plasma glucose \[milligrams per deciliter (mg/dL)\] at observation minus Baseline value).
Change From Baseline Body Weight	Baseline through Extension Follow-up Month 3	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.
Total Daily Long-Acting Insulin Dose (Unadjusted for Body Weight)	Month 3 through Extension Month 39	Total Daily Long-Acting Insulin Dose Unadjusted for Body Weight; long-acting insulin included NPH Insulin, Ultralente, and Insulin Glargine for both groups.
Total Daily Long-Acting Insulin Dose Adjusted for Body Weight	Month 3 through Extension Month 39	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.
Total Daily Short-Acting Insulin Dose (Unadjusted for Body Weight)	Month 3 through Extension Month 39	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.
Total Daily Short-Acting Insulin Dose Adjusted for Body Weight	Month 3 through Extension Month 39	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.
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.
Transition Dyspnea Index (TDI)	Week 4 through ,Extension Follow-up Month 6 and every 6 months thereafter 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.
Lipids	Week -4 through Month 24	Total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides measured as milligrams per deciliter (mg/dL).
Cough Questionnaire	Week 0 and if indicated through Extension Follow up Month 3	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.
Forced Vital Capacity (FVC)	Week -3 through Extension Follow-up Month 6 or End of Study	Forced Vital Capacity (FVC) measured in liters (L).
Total Lung Capacity (TLC)	Week -3 through Extension Follow-up Month 6 or End of Study	Total Lung Capacity measured in liters (L).
Insulin Antibodies	Baseline through Extension Month 39	Median insulin antibodies at each visit measured in micro units per milliliter (microU/mL).