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

• ClinicalTrials.gov Identifier: NCT00136916
• Recruitment Status: Terminated
• First Posted: August 29, 2005
• Results First Posted: January 18, 2010
• Last Update Posted: February 18, 2010
• Sponsor: Pfizer
• Information provided by: Pfizer

Tracking Information

• First Submitted Date: August 25, 2005
• First Posted Date: August 29, 2005
• Results First Submitted Date: December 10, 2009
• Results First Posted Date: January 18, 2010
• Last Update Posted Date: February 18, 2010
• Study Start Date: June 2002
• Actual Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 10, 2009)

• Change From Month 3 in Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: Month 3 through extension Month 60 ]
  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).
• Change From Baseline in FEV1 [ Time Frame: Baseline through extension follow up Month 3 ]
  Change from baseline: mean of (value of observed FEV1 [L] at treatment observation minus baseline value).
• Annual Rate of Change in FEV1 [ Time Frame: Week -2 through extension follow up Month 3 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).
• Summary of ≥ 15 % Decliners in FEV1 [ Time Frame: Month 3 through extension follow up Month 3 ]
  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.
• Annual Rate of Change in Carbon Monoxide Diffusion Capacity (DLco) [ Time Frame: Week -2 through extension follow up Month 3 or end of study ]
  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).
• Change From Baseline in Carbon Monoxide Diffusion Capacity (DLco) [ Time Frame: Baseline through extension follow up Month 3 ]
  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).
• Summary of ≥ 20 % Decliners in DLco [ Time Frame: Month 3 through extension follow up Month 3 ]
  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.

• Original Primary Outcome Measures (submitted: August 25, 2005): The primary outcome is to assess the toleration and safety of inhaled insulin compared to subcutaneous insulin therapy and the effects if any on measures of pulmonary function.

Current Secondary Outcome Measures (submitted: February 12, 2010)

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

• Original Secondary Outcome Measures (submitted: August 25, 2005): Secondary endpoints include: hbA1c, fasting plasma glucose, body weight, insulin dose, incidence and severity of hypoglycemic episodes, cough questionnaire, and baseline and transition dyspnea index.
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of Inhaled Insulin Compared With Subcutaneous Human Insulin Therapy in Adults With Type 2 Diabetes
• Official Title: 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

Brief Summary

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: 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Diabetes Mellitus

Intervention

• Drug: Inhaled Insulin
  Inhaled insulin with dose adjusted according to premeal blood glucose
  Other Name: Exubera
• Drug: Subcutaneous insulin
  Subcutaneous insulin with dose adjusted according to premeal blood glucose

Study Arms

• Experimental: Inhaled Insulin
  Inhalable short-acting insulin
  Intervention: Drug: Inhaled Insulin
• Active Comparator: Subcutaneous insulin
  Intervention: Drug: Subcutaneous insulin

Publications *

• Rosenstock J, Cefalu WT, Hollander PA, Klioze SS, Reis J, Duggan WT. Safety and efficacy of inhaled human insulin (exubera) during discontinuation and readministration of therapy in adults with type 2 diabetes: a 3-year randomized controlled trial. Diabetes Technol Ther. 2009 Nov;11(11):697-705. doi: 10.1089/dia.2009.0062.
• Rosenstock J, Cefalu WT, Hollander PA, Belanger A, Eliaschewitz FG, Gross JL, Klioze SS, St Aubin LB, Foyt H, Ogawa M, Duggan WT. Two-year pulmonary safety and efficacy of inhaled human insulin (Exubera) in adult patients with type 2 diabetes. Diabetes Care. 2008 Sep;31(9):1723-8. doi: 10.2337/dc08-0159. Epub 2008 Jun 5.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: October 8, 2009): 635
• Original Enrollment (submitted: August 25, 2005): 600
• Actual Study Completion Date: December 2008
• Actual Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Type 2 diabetes mellitus

Exclusion Criteria:

• COPD
• Asthma
• Smoking Pregnancy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 35 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Brazil, Canada, Puerto Rico, United States

Administrative Information

• NCT Number: NCT00136916
• Other Study ID Numbers: A2171029
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Director, Clinical Trial Disclosure Group, Pfizer, Inc.
• Original Responsible Party: Not Provided
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: December 2009