| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
BRIEF REPORT |
University of California at San Francisco (P.N.), Valley Research, Fresno, California 93720; Laval Clinical Research Center (R.D.), Quebec, Canada G1V 4G2; Pennington Biomedical Research Center (W.C.), Baton Rouge, Louisiana 70808; McGill Nutrition and Food Science Center (J.-F.Y.), Montreal, Quebec, Canada H3A 1A1; and Pfizer Global Research and Development (R.E., R.R., J.T.), New London, Connecticut 06320
Address all correspondence and requests for reprints to: Paul Norwood, M.D., University of California at San Francisco, Valley Research, 550 East Herndon No. 101, Fresno, California 93720. E-mail: norwood{at}pol.net.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Research Design and Methods: In a 24-wk multicenter study, 226 nonsmoking patients with type 1 diabetes and normal lung function were randomized to intensive regimens of premeal EXU or sc insulin for 12 wk (comparative phase), followed by sc insulin for 12 wk (washout phase). Glycosylated hemoglobin, hypoglycemia, general adverse events, and pulmonary function were measured. Forced expiratory volume in 1 sec and carbon monoxide diffusion capacity were measured using standardized equipment and methodology.
Results: Comparable declines from baseline in glycosylated hemoglobin were observed in both groups (0.5%) and sustained throughout the study. There was a higher rate of hypoglycemia (risk ratio 1.23; 90% confidence interval 1.16, 1.30) but a lower rate of severe hypoglycemia (risk ratio 0.51; 90% confidence interval 0.30, 0.86) with EXU vs. sc insulin. The treatment group differences in changes from baseline in forced expiratory volume in 1 sec and carbon monoxide diffusion capacity were small, occurred within 2 wk of EXU initiation, and were reversible shortly after discontinuation. More patients reported mild cough with EXU vs. sc insulin (30.9% vs. 7.8%, respectively).
Conclusions: Three months of EXU therapy is as effective and well tolerated as intensive sc insulin therapy. This study supports the role of EXU in type 1 diabetes.
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Inhaled human insulin [Exubera (EXU) insulin human (recombinant DNA origin) Inhalation Powder; Pfizer Inc., New York, NY; Nektar Therapeutics, San Carlos, CA] is a novel, pulmonary dry-powder human insulin delivery system, which was approved in the United States and European Union for the treatment of adult patients with type 1 or 2 diabetes. In phase II and III studies, EXU has demonstrated comparable efficacy to conventional sc insulin regimen in patients with type 1 or 2 diabetes (6, 7, 8). These studies have also shown some changes in pulmonary function parameters but were not designed to investigate this in detail.
This study provides a robust characterization of the impact of short-term EXU on glycemic control and pulmonary function in patients with type 1 diabetes.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Each site’s institutional review board approved this study. Written informed consent was obtained before subjects were screened and before study enrollment. Subjects with type 1 diabetes aged between 25 and 65 yr, receiving a stable sc insulin schedule were included in the study. As previously reported (9), this open-label, 24-wk, parallel-group study consisted of a 3-wk baseline run-in phase and a 24-wk treatment phase. During the run-in phase, all subjects received a sc insulin regimen. This consisted of two to three times of daily administration of insulin aspart/lispro or regular insulin, plus once- or twice-daily administration of ultralente or Neutral Protamine Hagedorn insulin or once-daily administration of insulin glargine before bedtime. Subjects were randomized to receive an EXU regimen or continue receiving sc insulin for 12 wk. The EXU regimen consisted of premeal EXU plus a single bedtime dose of ultralente, Neutral Protamine Hagedorn insulin, or insulin glargine. Subjects randomized to receive EXU during the comparative phase were crossed over during the washout phase to receive the sc insulin regimen.
Inhaled human insulin was administered via the inhalation of individual 1- or 3-mg doses [1-mg dose of EXU 
3 IU of regular insulin (7)]. Dose was adjusted weekly to achieve a mean fasting glycemic target of 80–140 mg/dl. Subjects in the sc arms of the study used similar glycemic target ranges.
Study parameters
This study was designed to investigate the efficacy and safety profile of EXU in patients with type 1 diabetes. Efficacy was assessed by change from baseline in glycosylated hemoglobin (HbA1c) levels, prevalence and severity of hypoglycemic events, fasting plasma glucose, and body weight. Pulmonary function [forced expiratory volume in 1 sec (FEV1) and carbon monoxide diffusion capacity (DLco)]) was measured as reported elsewhere (9, 10). A questionnaire was used to characterize the cough experienced by patients during the study.
Statistical analyses
In this study, the primary analysis population is used to report parameters of efficacy and pulmonary function. This includes all randomized subjects who had at least two post-baseline FEV1 measurements at or beyond 6 wk of treatment, and received the study drug for at least 50% of the comparative phase. The standard safety population is used to report adverse event findings. The sample size of 100 subjects per treatment group provided this study with the precision to detect differences in change from baseline FEV1 of 0.040 liter and DLco of 0.6 ml/min·mm Hg.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
A total of 353 adult patients were screened, 226 patients were randomized and 189 patients completed the study. The baseline demographic and clinical characteristics of subjects were comparable in both treatment groups at study entry.
Efficacy
More than 90% of subjects in both treatment groups administered premeal short-acting insulin three times daily during the comparative phase of the study (data not shown). Of EXU- and sc-treated subjects, 54% and 45% used analog-based insulin regimens during the comparative phase of the study (e.g. EXU + insulin glargine or insulin aspart/lispro + insulin glargine), respectively.
The baseline mean (SD) HbA1c values were similar: 7.5% (1.2) and 7.5% (1.1) for patients randomized to the EXU and sc groups, respectively. By wk 6 of the comparative phase, both groups experienced similar declines in mean HbA1c: 0.5% for EXU and 0.5% for the sc treatment group. Declines were sustained in both treatment groups throughout the comparative phase [7.1% (0.9) for EXU and 7.0% (0.8) for sc at wk 12] and to the end of the study [wk 24 values 7.2% (1.0) and 7.1% (0.9) for EXU and sc groups, respectively] (Fig. 1A
). Mean adjusted changes from baseline HbA1c at wk 12 of the comparative phase were –0.43% for EXU and –0.45% for sc insulin, respectively; between treatment difference was 0.02% [90% confidence interval (CI) –0.12, 0.15). At wk 24, mean adjusted changes from baseline HbA1c were –0.38% and –0.48% for EXU and sc insulin, respectively; between treatment difference was 0.10% (90% CI –0.09, 0.28).
|
7% at the end of the 12-wk comparative phase was 46% and 57% in EXU- and sc-treated patients, respectively.
The fasting plasma glucose declined with EXU therapy during the comparative phase but increased during the washout phase [mean (SD) change from baseline: –33.36 (94.44) and –17.87 (97.85) at wk 12; and –5.70 (96.74) and –7.50 (98.35) at wk 24 for EXU and sc, respectively] (Fig. 1B
). The average daily short- and long-acting insulin doses were 11.2 mg and 26.2 IU and 26.8 IU and 29.8 IU for EXU and sc groups, respectively, at the end of the comparative phase. By the end of the study, mean (SD) body weight had increased by 1.1 kg (3.2) in patients receiving EXU and 1.7 kg (2.7) in patients treated with sc insulin.
Safety
The majority of adverse events were mild to moderate. Hypoglycemia was the most commonly reported adverse event but declined over time throughout the study in both treatment groups. During the comparative phase, 95 patients in the EXU group had a total of 1926 hypoglycemic events, and 99 patients in the sc group had a total of 1622 hypoglycemic events. At wk 12, the rates of overall hypoglycemia (events/subject-month) for EXU compared with sc were 6.8 vs. 5.6, respectively, a risk ratio of 1.23 (90% CI 1.16, 1.30) for EXU vs. sc insulin. At wk 24, the risk ratio was 1.09 (90% CI 1.02, 1.17).
The rates of overall severe hypoglycemia for EXU compared with sc were 5.3 vs. 10.3 (events/100 subject-months), respectively, during the comparative phase. The overall risk of a severe hypoglycemic event was lower for the EXU group relative to the sc group, with a risk ratio of 0.51 (90% CI 0.30, 0.86).
The incidence of all-causality cough was higher in EXU vs. sc-treated subjects (30.9% vs. 7.8%, respectively) at the end of the comparative phase and comparable (8.5% vs. 6.9%) at the end of the washout phase. The supplemental cough questionnaire revealed that the majority of coughs reported with EXU therapy were mild, rarely productive, and occurred within seconds or minutes of dosing. Two patients in the EXU group discontinued due to cough. In both cases, the cough resolved shortly after discontinuation of EXU treatment.
Decreases from baseline in FEV1 and DLco were observed in both treatment groups during the comparative phase. The changes in FEV1 are reported in detail elsewhere (9). Treatment group differences in DLco were fully manifest within 2 wk, remained stable thereafter during the comparative phase, and were promptly resolved after discontinuation of EXU during the washout phase. The largest difference (mean ± 90% CI) in change from baseline DLco occurred at wk 4 of the comparative phase [–0.907 ml/min·mm Hg (–1.338, –0.477)](Fig. 2).
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
These findings are consistent with previously published data from EXU and sc studies, where both treatment groups show comparable efficacy in patients with type 1 or 2 diabetes (6, 7, 8). However, in this study, subjects were under better glycemic control on entry, with an average starting HbA1c of 7.5%, and the majority of both groups received premeal short-acting insulin at least three times daily during the comparative portion of the study. Furthermore, in distinction from previous studies of EXU therapy, this study allowed the use of insulin analogs, which were used by approximately 50% of subjects in both treatment groups during the comparative phase. The intensive level of insulin therapy administered in this study was reflected in the level of glycemic control achieved. In achieving this level of glycemic control, EXU-treated subjects experienced a slightly higher incidence of overall hypoglycemia and a reduced incidence of severe hypoglycemia. Therefore, the results of this study indicate that EXU may be used effectively with either conventional or analog basal insulins to achieve improved levels of glycemic control in type 1 diabetes patients with a moderately well-controlled disease.
The incidence and severity of all-causality cough that occurred in this study was similar to that reported in a previous study of EXU in patients with type 1 diabetes (27% and 5% for EXU and sc, respectively) (8). In addition, the specialized questionnaire used in this study characterized this cough as mainly mild and occurring immediately after dosing. Together, these results suggest that EXU therapy can be associated with a mild cough that is well tolerated in most individuals.
Similar to the short-term changes in FEV1, a small, nonprogressive but reversible treatment-associated effect of EXU was observed in pulmonary gas exchange (DLco). Although one limitation of the current study is the short study duration, further longer term studies are currently underway to characterize further the pulmonary safety profile of EXU.
In conclusion, this detailed characterization of the short-term efficacy and pulmonary safety profile of EXU provides more evidence to support the comparable efficacy of EXU vs. an intensive sc regimen and confirms pulmonary function changes observed in previous studies. This study further supports the role of EXU as an appropriate treatment for patients with type 1 diabetes.
|
Footnotes |
|---|
The authors were involved with interpretation of the data, preparation, review, and approval of the manuscript.
These data have been published as abstracts and presented as oral/platform presentations at the 65th Annual Meeting of the American Diabetes Association, June 10–14, 2005, San Diego, CA; and the 41st Annual Meeting of the European Association for the Study of Diabetes, September 10–15, 2005, Athens, Greece.
Some aspects of the data from this study have been previously published by J. G. Teeter and R. Riese (Am J Respir Crit Care Med 173:1194–1200; 2006).
This work was supported by Pfizer Inc. Editorial support was provided by N. Nuottamo, B.Sc., of PAREXEL and was funded by Pfizer Inc.
First Published Online September 26, 2006
Abbreviations: CI, Confidence interval; DLco, carbon monoxide diffusion capacity; EXU, Exubera; FEV1, forced expiratory volume in 1 sec; HbA1c, glycosylated hemoglobin.
Received March 22, 2006.
Accepted November 30, 2006.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  M. B. Drummond, P. F. Schwartz, W. T. Duggan, J. G. Teeter, R. J. Riese, R. C. Ahrens, R. O. Crapo, R. D. England, N. R. MacIntyre, R. L. Jensen, et al. Intersession Variability in Single-Breath Diffusing Capacity in Diabetics without Overt Lung Disease Am. J. Respir. Crit. Care Med., August 1, 2008; 178(3): 225 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Wise, J. G. Teeter, R. L. Jensen, R. D. England, P. F. Schwartz, D. R. Giles, R. C. Ahrens, N. R. MacIntyre, R. J. Riese, and R. O. Crapo Standardization of the Single-Breath Diffusing Capacity in a Multicenter Clinical Trial Chest, October 1, 2007; 132(4): 1191 - 1197. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
