John G. Teeter

Sources of Long-term Variability in Measurements of Lung Function: Implications for Interpretation and Clinical Trial Design

BACKGROUND The objective of the study was to characterize the biological and technical components of variability associated with longitudinal measurements of FEV(1) and carbon monoxide diffusing capacity (Dlco). Variability was apportioned to subject and instrument for five commercially available pulmonary function testing (PFT) systems: Collins CPL (Ferraris Respiratory; Louisville, CO); Morgan Transflow Test PFT System (Morgan Scientific; Haverhill, MA); SensorMedics Vmax 22D (VIASYS Healthcare; Yorba Linda, CA); Jaeger USA Masterscreen Diffusion TP (VIASYS Healthcare; Yorba Linda, CA); and Medical Graphics Profiler DX System (Medical Graphics Corporation; St. Paul, MN). METHODS This was a randomized, replicated cross-over, single-center methodology study in 11 healthy subjects aged 20 to 65 years. Spirometry and Dlco measurements were performed at baseline, 3 months, and 6 months. Repetitive simulations of FEV(1) and Dlco were performed on the same instruments on four occasions over a 90-day period using a spirometry waveform generator and a Dlco simulator. RESULTS The coefficient of variation associated with repetitive measurements of FEV(1) or Dlco in subjects was consistently larger than that associated with repetitive simulated waveforms across the five instruments. Instrumentation accounted for 13 to 58% of the total FEV(1) and 36 to 70% of the total Dlco variability observed in subjects. Sample size estimates of hypothetical studies designed to detect treatment group differences of 0.050 L in FEV(1) and 0.5 mL/min/mm Hg in Dlco varied as much as four times depending on the instrument utilized. CONCLUSIONS These results provide a semiquantitative assessment of the biological and technical components of PFT variability in a highly standardized setting. They illustrate how instrument choice and test variability can impact sample size determinations in clinical studies that use FEV(1) and Dlco as end points.

Original ResearchPulmonary Function TestingSources of Long-term Variability in Measurements of Lung Function: Implications for Interpretation and Clinical Trial Design

BACKGROUND The objective of the study was to characterize the biological and technical components of variability associated with longitudinal measurements of FEV(1) and carbon monoxide diffusing capacity (Dlco). Variability was apportioned to subject and instrument for five commercially available pulmonary function testing (PFT) systems: Collins CPL (Ferraris Respiratory; Louisville, CO); Morgan Transflow Test PFT System (Morgan Scientific; Haverhill, MA); SensorMedics Vmax 22D (VIASYS Healthcare; Yorba Linda, CA); Jaeger USA Masterscreen Diffusion TP (VIASYS Healthcare; Yorba Linda, CA); and Medical Graphics Profiler DX System (Medical Graphics Corporation; St. Paul, MN). METHODS This was a randomized, replicated cross-over, single-center methodology study in 11 healthy subjects aged 20 to 65 years. Spirometry and Dlco measurements were performed at baseline, 3 months, and 6 months. Repetitive simulations of FEV(1) and Dlco were performed on the same instruments on four occasions over a 90-day period using a spirometry waveform generator and a Dlco simulator. RESULTS The coefficient of variation associated with repetitive measurements of FEV(1) or Dlco in subjects was consistently larger than that associated with repetitive simulated waveforms across the five instruments. Instrumentation accounted for 13 to 58% of the total FEV(1) and 36 to 70% of the total Dlco variability observed in subjects. Sample size estimates of hypothetical studies designed to detect treatment group differences of 0.050 L in FEV(1) and 0.5 mL/min/mm Hg in Dlco varied as much as four times depending on the instrument utilized. CONCLUSIONS These results provide a semiquantitative assessment of the biological and technical components of PFT variability in a highly standardized setting. They illustrate how instrument choice and test variability can impact sample size determinations in clinical studies that use FEV(1) and Dlco as end points.

Effects of inhaled human insulin on airway lining fluid composition in adults with diabetes

Inhaled human insulin (Exubera® (human insulin of rDNA origin) Inhalation Powder) causes small, early and reversible changes in pulmonary function in subjects with diabetes mellitus. The present study assessed whether changes occur in cellular and soluble constituents of airway lining fluid consistent with inflammation as a possible cause for Exubera®-associated lung function alterations. Two 31-week, open-label, sequential design phase 2 studies were conducted, one with 20 subjects with type 1 and one with 24 subjects with type 2 diabetes. After run-in, all subjects received subcutaneous insulin for 12 weeks, followed after 1 week by 12 weeks of Exubera®. Bronchoalveolar lavage fluid cell counts and protein constituents were determined at baseline, after 12 weeks of subcutaneous insulin and after 12 weeks of Exubera®. Baseline cellular and soluble constituents of lavage fluid were similar to those reported for nondiabetic adults. Exubera® produced no consistent clinically or statistically significant changes in total or differential lavage fluid cell counts or protein concentrations, even though Exubera®-associated changes in pulmonary function are known to be fully manifest within 12 weeks. Therefore, 12 weeks of Exubera® treatment is not associated with evidence of pulmonary inflammation. The treatment effects on lung function observed in Exubera® trials are not caused by lung inflammation.

Updating clinical endpoint definitions

The 6-Minute Walk Distance (6-MWD) has been the most utilized endpoint for judging the efficacy of pulmonary arterial hypertension (PAH) therapy in clinical trials conducted over the past two decades. Despite its simplicity, widespread use in recent trials and overall prognostic value, the 6-MWD has often been criticized over the past several years and pleas from several PAH experts have emerged from the literature to find alternative endpoints that would be more reliable in reflecting the pulmonary vascular resistance as well as cardiac status in PAH and their response to therapy. A meeting of PAH experts and representatives from regulatory agencies and pharmaceutical companies was convened in early 2012 to discuss the validity of current as well as emerging valuable endpoints. The current work represents the proceedings of the conference.

Intersession Variability in Single-Breath Diffusing Capacity in Diabetics without Overt Lung Disease

RATIONALE American Thoracic Society guidelines state that a 10% or greater intersession change in diffusing capacity of the lung (DL(CO)) should be considered clinically significant. However, little is known about the short-term intersession variability in DL(CO) in untrained subjects or how variability is affected by rigorous external quality control. OBJECTIVES To characterize the intersession variability of DL(CO) and the effect of different quality control methods in untrained individuals without significant lung disease. METHODS Data were pooled from the comparator arms of 14 preregistration trials of inhaled insulin that included nonsmoking diabetic patients without significant lung disease. A total of 699 participants performed repeated DL(CO) measurements using a highly standardized technique. A total of 948 participants performed repeated measurements using routine clinical testing. MEASUREMENTS AND MAIN RESULTS The mean intersession absolute change in DL(CO) using the highly standardized method was 1.45 ml/minute/mm Hg (5.64%) compared with 2.49 ml/minute/mm Hg (9.52%) in the routine testing group (P < 0.0001 for both absolute and percent difference). The variability in absolute intersession change in DL(CO) increased with increasing baseline DL(CO) values, whereas the absolute percentage of intersession change was stable across baseline values. Depending on the method, 15.5 to 35.5% of participants had an intersession change of 10% or greater. A 20% or greater threshold would reduce this percentage of patients to 1 to 10%. CONCLUSIONS Intersession variability in DL(CO) measurement is dependent on the method of testing used and baseline DL(CO). Using a more liberal threshold to define meaningful intersession change may reduce the misclassification of normal variation as abnormal change.

Acute passive cigarette smoke exposure and inhaled human insulin (Exubera) pharmacokinetics.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Active cigarette smoking is associated with increased permeability of the pulmonary alveolar epithelium, resulting in faster absorption of inhaled drugs such as Exubera (EXU). Absorption of EXU is increased approximately twice to four times as much in chronic smokers compared with nonsmokers. The rate of clearance of radioaerosols such as technetium-labelled diethylenetriamine penta-acetic acid is decreased in response to passive smoke exposure. WHAT THIS STUDY ADDS Passive smoke exposure causes a decrease in lung permeability, an effect opposite to that of active smoking. Acute passive smoke exposure results in a decrease in EXU bioavailability and does not create a risk of hypoglycaemia. These results are consistent with previous studies of radioaerosol lung clearance. AIMS Relative to nonsmokers, the bioavailability of inhaled human insulin (Exubera(R); EXU) is markedly increased in chronic smokers. The pharmacokinetics of EXU following passive cigarette smoke exposure is unknown. METHODS In an open-label, crossover study, healthy nonsmoking volunteers received two treatments in randomized sequence separated by a 2-week wash-out: (i) EXU 3 mg with no passive smoke exposure and (ii) EXU 3 mg after passive smoke exposure (atmospheric nicotine levels 75-125 mug m(-3)) for 2 h. Blood samples were obtained at prespecified times up to 6 h after EXU administration. RESULTS Twenty-seven subjects completed both study periods. Mean plasma insulin AUC(0-360) decreased by 17% [ratio 83%, 95% confidence interval (CI) 68.8, 99.5] and mean C(max) by 29% (ratio 71%, 95% CI 59.8, 83.1) after passive cigarette smoke exposure. The median (range) t(max) was 60 min (20-120 min) and 75 min (20-360 min) in the EXU with no exposure and EXU passive exposure groups, respectively. EXU was well tolerated. CONCLUSIONS Unlike active chronic smoking, acute passive cigarette smoke exposure modestly decreases EXU bioavailability and thus should not increase hypoglycaemia risk. These results are consistent with those from published literature involving technetium-labelled diethylenetriamine penta-acetic acid and suggest that passive cigarette smoke exposure causes an acute decrease in lung permeability vs. active smoking, which causes an increase in permeability.

Trough Insulin Levels in Bronchoalveolar Lavage Following Inhaled Human Insulin (Exubera) in Patients with Diabetes Mellitus

BACKGROUND/AIM There are few data regarding insulin levels in the lungs during diabetes therapy with inhaled insulin. We examined the disposition of inhaled human insulin (Exubera(®) [EXU] human insulin [recombinant DNA origin], Pfizer, New York, NY) in the lungs by measuring trough insulin levels in bronchoalveolar lavage (BAL) fluid after 12 weeks of EXU treatment. METHODS After a 4-week run-in period of subcutaneous insulin therapy, 24 subjects with type 1 diabetes mellitus (T1DM) and 26 with type 2 diabetes mellitus (T2DM) continued their basal insulin regimen and received premeal subcutaneous (SC) insulin for 13 weeks, followed by 12 weeks of premeal EXU. BAL was performed approximately 12 h after the last insulin dose at (1) baseline, (2) following SC insulin, and (3) following EXU. RESULTS Twenty patients with T1DM and 24 patients with T2DM completed all three bronchoscopies. BAL trough insulin levels were undetectable at baseline or following SC insulin. After EXU therapy, they increased to a median of 4.5 nM (1.6-9.0 nM) and 2.3 nM (0.5-9.4 nM) in T1DM and T2DM, respectively. BAL trough insulin levels did not correlate with treatment efficacy, adverse effects, plasma insulin levels, or changes in pulmonary function. A larger proportion of previous EXU doses was present in the BAL in patients with T1DM. We found no correlation between average daily insulin doses and BAL trough insulin levels. CONCLUSIONS BAL trough insulin increased following EXU therapy, but this increase did not correlate with other clinical or laboratory parameters, suggesting no significant biological action. Further studies are warranted to better understand inhaled insulin deposition and clearance and possible effects of increased insulin levels on the lungs.

Cross-Sectional and Prospective Study of Lung Function in Adults With Type 2 Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study Response to Yeh et al.

The study of Yeh et al. (1) raises awareness of the pulmonary dysfunction associated with type 2 diabetes. Prospective 2-year controlled lung function data regarding subjects with type 2 diabetes from the inhaled insulin (Exubera) development program have recently been published (2,3) and extend the results reported by Yeh et al. The subjects enrolled in these studies were predominantly middle-aged, type 2 diabetic Caucasian men and women who had never smoked or who had stopped smoking and who had normal or near-normal lung function at study entry. Barnett et al. (2) observed mean annualized declines in forced expiratory volume in 1 s (FEV1) and carbon …

Assessment of long-term immunological and pulmonary safety of inhaled human insulin with up to 24 months of continuous therapy

ABSTRACT Background: This study was performed to characterize the long-term safety and efficacy of inhaled human insulin (EXU; Exubera* (insulin human [rDNA origin]) Inhalation Powder). * Pfizer Inc, New York, NY, USA Scope: Patients with type 1 or type 2 diabetes (N = 1290) who had successfully completed one of six controlled EXU open-label trials elected to receive open-label treatment with EXU for up to 3 years, after which they were randomized to discontinue EXU or to continue therapy for 6 months, then discontinue. Immunologic safety was assessed by insulin antibody (IAb) binding, and pulmonary safety was assessed by tests for forced expiratory volume in 1 second (FEV1) and carbon monoxide diffusing capacity (DLCO). In addition, changes over time in IAbs were compared with changes in FEV1, DLCO, hypoglycemia, and efficacy. Findings: Antibody binding increased in patients with either type 1 or type 2 diabetes after initiation of EXU and plateaued within 6–12 months (increases were higher in patients with type 1 diabetes than in patients with type 2 diabetes). Decreases in FEV1 occurred primarily during the first 3–6 months of EXU therapy. Among adult patients in the All Subjects set, the mean (± SE) annualized rate of decline in FEV1 was −0.053 ± 0.007 liters/year (95% CI, −0.065, −0.040) in adult patients with type 1 diabetes, and −0.076 ± 0.005 liters/year (95% CI, −0.085, −0.067) in patients with type 2 diabetes. Changes in DLCO occurred primarily during the first 3–6 months of EXU therapy. Among adult patients, in the All Subjects set, the mean (± SE) annual decline in DLCO was −0.738 ± 0.097 mL/min/mmHg/year (95% CI, −0.927, −0.548) and −0.688 ± 0.082 mL/min/mmHg/year (95% CI, −0.849, −0.527) in patients with type 1 and type 2 diabetes, respectively. Antibody binding did not correlate with changes in glycemic control, lung function, dose, or hypoglycemia. Following discontinuation of EXU, IAbs decreased to near baseline levels. Conclusion: These results are consistent with other trials showing long-term maintenance of safety and efficacy of EXU despite insulin antibody formation and small treatment group differences in pulmonary function. A limitation of the study was the lack of a comparator therapy.

Long-term intersession variability for single-breath diffusing capacity

Background: Characterizing long-term diffusing capacity (D<smlcap>l</smlcap>_CO) variability is important in assessing quality control for D<smlcap>l</smlcap>_CO equipment and patient management. Long-term D<smlcap>l</smlcap>_CO variability has not been reported. Objectives: It was the aim of this study to characterize long-term variability of D<smlcap>l</smlcap>_CO in a cohort of biocontrols and to compare different methods of selecting a target value. Methods: Longitudinal D<smlcap>l</smlcap>_CO monitoring of biocontrols was performed as part of the inhaled insulin development program; 288 biocontrols were tested twice monthly for up to 5 years using a standardized technique. Variability, expressed either as percent change or D<smlcap>l</smlcap>_CO units, was assessed using three different target values. Results: The 90th percentile for mean intersession change in D<smlcap>l</smlcap>_CO was between 10.9 and 15.8% (2.6–4.1 units) depending on the target value. Variability was lowest when the mean of all D<smlcap>l</smlcap>_CO tests was used as the target value and highest when the baseline D<smlcap>l</smlcap>_CO was used. The average of the first six D<smlcap>l</smlcap>_CO tests provided an accurate estimate of the mean D<smlcap>l</smlcap>_CO value. Using this target, the 90th percentile for mean intersession change was 12.3% and 3.0 units. Variability was stable over time and there were no meaningful associations between variability and demographic factors. Conclusions: D<smlcap>l</smlcap>_CO biocontrol deviations >12% or >3.0 units, from the average of the first six tests, indicate that the instrument is not within quality control limits and should be carefully evaluated before further patient testing.