A methodological assessment of diurnal variability of peak flow as a basis for comparing different inhaled steroid formulations

doi:10.1016/S0091-6749(96)70089-1

Journal of Allergy and Clinical Immunology

Volume 98, Issue 3, September 1996, Pages 555-562

https://doi.org/10.1016/S0091-6749(96)70089-1 Get rights and content

Abstract

BACKGROUND: A “survival” model offers certain ethical and practical advantages over alternative experimental designs if used to compare antiasthmatic inhaled steroid formulations. The model requires an objective daily measure of therapeutic effect (e.g., peak expiratory flow rate, which may be expressed as the lower of two daily measurements (LPF) or as diurnal variability (DVPF). The relative efficiency of these two measures is unknown. OBJECTIVE: This study was conducted to determine the relative efficiency of LPF and DVPF. METHODS: We analyzed data from a placebo-controlled comparison of an active inhaled formulation of budesonide versus an inactive oral formulation. The primary outcome measure in this design is the number of days from the time the test treatments start until a statistically significant deterioration occurs from an optimal asthma control value established at baseline. RESULTS: DVPF proved less sensitive than LPF; that is, fewer patients relapsed during the 8-week trial period: 32 versus 41, respectively. Also, the median interval until relapse was longer: 24 versus 9 days. With LPF, inhaled budesonide proved more effective than placebo or oral budesonide (p = 0.03), whereas DVPF failed to discriminate among the test treatments (p = 0.38). LPF correlated with all three symptom indices (p ≥ 0.003) and two of three spirometric indices measured concomitantly (p ≤ 0.04). DVPF did not correlate with any index (p ≥ 0.10). CONCLUSION: In this experimental model, LPF proved more sensitive and valid than DVPF as an indicator of differences in antiasthmatic potency between two inhaled steroid formulations. (J ALLERGY CLIN IMMUNOL 1996;98:555-62.)

Section snippets

METHODS

The test group comprised 47 adults with a clinical history of suboptimally controlled mild to moderate asthma characterized by variable wheezing and dyspnea responsive to β-agonist bronchodilator inhalant, diffuse wheezing on auscultation, obstructive pulmonary impairment, and no chronic airflow limitation.¹ Relevant demographic characteristics are shown in Table I.

The patients were initially treated for 4 weeks with doses of beclomethasone averaging 1.09 mg/day, inhaled through a 750 ml volume

RESULTS

The variability between LPF and DVPF, as separate indicators of asthma relapse, is illustrated for three representative patients in Fig. 1. In patient 1, changes in LPF but not DVPF indicated the occurrence of asthma relapse. The reverse applied in patient 2. In patient 3 both indices varied concordantly.

The changes observed in the two indices after conversion to the test treatments are compared in Fig. 2 for each person in the study group. LPF declined in 42 of 47 patients (Fig. 2, C and D),

DISCUSSION

In this placebo-controlled double-blind clinical trial, DVPF, determined from twice daily measurements of peak expiratory flow, proved less sensitive and less valid than LPF as an index of the variable course of chronic asthma (Fig. 3 and Table II).

Furthermore, when LPF was used as the primary response index to differentiate the three test treatments in terms of their antiasthmatic efficacy, low-dose inhaled budesonide treatment was found to be significantly more effective than the placebo and

Acknowledgements

We thank Patricia Foster for preparing the manuscript and Stat Lab, U.W.O., for statistical support.

References (25)

JH Toogood et al.
A study of the mechanism of the antiasthmatic action of inhaled budesonide
J ALLERGY CLIN IMMUNOL
(1990)
LA Laitinen et al.
A comparative study of the effects of an inhaled corticosteroid, budesonide, and β ₂-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial
J ALLERGY CLIN IMMUNOL
(1992)
JH Toogood et al.
Bioequivalent doses of budesonide and prednisone in moderate and severe asthma
J ALLERGY CLIN IMMUNOL
(1989)
JH Toogood
Concentrated aerosol formulations in asthma
Lancet
(1983)
PG Gibson et al.
A research method to induce and examine a mild exacerbation of asthma by withdrawal of inhaled corticosteroid
Clin Exp Allergy
(1992)
G Ryan et al.
Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, and airway calibre
Thorax
(1982)
AJ Woolcock et al.
Effect of therapy on bronchial hyperresponsiveness in the long-term management of asthma
Clin Allergy
(1988)
AJ Woolcock et al.
Prevalence of bronchial hyperresponsiveness and asthma in a rural adult population
Thorax
(1987)
T Haahtela et al.
Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma
N Engl J Med
(1994)
R Djukanovic et al.
Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma
Am Rev Respir Dis
(1992)

PK Jeffery et al.

Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma

Am Rev Respir Dis

(1992)

C Burke et al.

Lung function and immunopathological changes after inhaled corticosteroid therapy in asthma

Eur Respir J

(1992)

Cited by (12)

The utility of peak flow, symptom scores, and β-agonist use as outcome measures in asthma clinical research
2001, Chest
Several methods of utilizing peak expiratory flow (PEF) and other markers of disease activity have been suggested as useful in the management of asthma. It remains unclear, however, as to which surrogate markers of disease status are discriminative indicators of treatment failure, suitable for use in clinical trials.
We analyzed the operating characteristics of 66 surrogate markers of treatment failure using a receiver operating characteristic (ROC) curve analysis.
Information regarding FEV₁, symptoms, ββ₂-agonist use, and PEF was available from 313 subjects previously enrolled in two Asthma Clinical Research Network trials, in which 71 treatment failures occurred (defined by a 20% fall in FEV₁ from baseline).
None.
None of the measures had an acceptable ability to discriminate subjects with a ≥≥ 20% fall in FEV₁ from those without, regardless of the duration of the period of analysis or the criteria for test positivity employed. Areas under the ROC curves generated ranged from 0.51 to 0.79, but none were statistically superior. Sensitivity and specificity combinations were generally poor at all cutoff values; true-positive rates could not be raised without unacceptably elevating false-positive rates concurrently.
Studies that seek to detect treatment failure defined by a significant fall in FEV₁ should not use such individual surrogate measures to estimate disease severity.
Chronic glucocorticoid therapy-induced osteoporosis in patients with obstructive lung disease
1999, Chest
Long-term glucocorticoid (GC) therapy has been instrumental in decreasing morbidity and mortality in a variety of chronic inflammatory diseases, including persistent asthma. Long-term GC therapy is also widely prescribed for COPD. One of the important and often unrecognized side effects of chronic GC therapy is secondary osteoporosis. The risk of GC-induced bone loss is roughly correlated with daily dose, duration, and total cumulative lifetime dose of GC treatment. Oral prednisone increases the risk of bone loss and fracture. High doses of inhaled GCs may also increase the risk of osteopenia/osteoporosis, but the risk appears to be less than that associated with oral GCs. Hormone replacement therapy, oral and parenteral bisphosphonates, supplemental calcium and vitamin D, calcitonin, and fluoride compounds have been used, experimentally, in the management of GC-induced bone loss. Asthma and COPD specialists are key prescribers of oral and inhaled steroids and are likely to encounter patients with significant bone loss. Despite known risk factors and the availability of reliable diagnostic tools to recognize bone loss, the opportunity to slow, reverse, and treat bone loss is often missed. We present a review of the current literature regarding the incidence, treatment, and prevention of osteopenia/osteoporosis secondary to chronic GC therapy in adult asthma and COPD patients. Guidelines are presented regarding the identification of patients at risk for developing GC-induced secondary bone loss, and therapeutic alternatives are discussed.
Pharmacology of inhaled glucocorticoids. Comparative properties
1999, Immunology and Allergy Clinics of North America
The inhaled glucocorticoids are the most effective drugs currently available for the long-term control of persistent asthma and offer the broadest array of anti-inflammatory activity.⁷ The inhaled glucocorticoids were developed to provide the beneficial effects of glucocorticoids without the unwanted adverse effects. To achieve improved local or topical selectivity, physicochemical modifications of the basic steroid structure were made that result in both enhanced topical potency and diminished systemic activity. The structural changes have also produced differences in pharmacokinetics and potency among the various products.7, 14, 20, 37 As a result, the recently published National Asthma Education and Prevention Program (NAEPP) guidelines for asthma treatment provide a dosage table of approximately comparative clinical dosages for the available inhaled glucocorticoids (Table 1).⁴⁴ This table assumes that, aside from potency differences, only minimal differences in topical selectivity exist among products. Since the NAEPP guidelines were published, a number of comparative clinical trials have confirmed the existence of clinically significant differences in potency among the inhaled glucocorticoids.37, 48 There is some suggestion that significant differences in topical selectivity may also exist.
This article evaluates how the clinical pharmacologic differences among the inhaled glucocorticoid products might translate into significant differences in their clinical effectiveness. The clinical trials that concurrently evaluate safety and efficacy are reviewed to confirm clinically important differences among products.
Establishing a therapeutic index for the inhaled corticosteroids: Part I. Pharmacokinetic/pharmacodynamic comparison of the inhaled corticosteroids
1998, Journal of Allergy and Clinical Immunology
The inhaled corticosteroids contain physicochemical differences that alter both glucocorticoid receptor-binding characteristics and the pharmacokinetic variables of these drugs. Differences in receptor-binding affinity translate into differences in potency for different drugs. Differences in pharmacokinetics, however, determine the topical effect to systemic effect ratio, or the “pulmonary targeting” of the drug. Beneficial pharmacokinetic properties that may improve pulmonary targeting include low oral bioavailability, rapid systemic clearance, and slow absorption from the lung. Delivery devices can produce clinically significant differences in topical activity by altering the dose deposited in the lung and, for orally absorbed drugs, the amount deposited in the oropharynx and swallowed. Clinical trials have confirmed that differences in potency or drug delivery of 2-fold or more can be detected in patients with asthma. However, because of the relatively flat nature of the dose-response curve for morning peak expiratory flow and forced expiratory volume in 1 second, the trials must be adequately powered and well controlled. The use of bronchial provocation measures are problematic because of the prolonged lag time for response. Study design flaws can lead to misinterpretation of results. Clinical studies have indicated the following relative potency differences: fluticasone propionate > budesonide = beclomethasone dipropionate > triamcinolone acetonide = flunisolide. Current evidence suggests that potency differences can be overcome by giving larger doses of the less potent drug. However, because of these potency differences, studies of systemic effects should not be done in isolation of adequate topical activity studies to define the pulmonary targeting of the drugs. (J Allergy Clin Immunol 1998;102:S36-S51)
Domiciliary diurnal variation of exhaled nitric oxide fraction for asthma control
2014, European Respiratory Journal
The analysis of peak expiratory flow data using a three-level hierarchical model
2004, Statistics in Medicine

View all citing articles on Scopus

^☆: From ^aVictoria Hospital, London, Canada; ^b University of Western Ontario, Department of Medicine, London, Canada; and ^cUniversity of Western Ontario, Department of Statistical and Actuarial Sciences, London, Canada.

^☆☆: Supported by Research Fund of the Medical Associates of Victoria Hospital, and Allergy Research Fund, University of Western Ontario, London, Canada and by grants from AB Draco, Lund, Sweden.

^★: Reprint requests: John H. Toogood, MD, FRCPC, Victoria Hospital Allergy Clinic, 800 Commissioners Rd., E., London, Ontario, Canada N6A 4G5.

^★★: 0091-6749/96 $5.00 + 0 1/1/73129

View full text

A methodological assessment of diurnal variability of peak flow as a basis for comparing different inhaled steroid formulations☆,☆☆,★,★★

Abstract

Section snippets

METHODS

RESULTS

DISCUSSION

Acknowledgements

J ALLERGY CLIN IMMUNOL

J ALLERGY CLIN IMMUNOL

J ALLERGY CLIN IMMUNOL

Lancet

A research method to induce and examine a mild exacerbation of asthma by withdrawal of inhaled corticosteroid

Clin Exp Allergy

Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, and airway calibre

Thorax

Effect of therapy on bronchial hyperresponsiveness in the long-term management of asthma

Clin Allergy

Prevalence of bronchial hyperresponsiveness and asthma in a rural adult population

Thorax

Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma

N Engl J Med

Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma

Am Rev Respir Dis

Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma

Am Rev Respir Dis

Lung function and immunopathological changes after inhaled corticosteroid therapy in asthma

Eur Respir J