| 1. Asthma is an inflammatory disease of the airways |
The first inhaled corticosteroid, beclomethasone dipropionate (BDP) was introduced in the early 1970´ies (17). It was administered as one or two low doses four times daily, 50-100 µg q.i.d., and the main indication was as an oral steroid sparing medication. It was quite common that BDP was given as a last resort when all other asthma medications had been tried. One reason for this positioning was also that long-term safety had not yet been established.
Budesonide (Pulmicort®) was the next inhaled corticosteroid developed in the 1970`s and introduced on the first market in 1982. Systematic structure-activity work had resulted in an inhaled corticosteroid with an improved ratio between local anti-inflammatory activity and systemic activity compared with BDP (18,19).
Early studies with budesonide showed an acute dose-response for improvement in airway function (20) (Fig.1).
Fig.1. Dose-response after administration of single doses of budesonide to patients with allergic asthma. From Ref 20.
Studies in patients with allergic asthma exhibiting a dual allergic reaction when challanged with specific allergens - an early as well as a late reaction - revealed that not only the late allergic reaction was blocked, but also the early allergic reaction (EAR). The effect of budesonide on EAR was time dependent. A minor change was seen after treatment with budesonide for one week, but an almost complete blocking after treatment for 4 weeks (21)
(Fig. 2).
Fig.2. Effects on allergic early and late asthmatic reactions after pretreatment with placebo and budesonide 1000 µg/day (400 µg in the morning and 600 µg in the evening) for 7 days and 4 weeks. From Ref 21.
Studies investigating the effects of budesonide compared with terbutaline on bronchial hyperresponsiveness, BHR, were also performed (22). Effect on BHR was found to be a function not only of dose but also of time (23). In addition, treatment with budesonide resulted in a plateau effect indicating that patients using budesonide were protected againt maximal airway narrowing (24). This may partly explain why mortality has significantly decreased in countries using inhaled corticosteroids as first line treatment.
Fig.3. Effect of treatment with budesonide on methacholine challenge. Demonstration of a plateau effect. From Ref 24.
Despite these findings budesonide (and BDP) was only used for treatment of patients with moderate-to-severe asthma. Treatment of newly detected, mild asthma was always treated with inhaled or oral bronchodilators.
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| 2. Budesonide as first-line therapy of persistent asthma |
The first study to challenge the established treatment algorithm was the study by Haahtela et al (25). Patients with newly detected mild-to-moderate persistent asthma (asthma symptoms for less than 12 months), who normally should have been treated with a ß2-agonist used as needed or 2-3 times daily, were treated with budesonide (Pulmicort pMDI attached to a large volume plastic spacer, Nebuhaler®) 600 µg twice daily or terbutaline pMDI 375 µg twice daily for 2 years in a study with randomised, double-blind, parallel group design. Treatment with budesonide was found significantly more effective in improving airway function (Fig.4) and BHR (Fig.5) than the ß2-agonist.
Fig.4. Effect on morning PEF during 2-year treatment with budesonide or terbutaline. From Ref 25.
Fig.5. Effect of 2-year treatment with budesonide or terbutaline on BHR.
From Ref 25.
Bronchial biopsies were obtained before the study and showed a damaged epithelium, few ciliated cells, no distinct basement membrane structure, and a heavy infiltration with inflammatory cells such as eosinophils, mast cells and lymphocytes of the T-helper phenotype (CD 4+ cells) (Fig.6) (26). At that time the general understanding was that this type of inflammatory lesions were present only in patients with severe, chronic asthma.
Fig.6. Inflammatory reaction in the airway mucosa in a patient with early detected mild asthma. E=epithelium, BM=basement membrane,Eo=eosinophil, L=lymphocyte, M=mast cell. From Ref 26.
New bronchial biopsies were obtained after double-blind treatment for 3 months. They showed that treatment with budesonide, compared with terbutaline, restored the damaged airway epithelium, increased the number of ciliated cells and significantly reduced the number of eosinophils, T-lymphocytes and mast cells (Figs.7 and 8) (26).
Fig.7. Reduction in mucosal eosinophils after treatment with budesonide for 3 months From Ref 25.
Fig.8. Restoration of airway epithelium after treatment with budesonide for 3 months From Ref 25.
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| 3. Early intervention with budesonide |
The study was thereafter continued for a third treatment year (27). Patients treated for 2 years with budesonide were randomised to further double-blind treatment with placebo or a lower dose of budesonide, Pulmicort Turbuhaler, 200 µg twice daily. Patients treated with terbutaline for 2 years received in an open manner budesonide in an identical way as those patients treated with budesonide from the beginning, i.e. 600 µg b.i.d. as pMDI and spacer. The study design is shown in Fig. 9.
Fig.9. Study design of the two studies by Haahtela et al. From Ref 27.
Three important observations were made:
1) the lower dose of budesonide was enough to keep the patients on the same level of symptom control, airway function and BHR as during the 2-year part of the study with a higher dose of budesonide (Fig.10).
Clinical implication: After achieving good asthma control with a high dose of budesonide the daily dose can be reduced.
2) patients treated with placebo for the third year deteriorated as a group (Figs 10 and 11). Some patients, however, approximately one third of the placebo-treated patients, did not deteriorate during the placebo treatment year.
Clinical implication: Most patients with persistent asthma require regular maintenance treatment with an inhaled corticosteroid. Doses can be adjusted but treatment should not be discontinued.
3) terbutaline-treated patients who recevied budesonide with a 2-year delay improved in airway function and BHR but did not achieve the same level of control as those patients treated with budesonide from the beginning when they had had asthma symptoms for less than 12 months (Fig.11).
Clinical implication: Early treatment with budesonide is more effective than delayed treatment.
Fig. 10. Morning PEF during 3 years with the series of patients divided into three groups according to treatment during year 3. From Ref 27.
Fig. 11. PC15 histamine during 3 years with patients divided into three groups according to treatment during year 3. From Ref 27.
The results of these two publications (25,27) coined the term "early intervention" with inhaled corticosteroids in asthma. The findings were subsequently confirmed in other studies in asthmatic children (28) and adults (29,30).
The results of the studies by Haahtela et al and subsequent studies changed the treatment guidelines. A new algorithm was adopted and generally accepted. From now on international and national asthma treatment guidelines recommend that treatment of patients with persistent asthma should always be initiated with anti-inflammatory medication, preferably with an inhaled corticosteroid.
It was also shown that the immediate differences seen in response during the first treatment year between early and delayed introduction with inhaled corticosteroids was maintained many years after starting treatment (31). In one study patients with delayed introduction of budesonide had, five years after starting treatment, used significantly more corticosteroids and other asthma medications than patients starting treatment when asthma symptoms had persisted for less than two years (31). Treatment goals as stated in asthma guidelines had also been achieved significantly more often with early than with delayed therapy (Figure 12) (31).
| Early treatment | Delayed treatment |
| (n=206) | (n=129) |
| FEV1 >90% predicted normal | 78% | 41% |
| Exercise tolerance normal | 77% | 24% |
| Normal sleep | 83% | 78% |
Use of rescue medication
<4 times per week | 66% | 34% |
Exacerbations per patient per
year requiring predisolone | 0,03 | 0,4 |
Fig.12. Achievement of asthma treatment goals as stated in GINA guidelines. All differences were statistically significant. From Ref 31.
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| 4. The START study |
To finally confirm that early intervention in mild asthma is a successful strategy the world-wide 3-year double-blind START study was conducted (32). After the double-blind phase (Part A) all patients received budesonide for two additional years (Part B) (Fig. 13).
The aim was to investigate whether early treatment with budesonide improves asthma control in patients with mild persistent asthma (duration <2 years). Patients were treated with budesonide 200 µg (children <10 years of age) or 400 µg once daily or placebo administered via Turbuhaler in addition to any other asthma medication. The endpoint was the time to the first severe asthma-related event. The design of the study is shown in Fig. 13.
Fig. 13. Study outline of the START study. From Ref 32
A total of 7241 patients from 32 countries were randomized into the study and 5155 completed it. A total of 7167 patients could be included in the statistical analyses. Their mean age (SD) was 24 (15) years. 27% were children <10 years of age, 17% 11-17 years old, and 56% >18 years old. There were 65% Caucasian patients, 28% Oriental and 7% others; 46% of the patients were male. The patients mean prebronchodilator FEV1 was 86% predicted normal.
The risk of having a first severe asthma-related event was reduced by 44% with budesonide treatment; hazard ratio 0.56 (95% CI 0.45-0.71) (Fig.14). In patients with a prebronchodilator FEV1 of >80% predicted normal and who were not receiving corticosteroids at commencement of the study the risk was reduced by 47%.
Fig.14. Time to first asthma-related event in patients treated for three years with budesonide or placebo. From Ref 32.
A total of 117 and 198 patients in the budesonide and placebo groups, respectively, had experienced at least one severe asthma-related event after three years´ treatment, while 30 and 49 patients, respectively had had two or more severe asthma-related events. Life-threatening asthma exacerbations occurred in 9 and 24 patients, respectively. Patients in the budesonide group had significantly more symptom-free days than those in the placebo group.
Compared with placebo, budesonide increased both pre- and postbronchodilator FEV1, after treatment for one as well as for three years.
The results of the START study confirmed results of previous smaller studies that early intervention with an inhaled corticosteroid in patients with persistent asthma should be the treatment of choice.
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| 5. Dose-response with budesonide |
The presence of dose-response with inhaled corticosteroids has in some studies been difficult to demonstrate and it is obvious that the dose-response curve is rather flat. Nevertheless a dose-response exists. Usually, a statistically significant difference between doubling doses has not been possible to demonstrate for variables such as airway function (peak flow, FEV1), asthma symptoms, use of reliever medication etc. A four times higher dose has been required to show a statistically significant difference between improvements.
A large number of studies with two doses of budesoinde have been reported. Only a few studies have used three or more doses.
Miyamoto et al gave budesonide Turbuhaler, 100 µg, 200 µg and 400 µg twice daily, to 267 steroid naïve patients in a 6-week placebo-controlled study (33). A statistically significant dose-response was demonstrated for the primary variable of efficacy, increase in morning PEF, with a statistically significant difference between the lowest dose and the four times higher dose (Fig. 15).
Fig. 15. Dose-response in corticosteroid-naïve patients with asthma with budesonide Turbuhaler. From Ref 33.
Similarly, in a study in 473 patients previously treated with inhaled corticosteroids, Busse et al demonstrated a dose-response for four doses of budesonide delivered via Turbuhaler, 100 µg, 200 µg, 400 µg and 800 µg twice daily (34). As seen in Fig. 16, all doses were significantly more effective than placebo but no clinically important difference was seen between the two highest doses. With a dose of 400 µg twice daily a maximum level of efficacy seems to be achieved in patients with moderate severe asthma.
Fig. 16. Dose-response in previously corticosteroid-treated patients with asthma with budesonide Turbuhaler. From Ref 34.
A 12-week, placebo-controlled, dose-response study compared the efficacy of budesonide delivered by Turbuhaler, 100 µg, 200 µg and 400 µg twice daily in 404 children aged 6 to 18 years with moderate-to-severe asthma (35). All doses of budesonide produced significant improvements in morning PEF, which became apparent within 2 weeks of treatment and were maintained throughout the treatment period. The difference between the lowest and the highest doses was statistically significant (Fig.17).
Fig. 17. Dose-response in children with moderate-to-severe asthma treated with three doses of budesonide Turbuhaler. From Ref 35.
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| 6. Once-daily budesonide |
For many years it has been known that patients with mild-to-moderate asthma can be treated with budesonide once daily. A recent review covering the years 1986 to 2002 identified 23 controlled once-daily budesonide studies comprising 4466 adult patients and 1532 children with asthma (36). The once-daily doses have mostly been 200 µg or 400 µg via Turbuhaler once daily. As budesonide is rapidly absorbed from the airways due to relatively high water solubility compared with lipophilic corticosteroids such as e.g. mometasone fumarate, (which is also approved for once-daily dosing) budesonide can be dosed once either in the morning or in the evening without differences in efficacy. Studies with mometasone have shown that once-daily administration in the evening is more effective than morning dosing. This may be because mucociliary clearance is more effective during day than during night time. A lipophilic steroid staying for a long time in the airways before absorption is therefore partly subject to transport away from the airways before being absorbed.
For many years it was not understood why budesonide, being a less lipophilic substance, could have a prolonged duration of action allowing for once daily administration.
The detection of an intracellular esterification process of budesonide apparently gives the explanation for the duration of action. After absorption from the airways budesonide enters various inflammatory cells. Inactive budesonide fatty-acid esters are formed, which represent a depot from which active budesonide is gradually released via lipolysis over a long time (36,37). This is schematically shown in Fig. 18.
Fig. 18. Formation of intracellular, inactive, but reversible budesonide esters. From Ref 37.
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| 7. Budesonide suspension for nebulisation |
Budesonide suspension for nebulisation (Pulmicort Respules®) has been developed as a suitable inhaled corticosteroid formulation for use in infants and young children. It represents a safer alternative to systemic corticosteroids and was gained extensive worldwide experience. The budesonide suspension for nebulisation has been found more effectice than disodium cromoglycate and oral corticosteroids in treating asthma in infants, children and adults with asthma. Once daily dosing is appropriate in children with mild-to-moderate asthma. The budesonide suspension has also been found effective in the treatment of croup. Budesonide suspension for nebulisation provides an effective alternative to treatment when conventional delivery devices have failed and it has been well tolerated in all age groups.
The clinical documentation and experiences have been reviewed (38,39).
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| 8. Comparison with other inhaled corticosteroids |
Beclomethasone dipropionate (BDP)
Miyamoto et al performed a clinical study in patients who had been treated with BDP prior to the study. These patients were randomized to treatment with budesonide by Turbuhaler 100 µg b.i.d. or 400 µg b.i.d. or to continuous treatment with BDP 100 µg q.i.d. (40). The study showed no statistically significant difference between the daily doses of 200 µg budesonide Turbuhaler and 400 µg BDP administered as a pressurized metered dose inhaler with or without a large volume spacer (depending on the patient´s previous treatment), although the improvement in morning PEF was numerically better with budesonide Turbuhaler (Fig. 19).
Fig. 19. Change in morning PEF after administration of budesonide Turbuhaler 100 µg and 400 µg b.i.d. and BDP 100 µg q.i.d. From Ref. 40.
If this study had included only the two lower dose arms - 200 µg budesonide Turbuhaler per day and 400 µg BDP pMDI per day - it had not been possible to conclude that there was no difference between the two treatments because it might have been so that both treatments were on the plateau of the dose-response curve. In this study, however, a higher dose, budesonide Turbuhaler 400 µg b.i.d., was included and this dose was statistically significantly superior to both the other treatments, demonstrating that the doses to be compared did not reach the plateau, i.e. there had been room for improvements if 400 µg BDP had been superior to 200 µg budesonide. Thus it can be concluded that budesonide Turbuhaler is at least twice as effective as BDP delivered as pMDI (there is no difference between BDP pMDI and BDP Diskus/Diskhaler)
Fluticasone propionate (FP)
There are no studies comparing budesonide Turbuhaler and fluticasone (FP) using the same appropriate design as in the BDP study referred to above (40). Several studies have been performed with one dose of each and thereby it cannot be excluded that the doses have been on the plateau of the dose-response curve.
There is, however, another acceptable design for comparative studies, i.e. dose reduction studies where both treatments are started from the same microgram level and doses thereafter reduced according to predetermined criteria. Two such studies have been published.
Agertoft and Pedersen performed a dose reduction study in children with asthma comparing budesonide Turbuhaler with FP Diskhaler (41). Patients ended up in equal numbers on each dose step of reduction and the authors concluded that budesonide Turbuhaler and FP Diskhaler are equieffective microgram per microgram (Figs. 20 amd 21)
Fig. 20. Study design for dose-reduction study comparing budesonide Turbuhaler and FP Diskhaler in children with asthma. From Ref. 41
Fig. 21. Minimal effective doses of budesonide Turbuhaler and FP Diskhaler. From Ref. 41
A similar dose reduction study was performed by Kuna et al in adult patients with asthma comparing budesonide Turbuhaler with FP Diskus (42). The results are shown in Figs 22 and 23. Also in adult patients budesonide Turbuhaler and FP Diskus were equally effective.
Fig. 22. Study design for dose-reduction study comparing budesonide Turbuhaler and FP Diskus in adults with asthma From Ref. 42
Fig. 23. Minimal effective doses of budesonide Turbuhaler and FP Diskus. From Ref. 42
These comparative studies with scientifically correct study designs show that half the dose of budesonide Turbuhaler gives the same clinical efficacy as one dose of BDP (pMDI or Diskus/Diskhaler), and that budesonide Turbuhaler µg per µg gives the same efficacy as FP Diskus/Diskhaler. At the same time these results demonstrate the importance of the inhalation device. Turbuhaler gives a 20-35% lung deposition compared to 8-15% for Diskus and Diskhaler. Budesonide Turbuhaler has also been found twice as effective as budesonide pMDI (43). The higher pharmacological potency of FP compared with budesonide is therefore overturned by the differences in inhaler properties.
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