START study

 The challenge of mild asthma

 START study objectives

 The START protocol

 Once-daily Pulmicort is as effective as twice-daily therapy

 START participation

 A study designed to mimic real-life practice

 Results

 References

 The challenge of mild asthma

START (inhaled Steroid Treatment As Regular Therapy in early asthma) is the first worldwide, randomized, controlled, prospective study to investigate early intervention with inhaled corticosteroids (ICS) in newly diagnosed asthmatics. It will provide the robust data required on the benefits of early intervention with ICS in these patients. The study compares Pulmicort® Turbuhaler® once daily with usual asthma therapy in a 'real-world' setting.

• The START study is 5 years in duration and involves more than 7200 patients around the world.
• The patients completed the first 3 years of START in March 2001, and these data have been analysed to assess the anti-asthmatic effects of the therapies. The results are presented below.
• Data from the final 2 years of START will investigate the benefit of these therapies on long-term changes in lung function.
• All patients will have completed the full 5 years in the study by 2003.

Most asthma patients receive bronchodilator therapy to provide rapid relief of asthma symptoms, but the underlying disease process may go unchecked, particularly in patients with milder asthma. Asthma symptoms and exacerbations, including severe exacerbations, can occur in mild asthma. For example, one-third of patients with mild asthma in the placebo group of the OPTIMA study experienced a severe exacerbation during the 1-year study period.(1) The benefit of treatment with ICS in controlling the underlying inflammation in asthma is well established. Furthermore, preliminary evidence suggests that early use of ICS improves and maintains lung function in patients with newly diagnosed asthma, and may prevent asthma progressing to a severe and irreversible form. (2,3,4)

START is designed to meet the need for a large prospective clinical study to confirm these findings.

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START study objectives

The primary objectives of START are as follows:

• to evaluate whether early intervention with once-daily Pulmicort will affect the evolution of newly diagnosed asthma. The first primary endpoint is the time to the first Severe Asthma-Related Event (SARE) (defined as hospitalization or emergency treatment due to worsening of asthma or death due to asthma) over the first 3 years (Part A)
• to monitor the change in post-bronchodilator FEV1 % predicted from baseline to the end of the 5-year study period (Part B).

Some of the most important secondary variables of START are as follows:

• the number of asthma-related events during the double-blind period (Part A)
• the time to first addition of a steroid treatment (systemic or inhaled) during the double-blind period
• symptom-free days, data on healthcare utilization, days off work and lost school days.

START can also be expected to:

• compare the effects of early intervention in adults, adolescents, and children
• evaluate the cost-effectiveness ratio for early intervention
• evaluate the safety profile of Pulmicort during long-term treatment in patients with mild asthma

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The START protocol

START is a 5-year multinational, multicentre, study with two phases: a 3-year double-blind randomized phase followed by a 2-year open-label phase.5
During the first 3 years (Part A), patients received either Pulmicort Turbuhaler once daily or placebo once daily plus their usual asthma therapy. In the final 2 years (Part B), all patients receive inhaled Pulmicort once daily plus their usual therapy.

There are strict entry criteria for START. Patients must have asthma symptoms (wheeze, cough, dyspnoea, chest tightening, nocturnal waking due to any of these) at least once a week, but not every day, in the preceding 3 months, and reversible airway obstruction. Asthma must have been diagnosed no more than 2 years (preferably 1 year) prior to entry. Asthma patients aged between 6 and 60 years could be included in START.

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Once-daily Pulmicort is as effective as twice-daily therapy

Once-daily Pulmicort dosing is being used in START because a once-daily regimen has already been shown to be as effective as twice-daily therapy. There is good evidence to show that compliance with asthma therapy improves when the dosing frequency is decreased and hence once-daily administration of Pulmicort can be expected to lead to better compliance. Once-daily Pulmicort is preferred by patients and has been shown to improve their quality of life.

In mild-to-moderate asthma, once-daily administration of Pulmicort Turbuhaler 400 mcg has been shown consistently to be as effective as 200 mcg twice daily, both in steroid-naïve patients6,7 and in patients already receiving inhaled steroids at the time of entry to the trial.8

In studies of children with stable asthma, a dosage of 200 mcg once daily was as effective as 400 mcg once daily in controlling asthma.9 A 12-week clinical trial in children with mild asthma, who had not previously been treated with an inhaled steroid, showed that Pulmicort 200 mcg once daily was as effective as 100 mcg twice daily in protecting against exercise-induced asthma.10 The trial was continued for a further 24 months, and the results confirmed that both regimens continued to protect against exercise-induced asthma and were similarly effective in achieving near-normal lung function.11

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START participation

START patients were enrolled at 499 centres located in 32 countries/regions worldwide. More than 7200 patients are taking part in START, a large proportion of whom are children.

In order to ensure that local differences in asthma management do not affect the outcome of the study, patients have been randomized on a centre-by-centre and country-by-country basis. This means that local differences will be balanced between the two arms of the study.

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A study designed to mimic real-life practice

 
Many conventional asthma trials are of short duration and involve highly selected patient populations. Many patients typical of those seen in everyday clinical practice are excluded from trials and hence a large, long-term, 'real-world' study is needed to assess the benefits of inhaled glucocorticosteroids in all patients with newly diagnosed asthma. START is meeting this need as far as possible.

START aims to determine the true benefit of early intervention with once-daily Pulmicort in 'normal' life rather than under the potentially artificial conditions of a clinical trial. The study protocol was designed to ensure that, as far as possible, START subjects and their doctors may behave as though the patient is not in a study. For example:

• patients may discuss any symptoms with the investigators, who are free to treat them as they would under normal circumstances
• other asthma treatments, including other inhaled steroids, can be added and continued as usual
• entry to the study is based on a normal medical assessment, including access to the patients' medical records. No study run-in period is used
• treatment compliance is not measured in START, hence the outcome should reflect the compliance that can be expected in normal practice. The effective once-daily regimen should aid treatment compliance.

Patients may receive other asthma treatment in addition to the study treatment if judged appropriate by the investigators. Other asthma treatments can be added, changed or withdrawn during the study if considered necessary by the investigators. The study medication cannot be changed.

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Results 12

In Part A of the START study, 7241 participants were randomized to receive either Pulmicort* (n=3642) or placebo* therapy (n=3599). The efficacy analysis was based on 7165 patients and the safety analysis on 7221 patients.
* in addition to usual asthma therapy

The mean baseline prebronchodilator FEV₁ measured for all subjects in the study was 86% of predicted normal across all gender and age sub-groups. This is consistent with mild persistent asthma as classified in the Global Initiative for Asthma (GINA) and other guidelines.

Pauwels et al. Lancet 2003; 361: 1071–1076

Pulmicort significantly reduced the risk of a SARE
The results from the first 3 years of the START study show that treatment with low dose Pulmicort reduced the risk of a first Severe Asthma-Related Event (SARE) in patients with mild persistent asthma by 44%, which is highly significant. The protective effect of Pulmicort was consistent and persistent over the whole study period.

Fewer SAREs occurred and fewer patients experienced at least one SARE in the Pulmicort treatment group compared with the placebo group.

Benefits in patients with very mild asthma
The investigators also looked at the benefits of Pulmicort in the subgroup of patients with very mild asthma (4330 patients with a pre-bronchodilator FEV1>80% of predicted normal values and who were not on any glucocorticosteroid at study entry). In this subgroup, Pulmicort reduced the risk of a SARE by 47%, which is comparable to the overall protective effect of Pulmicort* in the whole study population.

First addition of any glucocorticosteroid
The START study protocol allowed physicians to prescribe concomitant asthma medications as required. Time to first addition of additional glucocorticosteroids was one of the secondary efficacy variables in the study.
Significantly fewer patients in the Pulmicort group received additional glucocorticosteroids over time compared with the placebo group (31% versus 45%, respectively). The addition of glucocorticosteroids as treatment explains why there was an improvement over time in the placebo group for some of the clinical parameters, such as percent symptom-free days.

Treatment with additional glucocorticosteroids
More patients in the placebo group than the Pulmicort group also received treatment with inhaled glucocorticosteroids. By the end of the study, 24% of patients in the placebo group had received treatment with inhaled glucocorticosteroids compared with 12.5% in the Pulmicort* group.

Looking at the pre-study period, four percent of subjects had received oral glucocorticosteroids in the 6 weeks prior to study entry. The percentage of patients requiring oral or systemic glucocorticosteroids decreased with time in both groups, but a greater decrease was seen in the Pulmicort treatment group.

Additional courses of glucocorticosteroids per patient-year
In comparison with patients in the placebo group, subjects receiving Pulmicort used less oral and/or systemic glucocorticosteroids (GCS) per patient-year in the START study. While subjects in the placebo arm required overall 0.206 courses of GCS per patient-year, this number was almost halved to 0.122 courses of GCS per patient-year among patients receiving Pulmicort.

Concomitant asthma medications
The START study protocol allowed physicians to prescribe concomitant asthma medications as required. Concomitant asthma medications used were divided into a number of sub-categories (inhaled/oral/systemic glucocorticosteroids, short- and long-acting ß2-agonists, xanthines, cromoglicate/nedocromil, leucotriene mod ifiers, and other asthma medications). Overall, there was less additional asthma medication use in all drug classes for the Pulmicort therapy compared with the placebo therapy.

Symptom-free days by treatment group
Percent symptom-free days was a secondary efficacy variable in the START study. An improvement in symptom-free days for both Pulmicort and placebo groups from baseline was seen over time. However, patients receiving Pulmicort had significantly more symptom-free days over the 3-year study period.

Treatment effect (Pulmicort-placebo)
A highly significant improvement in both prebronchodilator and postbronchodilator FEV1 % values was observed after 1 and 3 years of the study for the Pulmicort treatment group compared with the placebo arm. After 1 year the differences were 2.24% and 1.48% respectively (p<0.0001 for both) and after 3 years, 1.71%, p<0.0001 and 0.88%, p=0.0005, respectively.

Adverse events findings
Both treatment regimens were well tolerated and patients in both groups were affected by a similar range and rate of non-asthma related adverse events. The most frequent adverse events (occurring in more than 5% of patients) were: respiratory infections, rhinitis, pharyngitis, bronchitis, viral infections, sinusitis, headache, accidental injury, coughing, conjunctivitis and fever. There were 11 deaths in total during the study, eight placebo patients and three from the Pulmicort group. Only one death, of a patient in the placebo group, was directly related to asthma.

There was a small influence on growth in the children in the Pulmicort group, most pronounced at the beginning of the study. Growth was not an outcome in the protocol and height measurements were done for calculation of lung function, and the difference between the groups became statistically significant because of the large patient population. The effect on growth was half of the magnitude seen in children of contemporary ages, who participated in another long term Pulmicort study, where higher doses of the drug were used.13 In this study the children were followed until adult age and no influence of their expected final height was seen.

Conclusions

The authors of the study concluded once-daily low-dose Pulmicort decreases the risk of severe exacerbations and the need for additional systemic glucocorticosteroids in patients with mild, persistent asthma.

Pulmicort has been shown to improve overall control of asthma.

The benefits of Pulmicort treatment outweigh the small effect of growth in children.

The results of the study support recommendations in treatment guidelines for use of inhaled glucocorticosteroids in mild, persistent asthma.

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References

1) O'Byrne PM, Barnes PJ, Rodriguez-Roisin R et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001; 164: 1392-1397.

2) Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994; 88: 373-381.

3) Haahtela T, Järvinen M, Kava T et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med 1994; 331: 700-705.

4) Selroos O, Pietinalho A, Löfroos AB, Riska H. Effect of early versus late intervention with inhaled corticosteroids in asthma. Chest 1995; 108: 1228-1234.

5) Pauwels R, Busse W, O'Byrne P et al. The inhaled Steroid Treatment As Regular Therapy in early asthma (START) study: rationale and design. Control Clin Trials 2001; 22: 405-419.

6) Jones AH, Langdon CG, Lee PS et al. Pulmicort® Turbuhaler® once daily as initial prophylactic therapy for asthma. Respir Med 1994; 88: 293-299.

7) Herjavecz I, Blomqvist P, Serrano A. Efficacy of once- and twice-daily administration of budesonide via Turbuhaler as initial therapy in patients with mild persistent asthma. Respir Med 1999; 93: 230-235.

8) Venables TL, Addlestone MB, Smithers AJ et al. A comparison of the efficacy and patient acceptability of once daily budesonide via Turbuhaler and twice daily fluticasone propionate via disc-inhaler at an equal daily dose of 400 µg in adult asthmatics. Br J Clin Res 1996; 7: 15-32.

9) Shapiro GG, Mendelson LM, Pearlman DS. Once-daily budesonide inhalation powder (Pulmicort Turbuhaler) maintains pulmonary function and symptoms of asthmatic children previously receiving inhaled corticosteroids. Ann Allergy Asthma Immunol 2001; 86: 633-640.

10) Jónasson G, Carlsen K-H, Blomqvist P. Clinical efficacy of low-dose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids. Eur Respir J 1998; 12: 1099-1104.

11) Jónasson G, Carlsen K-H, Jonasson C, Mowinckel P. Low-dose inhaled budesonide once or twice daily for 27 months in children with mild asthma. Allergy 2000; 55: 740-748.

12) Pauwels RA, Pedersen S, Busse WW et al, on behlaf of the START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003; 361: 1071-76.

13) Agertoft L, Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Eng J Med 2000;343(15):1064-9.