Background In a previous study, we found that two years of treatmentwith an inhaled corticosteroid, budesonide, was more effectivethan treatment with an inhaled 2-agonist, terbutaline, in patientswith newly diagnosed, generally mild asthma. We continued thisstudy for a third year to investigate whether the steroid dosecould be reduced or discontinued and what effect crossover ofpatients from 2-agonist therapy to corticosteroid therapy wouldhave.
Methods A total of 37 patients treated for two years with inhaledbudesonide at a dose of 1200 µg per day were randomlyassigned to treatment with 400 µg of budesonide per day(19 patients) or placebo (18 patients) in a double-blind manner.Another 37 patients, who had received terbutaline during thefirst two years, were crossed over in an open-label manner totreatment with 1200 µg of budesonide per day during thethird year.
Results Treatment with the reduced dose of budesonide was sufficientlyeffective in 74 percent of the patients to maintain bronchialresponsiveness at a level similar to that achieved with thehigher dose. In contrast, improvement was maintained in only33 percent of the patients receiving placebo, and the differencesin pulmonary function between the steroid and placebo groupswere significant (for forced expiratory volume in one second,P = 0.007; for bronchial responsiveness to histamine, P = 0.025;and for peak expiratory flow in the morning, P = 0.040). Thecondition of patients who were crossed over from terbutalinetherapy to treatment with 1200 µg of budesonide per dayimproved. However, the degree of improvement in these patientsappeared to be less than in those who were treated with budesonideat the beginning of the three-year study.
Conclusions Early treatment with inhaled budesonide resultsin long-lasting control of mild asthma. Maintenance therapycan usually be given at a reduced dose, but discontinuationof treatment is often accompanied by exacerbation of the disease.
In a previous two-year study of patients with generally mildasthma, we found that treatment with an inhaled corticosteroid,budesonide (1200 µg per day), resulted in rapid improvementin symptoms and lung function, whereas similar changes werenot observed with the inhaled bronchodilator terbutaline1. Weconcluded that even in patients with mild asthma, treatmentshould be initiated with an inhaled corticosteroid such as budesonide.
There is some evidence that the early initiation of treatmentwith inhaled corticosteroids may provide long-lasting improvementeven after asthma therapy has been stopped2,3. We continuedour study for a third year to answer the following questions:Would the beneficial effects of treatment with budesonide bemaintained with a lower dose (400 µg per day)? How longwould the treatment effects last after budesonide was discontinued?What level of treatment efficacy could be obtained when budesonidetherapy was started after a delay -- that is, after two yearsof treatment with terbutaline?
Methods
In our initial, 2-year study we treated patients with newlydiagnosed asthma (with symptoms present for less than 12 months)and compared the effects of budesonide (600 µg twice daily)and terbutaline (375 µg twice daily), delivered from apressurized metered-dose inhaler through a large volume spacer(Nebuhaler, Astra, Sodertalje, Sweden)1. After two years thestudy was divided into a double-blind arm and an open arm andcontinued for a third year.
Study Design
Double-Blind Study Arm
In the double-blind study arm, patients from the previous budesonidegroup were treated either with budesonide at a reduced dose(200 µg twice daily) or with placebo. An inspiratory-flow-driven,multidose powder inhaler (Turbuhaler, Astra) was chosen fordrug delivery to permit the use of a placebo (lactose, 200 µgper dose) without the possible effects of chlorofluorocarbonsand lubricants4.
The study was performed as a multicenter, double-blind, randomized,placebo-controlled, parallel-group trial. Five centers participated,and the patients entered the trial at staggered intervals overa 12-month period immediately after completing the previous2-year treatment period with budesonide. During a four-weekrun-in period, the patients were switched over to open treatmentwith budesonide given by a flow-driven inhaler in a dose of600 µg twice a day. Lung function was evaluated by measuringforced expiratory volume in one second (FEV1) and forced vitalcapacity (FVC). Bronchial responsiveness was tested by challengewith six doubling concentrations, or dose steps, of histamine(1, 2, 4, 8, 16, and 32 mg per millimeter) administered by nebulizer.The FEV1 was measured after each 10-breath challenge. The histamineconcentration that induced a 15 percent decrease in the FEV1was called the "provocative concentration" (PC15). Peak expiratoryflow (PEF) was measured each morning and evening. Asthma symptomsand supplemental use of a 2-agonist were also assessed. Randomizationinto two treatment groups was made separately for each centerin blocks of four at the end of the run-in period.
During the treatment period, the patients received either budesonidegiven by a flow-driven inhaler in a dose of 200 µg twicea day or placebo, also given by a flow-driven inhaler. The patientsalso received terbutaline (500 µg per dose) to be givenby a flow-driven inhaler as needed. If, after randomization,asthma control was insufficient with the study medication andsupplemental terbutaline, the responsible physician could prescribeoral slow-release theophylline (Theo-Dur, 300 mg twice a day).Patients with severe exacerbations of asthma were allowed toreceive oral prednisolone for six days in decreasing doses (30,25, 20, 15, 10, and 5 mg per day).
Open Study Arm
The patients entered the open study arm of the trial at staggeredintervals over a 12-month period after completing the previous2-year treatment with terbutaline. The treatment was identicalto that used in the budesonide group during the initial two-yearstudy -- that is, budesonide delivered from a metered-dose inhalerat a dose of 600 µg twice a day. No run-in period wasincluded. If supplemental medication was needed, the patientswere allowed to take terbutaline from a metered-dose inhaler(250 µg per dose). The use of concomitant antiasthmatictherapy followed the guidelines established for the double-blindstudy.
Compliance
The use of study medication was checked by the investigatorat each visit. No objective method for confirming compliancewas available.
Patients
Informed consent was obtained from all patients. The study wasapproved by the Finnish Medical Board and the local ethics committees.
Double-Blind Study Arm
At the beginning of the initial two-year study, 50 patientswere randomly assigned to treatment with budesonide. Three patientsdid not fulfill all the inclusion criteria1. During the two-yearstudy, one patient was withdrawn because of insufficient treatmenteffect and seven were withdrawn for previously reported reasons1.Two patients did not wish to continue, since they deemed themselves"cured." The remaining 37 patients participated in the thirdyear of the study.
Open Study Arm
Initially, 53 patients were randomly assigned to treatment withterbutaline. Three patients did not fulfill all the inclusioncriteria. Ten patients were withdrawn during the two-year studybecause of insufficient treatment effect, and 3 were withdrawnfor other reasons. The remaining 37 patients continued in theopen study with budesonide for the third year.
Similarity of the Groups
When the three newly formed treatment groups were compared withthe use of patient data obtained at the start of the two-yearstudy, the groups were found to be similar in most respects(Table 1). However, the placebo group in the double-blind studyhad lower PC15 values than the two other groups. In the openstudy, a larger proportion of nonatopic patients had been withdrawnduring the two-year study, so that the group subsequently hadrelatively more patients with atopy (86 percent) than the twogroups in the double-blind study (68 percent in the group receivingbudesonide and 67 percent in the group receiving placebo) (Table 1).
Table 1. Characteristics of the Treatment Groups Assessed at the Start of the Initial Two-Year Study.
Recording Outcomes
The methods used to record outcomes were similar to those usedin the preceding study1 and will be described here briefly.During the run-in period (double-blind study only), the first12 weeks, and the last 4 weeks of the third year, the patientsrecorded their PEF values each morning and evening. They alsorecorded their asthma symptoms every day, assigning a singlescore of 0 (no symptoms) to 10 (severe symptoms) for each 24-hourperiod. The use of supplemental 2-agonist medication and adversereactions were also recorded.
The assessments performed at the clinic at the start and endof the 4-week run-in period (double-blind study only) and thenafter 6, 12, 28, 44, and 48 weeks of treatment included spirometry,a test for bronchial responsiveness, and checks of the patients'diaries.
Statistical Analysis
For the measurement of the three variables reflecting lung function-- FVC, FEV1 and PC15 -- the time of randomization was usedas the point of reference in the double-blind study, whereasthe start of treatment was used as the point of reference inthe open study. In the analyses, logarithmic values for PC15were used and the result was expressed as dose steps (i.e.,step 0 equaled 1 mg of histamine diphosphate per milliliter;step 1, 2 mg per milliliter; step 2, 4 mg per milliliter; andso on). The values for the four variables recorded in the diaries-- the morning PEF, the evening PEF, the asthma score, and thenumber of puffs of supplemental 2-agonist -- were first reducedto averages over the four-week run-in period (double-blind studyonly) and over the first week, the sixth week, and the lastmonth. The average for the run-in period was used as the referencevalue in the double-blind study, and the average for the lastfour weeks preceding the start of the new treatment was usedin the open study.
All seven variables were analyzed with respect to change fromthe reference value. Analyses between and within groups wereperformed by t-tests with averages for the last month (diarydata) or the last measurement (FVC, FEV1, and PC15) of the treatmentperiod. P values below 0.05 were considered to indicate statisticalsignificance. All tests were two-tailed.
Results
Lung Function and Symptoms
Double-Blind Study Arm
FVC values did not change significantly during the third yearor differ significantly between the groups (Table 2). The FEV1and PC15 values did not change significantly in the budesonidegroup, but in the placebo group the FEV1 fell by an averageof 0.25 liter (P = 0.010) and PC15 by 1.5 dose steps (P = 0.037).The differences in the changes in FEV1 and PC15 values betweenthe groups were significant (P = 0.007 and P = 0.025, respectively)(Table 2 and Figure 1). Bronchial responsiveness worsened duringthe third year in 5 of the 19 patients in the budesonide group(26 percent) and 12 of the 18 patients in the placebo group(67 percent).
Figure 1. Mean (±SE) PC as a Measure of Bronchial Responsiveness.
The PC15 dose steps 0, 1, 2, 3, 4, and 5 represent histamine concentrations of 1, 2, 4, 8, 16, and 32 mg per milliliter, respectively. The three groups of patients were treated as follows: double-blind budesonide for three years (solid line), double-blind budesonide for two years followed by double-blind placebo for one year (dotted line), and double-blind terbutaline for two years followed by open-label budesonide for one year (dotted-and-dashed line). The first two groups were treated as one until the beginning of the third year.
Morning and evening PEF values did not change significantlyin the budesonide group, but fell significantly in the placebogroup (P<0.001 and P = 0.017, respectively) (Table 2 andFigure 2A). In the placebo group the average decrease in PEF(from base line) was 22 liters per minute in the morning and13 liters per minute in the evening. There was a significantdifference between the two groups with respect to the changesin morning PEF values (P = 0.040). The asthma-symptom scoreincreased significantly in the placebo group (P = 0.037) (Table 2and Figure 2B). The use of supplemental terbutaline did notchange significantly in the two groups.
Figure 2. Day-to-Day Mean PEF (Panel A) and Asthma-Symptom Score (Panel B).
The PEF was measured in the morning. The range of possible asthma scores was 0 to 10. The groups of patients were treated as follows: double-blind budesonide for three years (thick solid line), double-blind budesonide for two years followed by double-blind placebo for one year (dotted line), and double-blind terbutaline for two years followed by open-label budesonide for one year (thin solid line).
Open Study Arm
The FVC and FEV1 values did not change significantly duringthe third year, but the improvement in PC15 approached significance(P = 0.05) (Table 2).
Morning PEF values increased by an average of 15 liters perminute (P = 0.005). An average increase in the evening PEF of6 liters per minute was not significant (P = 0.11) (Table 2and Figure 2A). The asthma-symptom score fell significantly(P = 0.009) (Table 2 and Figure 2B), as did the use of supplementalterbutaline (P = 0.009).
Comparison of Early and Late Therapy with Budesonide
We compared the changes observed in the group treated with budesonidefrom the beginning and the changes in the group treated withbudesonide after two years of terbutaline therapy. The changesin the measures of treatment efficacy were calculated for the1st week, the 6th week, and the 12th month after the start oftreatment with budesonide. There was a greater degree of improvementin all lung-function measures in the patients treated initiallywith budesonide (Table 3). A similar trend was seen for theasthma-symptom score and for the use of supplemental terbutaline.
Table 3. Comparison of Improvements in Patients Treated with Budesonide as First-Line Therapy within One Year of the Diagnosis of Asthma and Patients Treated More Than Two Years after Diagnosis.
Withdrawal, Extra Medication, and Side Effects
A 60-minute cosyntropin test7 to examine the adrenocorticalresponse was carried out in 42 of the 50 patients who had beenreceiving budesonide for two years and were eligible for thedouble-blind study. All patients fulfilled the criteria fora normal response and had a mean increase in plasma cortisolconcentrations of 369 nmol per liter (from 399 to 768 nmol perliter; reference value, >150 nmol per liter) at 30 minutesand of 542 nmol per liter (from 399 to 941 nmol per liter) at60 minutes.
Double-Blind Study Arm
During the third year three patients were withdrawn from thebudesonide group, two because of insufficient treatment effect(after 98 and 161 treatment days) and one because of pregnancy(after 219 days). Three patients were also withdrawn from theplacebo group, all because of insufficient treatment effect(after 50 days, 121 days, and nearly a year). Five of 19 patientstreated with budesonide reported throat irritation, as comparedwith 1 of 18 in the placebo group. No cases of oropharyngealcandidiasis or hoarseness occurred. Nine courses of oral prednisolonewere given to four patients in the budesonide group, and twoof them used two and three courses soon after the dose of budesonidewas reduced. Six patients in the placebo group used eight coursesof prednisolone. Theophylline was added to the treatment regimenof three patients in the placebo group (a total of 218 treatmentdays), but to none in the budesonide group.
Open Study Arm
One patient was withdrawn from the open study because of noncompliance.None of the patients dropped out because of adverse effects.Twelve courses of oral prednisolone were given to eight patients.Theophylline was added to the treatment regimen of five patients.
Discussion
During the third year of our study, one group of patients whohad previously received 1200 µg of budesonide per dayreceived a reduced dose, 400 microg. Measures of lung functionand clinical variables recorded in the patients' diaries remainedessentially unchanged after the dose of budesonide was reduced.A slight decrease in PEF values was observed at the beginningof the third year, but this was not accompanied by significantchanges in other measures of lung function or by an increasein symptoms. The PEF values improved again toward the end ofthe study year. In a few patients early deterioration of theclinical condition was observed, and 2 of the 19 patients hadto be withdrawn during the year because of insufficient treatmenteffect. Nevertheless, it is obvious that in the majority ofpatients the dose of budesonide can be reduced without importantdeterioration of lung function.
In the parallel double-blind placebo group, all variables deterioratedduring the third year. There seemed to be a gradual declineof lung function, which became more pronounced toward the endof the year. Bronchial responsiveness worsened -- the PC15 valuedecreased by an average of 1.5 dose steps -- but still remained1.2 steps above the base-line value observed at the start ofthe three-year study. At the beginning of the three-year study,the placebo group had worse bronchial reactivity than the othertwo groups, which indicates more severe asthma. However, theimprovements in lung function were maintained in 6 of the 18patients in the placebo group, which suggests that treatmentwith an inhaled steroid may be discontinued in some patients.Unfortunately, we have no means of identifying those whose conditionwill or will not deteriorate when treatment is discontinued.
In a previous study, when budesonide was stopped after onlysix weeks of treatment, the severity of symptoms and lung functionreverted rapidly to base-line values8. The beneficial effectremained for three months when treatment had continued for oneyear3. In both studies, patients had chronic asthma of at leastmoderate severity. When patients with newly diagnosed asthmawere treated with 400 µg per day of budesonide for oneyear, and treatment was then discontinued, mean bronchial responsivenessdeteriorated during the following six months; however, the meanremained better than that recorded before therapy9.
The patients in our open study arm, who had inhaled 750 µgof terbutaline per day for two years and then 1200 µgof budesonide per day during the third year, had a significantdecrease in asthma symptoms and in the use of supplemental terbutaline,and an improvement in morning PEF values during treatment withbudesonide. When the responses were compared with those in thegroup treated with budesonide from the outset, it was observedthat delayed treatment with budesonide resulted in consistentlypoorer responses. This trend was statistically significant atall time points for increases in morning PEF values from baseline.
Before the start of the third year, 16 of 53 patients in theoriginal terbutaline group had been withdrawn for various reasons.When these 16 patients were compared with the 37 patients whocontinued the study, their age, duration of asthma, blood eosinophilcount, spirometric values, and PC values were similar. The frequencyof atopy was different: it was 50 percent in the group thatwithdrew and 86 percent in those who continued. This does notexplain the differences in the response to budesonide treatment,since patients with atopy would be expected to respond as favorablyas those without atopy to treatment with an inhaled steroid10.Some of the patients who withdrew had obviously more severeasthma than those who were able to continue receiving terbutaline.This could have resulted in a selection bias affecting the responseto steroid therapy. On the other hand, the remaining patientsin the open study group and the group treated with budesonidefrom the beginning had similar base-line values for lung function(Table 1) and, on these grounds, as much room for improvement.
It has been suggested that bronchodilators may mask the underlyingdisease and the ongoing inflammatory process by temporarilyrelieving symptoms while allowing slow deterioration in lungfunction to proceed11,12. The poorer response to delayed steroidtreatment that we observed is in line with this idea, but furtherconfirmation is needed. Further studies are also needed to uncoverthe underlying mechanisms.
From our three-year study, we reach the following general conclusions.It seems possible to obtain long-term control of asthma withearly treatment with an inhaled corticosteroid (in this case,budesonide). Control of the disease in most patients can bemaintained with a lower dose of the corticosteroid than wasinitially needed to normalize lung function. Decreasing thedose should reduce the risk of side effects. If treatment isdiscontinued, patients should be monitored carefully, sincelung function will often deteriorate. In addition, we foundsome indication that delays in initiating inhaled corticosteroidtherapy may lead to an impaired response. This observation shouldbe confirmed before clinical conclusions are drawn.
Source Information
From Helsinki University Central Hospital, Helsinki, Finland (T.H., K.K., A.S., B.S.-A., L.A.L.); Kanta-Hame Central Hospital, Hameenlinna, Finland (M.J.); Pohjois-Karjala Central Hospital, Joensuu, Finland (T.K.); Kiljava Hospital, Kiljava, Finland (S.K., R.T.); Etela-Saimaa Central Hospital, Lappeenranta, Finland (K.L.); and Astra Draco AB, Lund, Sweden (K.N., T.P., O.S., T.S.).
Address reprint requests to Dr. Haahtela at the Department of Allergic Diseases, Helsinki University Central Hospital, Meilahdentie 2, SF-00250 Helsinki, Finland.
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2-agonist, terbutaline, in patients with newly diagnosed, generally mild asthma. We continued this study for a third year to investigate whether the steroid dose could be reduced or discontinued and what effect crossover of patients from 
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