Resph'atory Medicine (1990) 84, 317-323

Tolerance to reduction of oral steroid dosage in severely asthmatic patients receiving nedocromil sodium L.-P, BOULET*, A, CARTIER~', D, W. COCI 1000 Mean dose (,ug day - ') Range (/tg day-i)

25 + 1~ 19 + 1' 5 1 20 + I t

10 7 3 0 10

0 8 + 1~ 6

I 3 2 2 2

3

2 1 542.4 200-1930

0

510.7 169-800

"Diary card data. bone noncooperating patient (withdrawn) did not fill in diary cards. According to admission data, concomitant medication comprised inhaled fl2-agonist, inhaled corticosteroid, theophylline. ~ patient was withdrawn (noncooperation). ~Beclomethasone dipropionate. follow-up) and eight (31%) to worsening asthma. Seven withdrew from the placebo-group; one patient was lost to follow-up and six (55%) experienced worsening asthma. The withdrawal rates did not differ significantly between the active and placebo groups. SURVIVALTIMEIN THE STUDY Since withdrawals occurred throughout the study and thus the denominator for survival in the study changed with time, a 'survival' analysis which takes account o f the time to withdrawal was considered

appropriate (Fig. 2). Treating the data from the two patients who withdrew because of non-cooperation as censored, the mean survival time in the nedocromil sodium group (10' 3 weeks) was greater than that o f the placebo treated patients (7.6 weeks) but the difference just failed to reach statistical significance (P = 0.059). REDUCTION IN ORALSTEROIDS To assess this variable, we considered the lowest oral steroid dose achieved which did not result in withdrawal due to treatment failure, defined as the 'lowest

L . - P . B o u l e t et al.

320

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Fig. 2 Probability of subjects continuing in the study while receiving nedocromil sodium or placebo during the oral ster-

oid reduction phase. Mean times to withdrawal = 10.3 weeks (nedocromil sodium) and 7.6 weeks (placebo) (P = 0.059). 20

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come offoral steroids completely, compared with none in the placebo group (difference between groups not significant; P=0.07). Although a long-term follow-up was not done after the 12-week steroid withdrawal phase, only one of these eight nedocromil sodium treated patients stopped steroids completely for less than 4 weeks. Conversely, nine patients could not withstand any reduction in oral steroid: four from the nedocromil sodium group and five placebo patients (betweengroup difference not significant; P = 0.08). The reduction in dosage from the starting dose to the LTD was analysed in two ways. In the nedocromil sodium group, the mean change was - 4 . 6 mg daycompared with - 2.0 mg day- ~ for placebo (not significant, P = 0.054), or -- 61% and - 28%, respectively, (P=0.03). Median values were also considered, to allow for gross distortion by extreme results; this analysis gave similar results both for absolute change ( - 3'75 vs - 1.25 mg day- J; not significant at P > 0.05) and percentage change ( - 83 % vs - 17%; P < 0'05).

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Lowest tolerable steroid dose, in equivalent dose of prednisone, plotted against oral steroid dosage on entry to the oral steroid withdrawal phase [+, nedocromil sodium (n= 25); 9 placebo (n= I0)]. Mean changes in dosage were -60.6% for nedocromil sodium patients, and -28.3% for placebo patients (P = 0.03). Fig. 3

The aim o f the clinical assessments (asthma severity and frequency) and diary card records (asthma symptoms, PEF and inhaled fl2-agonist usage) was to provide the clinician with a basis for the decision of whether to reduce the oral steroid dose. It was also important, however, to establish retrospectively that the reduction in oral steroid had not been achieved at the expense of deterioration in patients' condition. We regarded the 4-week period hnmediately preceding the present study as our baseline, and looked for any change in clinical assessments and diary card symptom scores between this baseline and the point at which the LTD of oral steroid had been achieved. Ideally, these scores should not differ since patients were to be withdrawn if asthma had deteriorated, and the LTD refers to the dose taken during the 2 weeks prior to any deterioration. This proved to be the case, with no significant differences from baseline to LTD for any of the scores (Table 3). SAFETY

tolerable dose' (LTD). This means that the LTD could be the dose at satisfactory conclusion of the study, or the previously higher dose than the one on which the patient had to be withdrawn. The two withdrawals due to noncooperation were not included in this analysis (although their inclusion did not affect the outcome). Thus the following results consider 25 nedocromil sodium patients and ten placebo patients. A plot of L T D against starting dose (Fig. 3) shows that eight nedocromil sodium patients were able to

No withdrawals were due to adverse drug events. Fifteen patients (nedocromil, 12: placebo, three) reported unusual events during the trial. The main event reported with nedocromil was unpleasant taste (4/12). However, none of these effects was regarded as serious in relation to test treatment. During the treatment period 15 patients had abnormal blood or urine results, which were either attributed to nontreatmerit-related causes or were considered not clinically significant.

Nedocromil sodium in steroid-dependent asthmatics

321

Table3 Mea~achanges from baseline in clinical assessments and diary card symptom scores Nedocromil sodium patients (n = 25)

Variable Asthma severity (0-4 scale) Asthma frequency (0-4 scale) Daytime asthma (0--4scale) Night-time asthma (0-4 scale) Morning tightness (0--4scale) Cough (0-4 scale) Day use of inhaled fl2-agonist (puffs day -~) Night use of inhaled/?2-agonist (puffs day -~) Morning PEF (lmin -R) Evening PEF (1rain - t)

Change from baseline Baseline to LTD

Placebo patients (n = 10) Change from baseline Baseline to LTD

1'81 2.96 l. t9 0.67 1.19 0.68

0.11 --0.12 0.04 0.03 --0.1 l --0.06

2"10 3.18 t.75 0.89 1"72 1.I2

0-05 -0.23 - 0' 12 -0.03 -0.06 -0.31

4.60

0.23

5.8P

0.34"

0.55 307.1 326.1

0.14 - 10.2 9.2

0.76 285.8 324.5

0.03 2.9 16"8

"Patients - 9 None of the changes in variables between baseline and LTD was statistically significant. The between-group differences between active and. placebo groups at baseline reflect the improvements that had been noted with active treatment during the previous 12 weeks (19). Discussion Recent data on the role of inflammation in the development and maintenance of asthma have led physicians to consider early and aggressive intervention with preventive and preferably antiinflammatory therapy (in conjunction with bronchodilators for symptomatic relief) in all but the mildest asthmatics (11,22). The mainstay of such antiinflammatory therapy is the corticosteroids, which are efficacious and, in aerosol form, have minimal sideeffects and can provide a reduction in airway hyperresponsiveness (23-25). Inhaled steroids therefore have an important place in asthma therapy. They may be useful in reducing systemic steroid dosage. It should be noted, however, that, as with the oral administration, both the benefits and the systemic side-effects are dose-related (26,27). F o r the severely ill, chronic asthmatic who is dependent on oral steroid maintenance therapy despite high doses of inhaled steroid, there is a risk of serious longterm systemic side-effects (22,28). This factor underlies the need for an agent that will allow dose reduction (if not withdrawal) of the oral steroid. Our analysis of nedocromil's oral steroid-sparing capacity showed encouraging results. The rapid reduction in oral steroid, cutting the daily dose by up to 2.5 mg every 2 weeks, was a severe test of its efficacy in this group of patients within the 12-week time-scale of the study. Despite the small number of patients and the wide variabilitybetween patients in their ability to withstand dosage reduction of oral steroid, both militating

against the likelihood of statistical significance being achieved, there was a significant effect in the percentage reduction from the original dose to the lowest tolerable dose of oral steroid. The mean reduction of61% (comp a r e d with 28% on placebo) appears to indicate that nedocromil sodium may have a clinical use as an oral steroid-sparing agent. This reduction was achieved without any change in clinical assessment and asthma symptom scores. Interpretation of these results should not be confounded by the fact that subjects were on multiple drugs. During the study, only the oral steroid dose was altered and fl-agonists were taken on a PRN basis as before the study. Furthermore, bronchodilator usage at the time o f withdrawal did not differ significantly from the beginning of the study. Although troleandomycin (6,7), gold salts (8,9) and methotrexate (10) are potential steroid-sparing drugs, these agents are not without significant toxicity (7,11,29). Since the aim of the search for an oral steroid-sparing agent is to reduce the adverse effects associated with long-term use of systemic steroids, nedocromil's freedom from serious side-effects (30) makes it an attractive candidate. In our previous study o f 188 patients (127 on nedocromil), unusual events were mild and transient; more severe effects such as headache and nausea were distributed equally between the nedocromil sodium and placebo groups (19,30). In some patients nedocromil sodium has a highly distinctive taste, while other patients taste nothing. The incidence of reports of taste with nedocromil sodium has

322

L . - P . Boulet et al.

been reported as 14% (30). In the previous study (19), 24% of the nedocromil sodium group commented on taste but 18% of placebo patients also made the same comment, and taste led to the withdrawal of only one patient (nedocromil sodium). I n addition, all the study patients were naive to nedocromil sodium treatment and we believe that active treatment was not readily identifiable as such. Nedocromil shares many properties with cromoglycate but marked differences have been reported in favour of nedocromil (18,31). To our knowledge, there has been no other study using the same design as ours to look at the steroid-sparing properties of cromogtycate. There were initial reports of reductions in steroid usage in patients on cromoglycate but subsequently it was suggested that cromoglycate was of little value in steroid-dependent asthma (32-35). In a recent trial nedocromil was found to have little or no oral steroid-sparing effects (36). Among factors which can explain the differences with our study is that, in this last study, patients were on nedocromil for a shorter period of time (4 weeks instead of 12) before starting the steroid withdrawal, It is possible that the influence of the anti-inflammatory effects of nedocromil on medication needs may be observed only after a period of more than 4 weeks of intake. Although our study design makes it difficult, but not impossible, to repeat the present study, this theory requires testing in a larger group of patients. Our present results do not permit us to conclude that nedocromil sodium can replace oral steroids. The study included ave ry rapid rate ofsteroid withdrawal which is unlikely to be repeated in clinical practice, and eight out of 25 nedocromil sodium patients were unable to continue because of deteriorating asthma. This emphasizes the need for caution when any attempt to reduce or withdraw this type of therapy is undertaken, and for continued close monitoring of any long-term deterioration in the patient's condition (23). In addition, it is possible that the period in the previous trial and the number of patient withdrawals during that period may have selected patients for the present study who had done well on nedocromil sodium, thus biasing the results in its favour. However, in view of the urgent need for a nontoxic steroid-sparing agent, nedocromil sodium certainly warrants closer scrutiny and further clinical investigation.

Acknowledgements The authors thank Fisons Corporation, Ontario, Canada, for financial assistance with the study and Fisons plc R&D Laboratories in Loughborough, U.K.,

inparticular S. A. L. Filcek (Medical Communications) and M. T. Stevens (Statistics), for their technical help in presenting our results.

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