Early Use of Inhaled Nedocromil Sodium in Children Following An

308 Thorax 1999;54:308–315 Early use of inhaled nedocromil sodium in

children following an acute episode of asthma Thorax: first published as 10.1136/thx.54.4.308 on 1 April 1999. Downloaded from University Medicine, Southampton General Hospital, A M Edwards, J Lyons, E Weinberg, F Weinberg, J D Gillies, G Reid, C F Robertson, Southampton, UK P Robinson, M Dalton, P Van Asperen, C Wilson, J Mullineux, A Mullineux, P D Sly, A M Edwards M Cox, A F Isles

PO Box 131, North Ryde, NSW 2113, Australia J Lyons Abstract and evening PEF, and the usage of rescue —Current guidelines on the inhaled bronchodilators; 53% of patients Allergy Unit, Red Background Cross Children’s treatment of childhood asthma recom- reported nedocromil sodium to be very or Hospital, 7700 mend the introduction of an anti- moderately eVective compared with 44% Cape Town, South inflammatory drug in children who have placebo. Improvement in asthma symp- Africa persistent symptoms and require regular toms, PEF, and reduction in use of rescue E Weinberg treatment with a bronchodilator. The eY- bronchodilators did not reach statistical F Weinberg cacy and safety of inhaled nedocromil significance until after six weeks of treat- Anglesea Paediatrics sodium (Tilade Mint aerosol) adminis- ment. Twenty two patients were with- Ltd, Hamilton, tered using a Fisonair spacer at a dose of drawn or dropped out during the New Zealand 4 mg three times daily was compared with treatment phase, 12 due to uncontrolled J D Gillies placebo in the treatment of asthmatic asthma or persistence of asthma symp- G Reid children aged 6–12 years who are sympto- toms, four due to suspected adverse drug Department of matic and recovering from an acute exac- reactions (nedocromil sodium 3 (head- Thoracic Medicine, erbation of asthma. aches 2, angio-oedema/urticaria 1), pla- Royal Children’s Methods—A group comparative, double cebo 1(persistent cough)), and six due to Hospital, Melbourne, blind, placebo controlled trial was per- non-treatment related reasons. Seventy Victoria 3052, formed in children who were recovering one adverse events were reported by 27 Australia C F Robertson from an acute episode of asthma following patients in the nedocromil group and 75 P Robinson treatment in the emergency department by 30 patients in the placebo group. M Dalton of the hospital or in children referred Conclusions—Asthma symptoms, use of from their general practitioner following a bronchodilators, and lung function can be Department of wheezing episode and documented evi- improved significantly in children recov- Respiratory Medicine, dence of at least two previous episodes of ering from an acute exacerbation of Royal Alexandra http://thorax.bmj.com/ Hospital for Children, wheezing. A two week baseline period on asthma or wheeze and currently receiving Parramatta, NSW existing bronchodilator treatment was fol- treatment with bronchodilators alone by 2124, Australia lowed by a 12 week treatment period on the addition of inhaled nedocromil so- P Van Asperen either nedocromil sodium (2 mg/puV)or dium at a dose of 4 mg three times daily C Wilson placebo. Both treatments were adminis- administered using a Fisonair holding chamber. Department of tered using a Fisonair spacer at a dose of ( 1999; :308–315) Paediatrics, Gabarone two puVs three times daily. Changes from Thorax 54 Private Hospital, baseline values in daytime asthma and Botswana Keywords: asthma; nedocromil sodium; childhood night time asthma symptom scores, usage on October 1, 2021 by guest. Protected copyright. J Mullineux asthma; spacer A Mullineux of rescue bronchodilators, mean peak expiratory flow (PEF) recorded twice TWVT Institute for daily on diary cards, patients’ opinion of The current international guidelines on the Child Health treatment, and withdrawals due to treat- management of asthma in children1 recom- Research, Princess ment failure were measured during the mend a stepwise approach in which children Margaret Hospital for primary treatment period (last six weeks with infrequent episodic asthma commence Children, West Perth, WA6872, Australia of treatment). treatment with intermittent short acting â2 P D Sly Results—One hundred and forty two chil- adrenergic drugs. Once these are used more MCox dren aged 6–12 years entered the baseline than three times a week, or exacerbations occur period. Sixty three were withdrawn due to more frequently than every 4–6 weeks, prophy- Royal Children’s failure to meet the entry criteria (18) or lactic treatment is indicated. Inhaled sodium Hospital, Brisbane 4029, Australia the criteria for asthma symptom severity cromoglycate is the first prophylactic com- A F Isles (15) or reversibility (9), because they pound to be introduced and inhaled cortico- developed uncontrolled asthma (2), be- steroids should be substituted if this fails to Correspondence to: cause they took disallowed treatment (2), control symptoms. In the UK either inhaled Dr A M Edwards, 7 Fallowfield Close, or for other non-trial related reasons (17). sodium cromoglycate or inhaled cortico- Caversham, Reading RG4 Seventy nine patients (46 boys) of mean steroids are recommended as the first line pro- 8NQ, UK. age 8.8 years entered the treatment pe- phylactic treatment. riod. There were significant diVerences in Nedocromil sodium is a chromone. It is the Received 30 March 1998 Returned to author the changes from baseline values during disodium salt of a pyranoquinoline dicarboxy- 22 May 1998 the last six weeks of treatment in favour of lic acid developed as an anti-inflammatory Revised manuscript received nedocromil sodium compared with pla- treatment for asthma2 and is administered from 20 November 1998 Accepted for publication cebo in the primary variables of daytime a metered dose inhaler in unit doses of 2 mg. It 9 December 1998 asthma and night time asthma, morning has been compared with sodium cromoglycate Nedocromil sodium in childhood asthma 309

in in vitro and in vivo models of asthma and has the children were randomised to receive been shown to be up to 10 times more treatment with either inhaled nedocromil potent.3–5 A number of clinical trials have been sodium or inhaled placebo for a period of 12 conducted in adult patients6–9 and a meta- weeks. Patients were seen by the investigator at Thorax: first published as 10.1136/thx.54.4.308 on 1 April 1999. Downloaded from analysis of all placebo controlled trials has the beginning and end of the baseline period shown that the drug is an eVective treatment and every two weeks during the trial. for adult asthma.10 However, there have been The trial was conducted according to the very few trials of this drug to date in children principles established by the declaration of with asthma. Helsinki (as modified in Tokyo in 1975, Venice Many children who attend hospital accident in 1983, and Hong Kong in 1989). As the trial and emergency departments with acute epi- was conducted in three countries, both the sodes of asthma are not receiving anti- clinical investigators and the nurses responsible inflammatory therapy. In addition, there are for patient recruitment and monitoring met on many asthmatic children under the care of their at least one occasion in order to ensure a com- general practitioners who have not been started mon understanding of the trial protocol. on anti-inflammatory treatment despite having

recurrent episodes of wheezing. We therefore TEST MEDICATIONS decided to evaluate the eYcacy and safety of The test medications were administered from a nedocromil sodium in the treatment of chil- metered dose inhaler using a 750 ml spacer dren who had recently attended a hospital (Fisonair). As the active drug was yellow in emergency department with an acute episode colour, the spacers were made of yellow mate- of asthma, and symptomatic children referred rial in order to maintain blindness. The test by their general practitioners who had had a medications were either inhaled nedocromil recent episode of wheezing and were currently sodium (2 mg per puV) or placebo (containing receiving bronchodilator treatment alone. liquefied gas propellants and excipients only), administered at a dose of two puVs three times Methods daily. PATIENTS Patients were allowed to use inhaled bron- Patients with asthma of either sex aged 6–12 chodilators as needed to control acute attacks years were eligible for selection. Those with a of wheezing or bronchospasm. The number of history of renal, hepatic, or cardiovascular dis- doses they required over each 24 hour period ease, or chronic respiratory disease other than was recorded on the daily diary card. The asthma were excluded. Patients had either had inhaled bronchodilators could be administered a recent episode of asthma treated at hospital via a metered dose inhaler, a dry powder deliv- or were referred by their general practitioner ery system, or an aqueous nebuliser. Oral with a current episode of wheeze and with bronchodilators were not allowed. Patients documented evidence of at least two previous were allowed to use topical nasal and/or http://thorax.bmj.com/ episodes of wheeze in the previous six months. ophthalmic preparations or antihistamines as Asthma was defined as current wheeze with required for the relief of nasal and ophthalmic airways obstruction that is reversible by at least symptoms, but were not allowed to use any 15% or an increase in forced expiratory volume form of corticosteroid (apart from topical in one second (FEV1)of>140 ml following the corticosteroids to the skin) or any other inhalation of two puVs of a bronchodilator anti-asthma treatment. administered by a metered dose inhaler. All patients had to have a minimum score of asthma symptoms (22) on a daily diary card MEASUREMENTS on October 1, 2021 by guest. Protected copyright. during a two week baseline period. Patients and Patient diary cards their parents had to be co-operative, to keep a Throughout the trial, including the baseline daily diary card for the duration of the trial, and period, parents kept a daily diary card on which to be able to use a pressurised metered dose they recorded the severity of daytime and night aerosol, a peak flow meter, and a spacer time asthma symptoms, the morning and (Fisonair). Patients could have received a short evening peak expiratory flow (PEF), and the course of treatment with oral corticosteroids number of doses of rescue bronchodilators for their recent asthma attack, but could not be used during the 24 hours. Details of the scoring receiving current treatment with either inhaled system used to record the severity of symptoms sodium cromoglycate, oral or inhaled cortico- are presented in Appendix 1. steroids. Patients were also excluded if they had The PEF reading was the best of three been treated with inhaled sodium cromogly- measurements taken standing before any medi- cate during the previous month or with inhaled cation was administered. corticosteroids during the previous three months. Investigator assessments Patients and/or their parents gave written At each visit the investigator asked the parent informed consent and the protocol was ap- or guardian to grade the severity of the day and proved by the local ethics review committee. night asthma symptoms over the preceding 14 days using a five point scale. The scoring TRIAL DESIGN system used was similar to that used on the The trial was of a double blind, group patient diary card but covered a two week comparative design. After a two week baseline period. Pulmonary function tests were carried

period during which they had to have a out at each clinic visit and included FEV1, minimum asthma symptom score (see below), forced vital capacity (FVC), and PEF. 310 Edwards, Lyons, Weinberg, et al

Table 1 Patient characteristics Table 2 Details of acute episodes

Nedocromil sodium Placebo Nedocromil Placebo

(n=38) (n=41) Factor precipitating acute episode sodium (n = 38) (n=41) Thorax: first published as 10.1136/thx.54.4.308 on 1 April 1999. Downloaded from Sex: Infection (usually URTI) 17 20 Boys 23 23 Weather 7 3 Girls 15 18 Exercise 1 2 Mean (range) age (years) 8.6 (6–12) 9.0 (6–12) Exposure to allergen 0 2 Mean (range) height (cm) 134.1 (115–159) 134.3 (104–161) Other 0 4 Mean (range) weight (kg) 31.7 (22–49) 32.8 (17–68) Referred with episodes of wheeze 2 2 Atopic status Not known 11 8 Atopic 24 20 Duration of acute episode (hours) Non-atopic 3 9 Mean 50.3 54.5 Unknown 11 12 Min 2 5 Mean (SD, range) lung function (pre-bronchodilator) Max 252 504

FEV1 (l) 1.424 (0.542, 0.51–2.83) 1.438 (0.604, 0.53–2.66) Medications used for treatment of acute episode: FVC (l) 1.880 (0.609, 0.81–3.48) 1.813 (0.663, 0.63–3.06) Corticosteroid 16 22 PEF (l/min) 186 (75.57, 69–364) 192.8 (65.91, 93–347) Bronchodilator 30 33 Mean (SD, range) lung function (post-bronchodilator) Anticholinergic 7 12

FEV1 (l) 1.627 (0.510, 0.80–2.88) 1.595 (0.566, 0.67–2.73) Sodium cromoglycate 1 0 FVC (l) 1.982 (0.583, 1.00–3.39) 1.957 (0.597, 0.77–3.31) Other 3 5 PEF (l/min) 215.3 (67.71, 103–363) 214.9 (72.81, 84–368) Mean (SD, range) reversibility of URTI = upper respiratory tract infection.

FEV1 (%) 19.8 (17.68, 2–57) 16.6 (12.68, 2–68) Oral corticosteroids used in treatment of acute attack: Ye s 1 6 2 2 No 17 11 Before the trial it was estimated that 80 Asthma treatment on admission: patients per treatment group would be required â2 agonists 35 41 Theophyllines 7 4 to detect a true diVerence of 0.27 in the change Beclomethasone dipropionate 0 1 from baseline for the symptom scores recorded Ipratropium bromide 0 1 on the daily diary cards. This calculation was Sodium cromoglycate 0 1 made using a two sided statistical test with

FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; PEF = peak expira- alpha = 0.05 and 80% power assuming a tory ﬂow. standard deviation of 0.6. Global assessments The analysis was performed on an “intention At the end of the trial the parent/guardian and to treat” basis. Patients who did not complete the investigator recorded the overall eYcacy of the study for both treatment related and the test treatment administered using a ﬁve non-treatment related reasons were included in point scale where1=veryeVective, 2 = mod- the analysis as far as possible. Patients who erately eVective, 3 = slightly eVective, 4 = no were withdrawn because of lack of eYcacy of eVect, and 5 = made condition worse. the test treatment were included in all analyses of eYcacy using imputed data. For the diary

card variables the imputed data were the mean http://thorax.bmj.com/ Safety and tolerability of the three days before withdrawal. For clinic At each clinic visit the investigator asked the assessments (with the exception of pulmonary parent/guardian if the child had had any function) they were included as extreme cases unusual event since the previous visit. An un- following withdrawal for that treatment period. usual event was defined as any symptom, sign, For patient opinions they were included as illness, or experience that developed or in- treatment failures. Patients were included pro- creased in severity during the course of the vided that the test medication had been taken study. It included any major alteration in labo- for at least seven days. Patients who dropped ratory values and any apparently unrelated out for reasons not related to treatment efficacy on October 1, 2021 by guest. Protected copyright. illness, accident, or unanticipated surgery. Any were included in the analyses up to the time of suspected adverse drug reactions related to the withdrawal. Patients who failed to take the test test treatment were also recorded. treatment for five or more days in any 14 day Children could be withdrawn from the trial period were excluded from the analysis of that at any stage at the request of the parents/ period. guardian and the investigator could also The mean values of all diary card variables withdraw patients. The reason for withdrawal were calculated both for the primary period was recorded. (weeks 6–12) and for each two week period of the trial. The results were compared between STATISTICAL ANALYSIS treatment groups as changes from baseline. The primary variables for defining the eYcacy The severity of symptoms and pulmonary of the test treatments were the diary card function recorded at each clinic visit was symptom scores, the morning and evening analysed as changes from those recorded at the PEF, and the usage of rescue inhaled bron- end of the baseline and the treatment groups chodilators during the last six weeks of the compared. In addition, median values, the treatment period. The global opinion of change from baseline, and the diVerence treatment eYcacy as assessed by the patients between treatment groups for diary card symp- and withdrawals due to treatment failure were tom scores and bronchodilator usage were cal- also primary variables. culated together with the 95% confidence The secondary variables were the assessment intervals for the diVerences. of symptom severity carried out at the clinic Pulmonary function data at clinic visits and visits, the pulmonary function tests performed recorded on the daily diary card were analysed at the clinic visits, and the investigator’s global using two sample t tests. All other data were opinion of treatment eYcacy. analysed using the Wilcoxon rank sum test. All Nedocromil sodium in childhood asthma 311

Table 3 Mean (SD) baseline values and changes from baseline in diary card primary variables during primary period (last six weeks of treatment)

Nedocromil sodium Placebo p value Thorax: first published as 10.1136/thx.54.4.308 on 1 April 1999. Downloaded from

Weeks 6 to Weeks 6 to Baseline 12—baseline Baseline 12—baseline Weeks 6 to Variable (n = 38) (n=33) (n=40) (n = 36) Baseline 12—baseline

Daytime asthma 1.6 (0.72) −0.8 (1.04) 1.4 (0.62) −0.4 (0.74) 0.331 0.030 Night time asthma 1.6 (0.63) −1.0 (0.66) 1.3 (0.46) −0.3 (0.81) 0.037 0.001 Morning PEF (l/min) 222.7 (72.12) 23.8 (28.08) 227.2 (74.33) 4.1 (45.47) 0.778 0.036 Evening PEF (l/min) 231.9 (71.72) 16.8 (38.82) 241.2 (75.11) −5.6 (45.74) 0.582 0.033 Bronchodilator use (doses/24 hours) 2.3 (1.8) −0.9 (2.16) 1.9 (2.00) −0.1 (1.59) 0.131 0.011 Patient/parent opinion of eYcacy: Ver y eVective 17 9 Moderately eVective 3 9 Slightly eVective 5 5 0.059 No eVect 3 3 Made condition worse 4 9 Not recorded 6 6

PEF = peak expiratory ﬂow. p values are for comparisons between nedocromil and placebo groups.

tests were two tailed and treatment eVects were suspected cause of the acute attack, its based onapvalue of 0.05. duration, and the treatment used are shown in A secondary analysis was carried out for the table 2. primary variables during the primary period Twenty two children were withdrawn during which stratiﬁed the patients according to the treatment phase of the trial, 12 (four from whether they had received a course of oral the nedocromil sodium group and eight from corticosteroids during their acute attack which the placebo group) because of the onset of preceded participation in the study. Analysis of uncontrolled asthma (11 patients) or due to variance was used for this analysis with steroid persistent asthma symptoms not controlled by use and treatment group used as factors. test treatment (one patient). These 12 patients were classiﬁed as treatment failures and were included in all analyses of eYcacy using Results imputed data. Ten patients dropped out or PATIENT CHARACTERISTICS were withdrawn for reasons not related to eY- One hundred and forty two patients were cacy. Four or these were withdrawn because of entered into the study at seven centres, four in suspected adverse drug reactions, three from

Australia, one in New Zealand, and two in the nedocromil sodium group (two with head- http://thorax.bmj.com/ South Africa. Sixty three patients were with- aches and one with angio-oedema and urti- drawn from the study before being randomised caria) and one from the placebo group with to test treatment. Eighteen patients did not sat- persistent cough. Four patients in the placebo isfy the entry criteria, 15 did not meet the group dropped out because they were unable to required level of symptom severity during the comply with the requirements of the protocol. baseline period, nine did not meet the require- Two patients in the nedocromil sodium group ments for reversibility, and 15 were unable to were withdrawn at the third visit because they comply with the requirements of the trial pro- had not satisfied the entry criteria. One was tocol, The remaining six subjects either devel- taking sustained release theophylline and in the on October 1, 2021 by guest. Protected copyright. oped uncontrolled asthma (2), took cortico- other reversibility had not been demonstrated steroids during the baseline (2), or were at the baseline visits. These 10 cases were excluded for other non-specified reasons (2). included in the analyses up to the time of with- None of these patients was included in the drawal. analysis. Seventy nine patients (46 boys) of mean age EFFICACY 8.8 years (range 6–12) were randomised to The mean baseline values and diVerences in receive test treatment, 38 to treatment with the changes from mean baseline values to nedocromil sodium and 41 to placebo. The mean values during the primary period for all characteristics of these patients are summa- primary variables are shown in table 3. The rised in table 1. Information concerning the baseline values for these variables were not acute attack that resulted in admission to the significantly diVerent apart from night time trial was available in 67 cases. Details of the asthma. For this variable the baseline value for Table 4 Comparison of change from baseline to last six weeks of treatment between the nedocromil sodium group was 1.6 (0.63) nedocromil sodium and placebo for median values (symptom scores, bronchodilator use) and and for the placebo group 1.3 (0.46) (p = mean values (PEF) 0.037). There were significant diVerences in the changes from baseline values to the last six Nedocromil 95% confidence Variable sodium Placebo DiVerence intervals weeks of treatment in favour of nedocromil sodium compared with placebo in the primary Daytime asthma −0.81 −0.43 −0.38 −0.88 to –0.09 Night time asthma −1.02 −0.54 −0.48 −0.95 to –0.28 variables of daytime asthma (p = 0.03) and Bronchodilator usage −0.79 −0.24 −0.55 −1.38 to –0.19 night time asthma (p = 0.001), morning PEF Morning PEF (l/min) 23.8 4.1 19.7 1.4 to 38.0 (p = 0.036) and evening PEF (p = 0.033), and Evening PEF (l/min) 16.8 −5.6 22.4 2.0 to 42.8 the use of rescue inhaled bronchodilators (p = PEF = peak expiratory flow. 0.011) The size of the diVerences in treatment 312 Edwards, Lyons, Weinberg, et al

A 40 0.0 A 30

20 Thorax: first published as 10.1136/thx.54.4.308 on 1 April 1999. Downloaded from –0.5 10 0 –1.0

(scale 0–5) –10

morning PEF (l/min) –20

daytime asthma score –1.5 Change from baseline for

Change from baseline for 0 1–2 3–4 5–6 7–8 9–10 11–12 0 1–2 3–4 5–6 7–8 9–10 11–12 30 B B 0.0 20

10 –0.5 0

–10 –1.0 (scale 0–5)

evening PEF (l/min) –20 Change from baseline for –1.5 0 1–2 3–4 5–6 7–8 9–10 11–12 night time asthma score Change from baseline for Weeks 0 1–2 3–4 5–6 7–8 9–10 11–12 Weeks Figure 2 Mean change from baseline values for (A) morning and (B) evening peak expiratory ﬂow (PEF) Figure 1 Mean change from baseline values for (A) with nedocromil sodium (x) and placebo („). Data were daytime and (B) night time asthma symptom scores with analysed every two weeks. Error bars show standard errors nedocromil sodium (x) and placebo („). Data were of means. Baseline values for morning PEF: 222.7 analysed every two weeks. Error bars show standard errors (72.12) l/min for nedocromil sodium group, 227.2 of means. Baseline values (scale 0–5) for daytime asthma: (74.33) l/min for placebo group; evening PEF 231.9 1.6 (0.72) for nedocromil sodium group, 1.4 (0.62) for (71.72) l/min for nedocromil sodium group, 241.2 placebo group; night time asthma 1.6 (0.63) for nedocromil (75) l/min for placebo group. sodium group, 1.3 (0.46) for placebo group.

1 eVects between nedocromil sodium and placebo are shown in table 4 which details the changes from baseline of median values (diary 0 card symptoms and bronchodilator usage) and mean values (PEF) together with the diVer- http://thorax.bmj.com/ ences between treatments and the 95% confidence intervals of the diVerences. The mean –1 changes in the two weekly values are illustrated in figs 1, 2, and 3. The distribution of catego- ries of patients’ opinions of treatment, as Change from baseline in –2 shown in table 3, just failed to reach 0 1–2 3–4 5–6 7–8 9–10 11–12 bronchodilator use (doses/24 hours) significance (p = 0.059); 53% of nedocromil Weeks sodium treated patients considered the test Figure 3 Mean change from baseline values for mean treatment to be very or moderately eVective on October 1, 2021 by guest. Protected copyright. compared with 44% of those treated with pla- daily usage of rescue bronchodilators with nedocromil sodium (x) and placebo („). Data were analysed every two cebo. weeks. Error bars show standard errors of means. Baseline The secondary variables at baseline and after values 2.3 (1.8) doses/24 hours for nedocromil sodium 12 weeks of treatment are presented in table 5. group, 1.9 (2.00) doses/24 hours for placebo group. There was no diVerence between nedocromil sodium and placebo for these variables at this During the course of the treatment 27 time point. No diVerences were seen in the patients treated with nedocromil sodium treatment eVects according to whether cortico- reported 75 adverse events and 30 patients steroids had been used in the treatment for the treated with placebo reported 71 adverse acute attack, but the relative numbers in the events. Adverse events were generally reported groups were small. as being of minor clinical significance. Head- ache was reported on eight occasions by SAFETY AND TOLERABILITY patients treated with nedocromil sodium and Fifty one patients found the test treatment to on four occasions by patients treated with pla- be acceptable (nedocromil sodium 25, placebo cebo. Apart from events related to the respira- 26) and four patients (nedocromil sodium 3, tory tract which were reported more fre- placebo 1) found it to be unacceptable. The quently by placebo treated patients, all reports acceptability was not recorded in 24 cases. Of were either in equal numbers or one or two the three patients who found nedocromil reports only. In four cases patients were with- sodium to be unacceptable, one reported that drawn from the trial because of adverse events the treatment dried out his throat, one did not (three on nedocromil sodium (headaches in like the taste, and one did not like having to two cases and angio-oedema/urticaria in one) take the inhaler three times a day. The placebo and one on placebo who developed a persist- treated patient did not like the taste. ent cough). Nedocromil sodium in childhood asthma 313

Table 5 Mean (SD) baseline values and changes from baseline in assessments and lung function recorded at ﬁnal clinic visit (after 12 weeks of treatment)

Nedocromil sodium Placebo p value Thorax: first published as 10.1136/thx.54.4.308 on 1 April 1999. Downloaded from

Change at ﬁnal visit Change at ﬁnal visit Final Variable End of baseline (end of week 12) End of baseline (end of week 12) Baseline visit—baseline

Daytime asthma 2.29(0.927) −1.03(1.571) 2.12(0.748) −0.36(1.959) 0.607 0.149 Night time asthma 2.18(0.865) −1.0 (1.904) 2.10(1.044) −0.22(2.282) 0.790 0.120

FEV1 (l) 1.45(0.497) 0.14(0.234) 1.54(0.549) 0.06(0.187) 0.448 0.150 FVC (l) 1.91(0.582) 0.22(0.347) 2.00(0.593) 0.23(0.440) 0.469 0.859 PEF (l/min) 215.32(65.702) 14.29(41.672) 216.78(69.316) 13.93(31.89) 0.925 0.739 Investigator opinion of eYcacy Ver y eVective 6 2 Moderately eVective 9 11 Slightly eVective 8 7 0.180 No eVect 6 7 Made condition worse 4 8 Not recorded 5 5

FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; PEF = peak expiratory flow. p values are for comparisons between nedocromil and placebo groups. Discussion regarded as an alternative first line anti- Nedocromil sodium is an anti-inflammatory inflammatory treatment to sodium cromogly- drug developed as a prophylactic treatment of cate or inhaled corticosteroids in asthmatic asthma. A meta-analysis of trials has shown its children. There are no direct comparative eYcacy in adult asthma,10 buttodatefew therapeutic trials in childhood asthma between therapeutic trials have been carried out in chil- sodium cromoglycate and nedocromil sodium. dren. This report demonstrates the eYcacy of However, there have been comparative studies nedocromil sodium in paediatric patients with of nedocromil sodium and sodium cromogly- asthma. cate in exercise induced asthma. Comis et al14 Businco et al11 compared nedocromil sodium compared 10 mg sodium cromoglycate with and placebo in 31 patients aged 4–21 years 4 mg nedocromil sodium, with and without a with grass pollen asthma. The dose used was Fisonair. There was no diVerence in eYcacy 4 mg four times daily and the treatment period between the two compounds but both were was four weeks. There were significant diVer- better than placebo. The use of the Fisonair did ences in favour of nedocromil sodium for not confer any advantage. Novembre et al15 also morning tightness and daily mean morning compared the eVects of 10 mg sodium cromo- PEF, the use of inhaled bronchodilators, and glycate, 4 mg nedocromil sodium, and placebo pulmonary function tests. Armenio et al12 com- in exercise induced asthma in 19 children aged pared nedocromil sodium and placebo in 209 6–15 years. Nedocromil sodium gave a better http://thorax.bmj.com/ asthmatic children aged 6–17 years. Test treat- overall performance with complete protection ments were given in addition to existing in 14 patients compared with nine patients therapy. Statistically significant diVerences in pre-treated with sodium cromoglycate and two favour of nedocromil sodium were seen for cli- patients with placebo. A similar comparison in nician assessment of asthma severity, diary card 17 children has been carried out by de symptoms, pulmonary function, and the use of Benedictis et al16 who also compared the dura- 17 inhaled â2 bronchodilators. In this trial the total tion of action. Both drugs were shown to pro-

symptom score was reduced by 50% during the vide significantly better protection than pla- on October 1, 2021 by guest. Protected copyright. last four weeks of treatment compared with cebo but with no diVerence between them. baseline scores. This is very similar to the result Both provided significant protection when of our study. The trials reported by Businco et given 20 minutes before exercise but not at 140 al and by Armenio et al used a dose of 4 mg minutes. It is diYcult to extrapolate from the four times daily and neither used a holding results of challenge studies, but the results of chamber to assist delivery. In our trial we used these trials in exercise induced asthma do sug- a dose of 4 mg three times daily delivered by a gest that nedocromil sodium is the more potent spacer. Foo et al13 used a spacer and a dose of compound and is at least as eVective as, and 4 mg three times daily in 120 children aged may be more eVective than, sodium cromogly- 6–19 years. However, the patients in their trial cate. had stable asthma with low symptom scores. There have been no direct comparisons of The main objective of their trial was to examine nedocromil sodium and inhaled cortico- the eVect of nedocromil sodium on histamine steroids in children so it is not possible to pre- responsiveness. No eVect on histamine respon- dict the comparative usefulness. Recent trials siveness nor symptom scores was seen but of sodium cromoglycate or inhaled cortico- there was a significant increase in pulmonary steroids compared with placebo have not used function. The results of our trial are in line with similar designs to our own and comparisons those of other paediatric studies but provide between such trials are not therefore valid. more consistent evidence of drug eYcacy. We A comparison of the three treatments was have also demonstrated the eVectiveness of made in 1996 using an open retrospective nedocromil sodium in the circumstances in design by Korppi and Renes18 who reviewed which it was used. the lung function of 297 school-aged children Perhaps the more important question to who had been treated since 1989 according to answer is whether nedocromil sodium can be international guidelines. Sixty children were 314 Edwards, Lyons, Weinberg, et al

not using any preventive drugs, 169 were using steroids but consideration is not always given at chromones (97 sodium cromoglycate, 72 that stage to the longer term needs. In a review nedocromil sodium), and 68 inhaled cortico- of 422 children with acute asthma who steroids (three beclomethasone and 65 budeso- attended the emergency department of the Thorax: first published as 10.1136/thx.54.4.308 on 1 April 1999. Downloaded from nide). The mean values for PEF, FVC, and Royal Children’s Hospital in Parkville, Victo-

FEV1 were over 95% of the height related ria, Australia between 1 January and 31 reference values in all treatment groups and the December 1989, Barnett and Oberklaid19 lower limits of the 95% confidence interval found that 39% had been taking no medication were at the level of more than 90% of those at all and only 24% had been taking regular predicted. Only minor diVerences between the anti-inflammatory treatment. In their study diVerent therapeutic groups were observed and upper respiratory tract infections were the pre- the authors concluded that, in their population, cipitating cause of the acute attack in 82% of up to 70% of asthmatic children requiring cases in which it was recorded compared with maintenance therapy for asthma can be treated 54% in our study. On discharge from their with chromones. study 33% of patients had been prescribed Clinical trials of new drugs in children with anti-inflammatory treatment and in 45% of asthma attending hospital clinics do present cases no arrangements for follow up were problems. Most children are either well main- documented. The relative lack of improvement tained on currently available eVective treat- of the placebo treated patients in our trial ments for childhood asthma such as sodium would suggest that children who have had a cromoglycate and inhaled corticosteroids or recent episode of wheezing requiring acute have severe asthma which makes them unsuit- treatment and who have some degree of able for placebo controlled trials. Patients persistent symptoms would benefit from the whose asthma is well controlled are usually free addition of an anti-inflammatory drug such as of symptoms and have normal or near normal nedocromil sodium. This conclusion is sup- lung function apart from when they have an ported by a retrospective review of the eVect of acute exacerbation. In such patients there is drug treatment on the long term outcome of minimal room for improvement in the primary childhood asthma. König and ShaVer20 have measures of asthma severity. It is unethical to concluded that treatment with anti- withdraw treatment to induce symptoms or inflammatory drugs (cromolyn sodium or reduce lung function and then to substitute a inhaled corticosteroids), but not as needed placebo or an untried treatment. The pre-trial bronchodilators alone, improves the long term estimate of the need for 160 patients (80/ prognosis of asthma. treatment group) was not achieved as 63 were It is uncertain whether the use of the rejected because of low symptom scores. How- Fisonair spacer increased the eYcacy of ever, this planned sample size was based on an nedocromil sodium. Barry et al21 in an in vitro

estimated diVerence in symptom scores of study measuring particle size showed that the http://thorax.bmj.com/ 0.27. In the actual trial the diVerence was 0.4 use of a Fisonair spacer increased the amount for daytime asthma and 0.7 for night time of drug below 5 µm delivered from 0.417 mg asthma and significant diVerences were ob- for a standard metered dose inhaler to tained with fewer numbers. 0.498 mg for the Fisonair. The equivalent Patients are most likely to be symptomatic amounts for particles below 3 µm were when recovering from an acute episode of 0.206 mg and 0.294 mg. This was dependent asthma or wheezing and this trial with upon only one actuation being put into the nedocromil sodium illustrates the importance holding chamber at a time and there being no and value of adding an anti-inflammatory drug delay between actuation and inhalation. This on October 1, 2021 by guest. Protected copyright. to the treatment of such patients, in this case, was the technique used in our trial. As well as children. The trial also demonstrates the having the advantage of the lack of need to importance of clearly defining the degree of co-ordinate actuation with inhalation, the severity of asthma required in order to ensure Fisonair, as with other spacers, reduces the that a treatment eVect would be seen if the test amount of ineVective drug being deposited in drug is therapeutically active. Although this the oropharynx and results in an increase in the meant the rejection of a number of patients as amount reaching the lungs. they did not meet the entry criteria, it did This trial has shown that nedocromil sodium ensure that a homogeneous population entered at a dose of 4 mg three times daily delivered by the treatment phase. a Fisonair holding chamber provides signifi- All of the key measures of asthma severity cant and clinically useful improvements in used in the present study improved both asthma control in children recovering from an significantly compared with a placebo treat- acute episode of asthma. We conclude that this ment and clinically in terms of asthma control. treatment regimen can be considered as a pos- The absence of a significant eVect in the sible first line prophylactic treatment in chil- secondary variables illustrates the importance dren with mild to moderate episodic asthma. of using outcome measures that reflect the day by day variation in asthma severity rather than Appendix 1: Scoring system used on daily clinic assessments at wide intervals when the diary cards patient will reflect the condition on that day NIGHT TIME ASTHMA rather than over a period. The night time asthma symptoms were based In paediatric practice acute attacks of asthma on the severity of cough, wheeze, chest are frequently treated appropriately with bron- tightness, and shortness of breath that resulted chodilators and a short course of cortico- in disturbed sleep using the following 0–5 Nedocromil sodium in childhood asthma 315

scale: 0 = No symptoms during the night or on lung mast cells obtained by bronchoalveolar lavage and by dispersion of lung fragments. Eur J Respir Dis 1986; waking in the morning. 1 = No symptoms dur- 69(Suppl 147):223–6. ing the night, but symptoms on waking at the 5 Altounyan REC, Lee TB, Rocchiccioli KMS, et al. A com-

parison of the inhibitory eVects of nedocromil sodium and Thorax: first published as 10.1136/thx.54.4.308 on 1 April 1999. Downloaded from usual time. 2 = Symptoms during the night but sodium cromoglycate on adenosine monophosphate- not causing the child to wake. Awake at the induced bronchoconstriction in atopic subjects. Eur J Respir Dis 1986;69(Suppl 147):277–9. usual time. 3 = Symptoms during the night 6 Wells A, Drennant C, Holst P, et al. Comparison of causing the child to wake (including waking nedocromil sodium at two dosage frequencies with placebo in the management of chronic asthma. Respir Med 1992;86: early).4 = Symptoms causing the child to be 311–6. awake for most of the night. 5 = Symptoms so 7 Callaghan B, Teo NC, Clancy L. EVects of the addition of nedocromil sodium to maintenance bronchodilator therapy severe that the child did not sleep at all. in the management of chronic asthma. Chest 1992;101: 787–92. 8RuYn RE, Alpers JH, Kroemer DK, et al. A 4-week DAYTIME ASTHMA Australian multicentre study of nedocromil sodium in The daytime symptoms were based on the asthmatic patients. Eur J Respir Dis 1986;69:336–9. 9 Schwartz HJ, Blumenthal M, Brady R, et al. A comparative severity of cough, wheeze, and breathlessness study of the clinical eYcacy of nedocromil sodium and pla- on exertion experienced during the day using cebo. How does cromolyn sodium compare as an active control treatment? Chest 1996;109:945–52. the following 0–5 scale: 0 = No symptoms dur- 10 Edwards AM, Stevens MT. The clinical eYcacy of inhaled ing the day. 1 = Symptoms for one short period nedocromil sodium (Tilade) in the treatment of asthma. Eur Respir J 1993;6:35–41. during the day. 2 = Symptoms for two or more 11 Businco L, Cantani A, Di Fazio A, et al. A double-blind, short periods during the day. 3 = Symptoms for placebo-controlled study to assess the eYcacy of nedocromil sodium in the management of childhood most of the day which did not aVect the child’s grass-pollen asthma. Clin Exp Allergy 1990;20:683–8. normal daily activities. 4 = Symptoms for most 12 Armenio L, Baldini G, Bardare M, et al. Double-blind, placebo controlled study of nedocromil sodium in asthma. of the day which did aVect the child’s normal Arch Dis Child 1993;68:193–7. daily activities. 5 = Symptoms so severe that 13 Foo AL, Lanteri CJ, Burton PR, et al. The eVect of nedocromil sodium on histamine responsiveness in clini- the child could not go to school or perform cally stable asthmatic children. J Asthma 1993;30:381–90. normal daily activities. 14 Comis A, Valletta E A, Sette L, et al. Comparison of nedocromil sodium and sodium cromoglycate administered by pressurised aerosol, with and without a spacer This study was funded by Fisons Pharmaceutical Division who device in exercise-induced asthma in children. Eur Respir J also supplied the medications and Fisonair holding chambers. 1993;6:523–6. We wish to extend our thanks toMTStevensofEMStat Ltd 15 Novembre E, Frongia GF, Veneruso G, et al. Inhibition of who checked the statistical analysis and to Sue Bryan, Ian Mur- exercise-induced asthma by nedocromil sodium and phy, and Carolyn Newton who contributed to the organisation. sodium cromoglycate in children. Pediatr Allergy Immunol 1994;5:107–10. Conﬂicts of interest: A M Edwards and J Lyons were employees 16 de Benedictis FM, Tuteri G, Bertotto A, et al. Comparison of the sponsors, Fisons Pharmaceuticals, at the time this trial of the protective eVects of cromolyn sodium and ne- was undertaken. Current positions: AME is Honorary Clinical docromil sodium in the treatment of exercise-induced Assistant, University Medicine, Southampton General Hospi- asthma. J Allergy Clin Immunol 1994;94:684–8. tal, Southampton, UK and JL is Clinical Project Manager, Astra 17 de Benedictis FM, Tuteri G, Pazzelli P, et al. Cromolyn ver- Pharmaceuticals Pty Ltd, North Ryde, NSW, Australia. sus nedocromil: duration of action in exercise-induced asthma. J Allergy Clin Immunol 1995;96:510–4. 18 Korppi M, Remes K. Asthma treatment in schoolchildren: 1 Warner JO, Naspitz CK, Cropp GJA. Third international lung function in diVerent therapeutic groups. Acta Paediatr

pediatric statement on the management of childhood 1996;85:190–4. http://thorax.bmj.com/ asthma. Pediatr Pulmonol 1998;25:1–17. 19 Barnett PJ, Oberklaid F. Acute asthma in childhood: evalu- 2 Rainey DK. Evidence for the anti-inﬂammatory activity of ation of management in an hospital emergency depart- nedocromil sodium. Clin Exp Allergy 1992;22:976–9. ment. Med J Aust 1991;154:729–33. 3 Eady RP, Greenwood B, Jackson DM, et al. The eVects of 20 König P, ShaVer J. The eVect of drug therapy on long-term nedocromil sodium and sodium cromoglycate on antigen- outcome of childhood asthma: a possible preview of the induced bronchoconstriction in the Ascaris-sensitive mon- international guidelines. J Allergy Clin Immunol 1996;98: key. Br J Pharmacol 1985;85:323–5. 1103–11. 4 Leung KPB, Flint KC, BrostoV J, et al. A comparison of 21 Barry PW, Robertson CF, O’Callaghan C. Optimum use of nedocromil sodium and sodium cromoglycate on human a spacer device. Arch Dis Child 1993;69:693–4. on October 1, 2021 by guest. Protected copyright.