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A double-blind trial of disodium cromoglycate in bronchial asthma with assessment by four observers
Brit. ,7. Db. Chest (x969) 63, '55.
A Double-blind Trial of Disodium Cromoglycate in Bronchial Asthma with Assessment by Four Observers I. WEINBREN,
J.
B O U N D AN D L. CA PP ER
Departments of Medicine, Pediatrics and Chest Medicine, Victoria Hospital, Blackpool
ALTOUNYAN (I967) first described the protective effect exerted by disodium cromoglycate in preventing the development of antigen-induced asthma. His observations were made on himself--an atopic subject. This power of the drug to inhibit immediate bronchial asthma has been confirmed by P e w s et al. (i968). The clinical effectiveness of the drug has been reported by Howell and Altounyan (I967) , Kennedy (I967) , Smith and Devey (I968) and Moran et al. (i968). Grant et al. (i967) reported no worthwhile effect. In comparing their results with those of Howell and Altounyan, Grant et al. state that they placed much greater reliance on the FEV1 as an index of improvement and were much less ready to accept patients' subjective assessments of the value of the drug. Howell and Altounyan (I967) reported an improvement of the F E V 1 greater than 2o~o in only four out of ten subjects and stated there was no a priori reason why such symptoms as cough, sputum, morning tightness or intermittent attacks of dyspnoea should be reflected in a change of the F E V 1. Kennedy (i967) did not report changes of the FEV. Smith and Devey (I968) found significant improvement in spirometric results in favour of the drug in patients whose F E V 1 or F V C values were less than 8o~o of predicted value in either period. Moran et al. (I 968) relied on symptomatic assessment and found no significant improvement in the F E V 1 during treatment with the active drug. Thus the place of disodium cromoglycate in the treatment of asthma rests heavily on assessment of symptoms. In view of this and its potential importance in therapeutics, a trial has been carried out which attempts to establish the reliability of symptomatic assessment. Symptoms were assessed by four independent observers (three medical and one lay). Concordance between observers was tested and also between observer assessment and patient assessment. Patients and M e t h o d s
Patients Patients were included in the trial (i) if their asthma was severe enough to need continuous corficosteroid therapy, and (2) if they were able and willing (Receivedfor lbublication, ~anuary z969)
156
WEINBREN,
BOUND AND CAPPER
to assess a n d record s y m p t o m s twice daily o n special charts for the six weeks o f the trial. T h r e e patients failed to c o m p l e t e the trial; two defaulted for personal reasons; a n d one d e v e l o p e d a n a c u t e e x a c e r b a t i o n o f cough,, s p u t u m a n d d y s p n o e a , necessitating hospital admission soon after the trial b e g a n . Details o f the i o patients w h o c o m p l e t e d the trial are s h o w n in T a b l e I. TABLE I.
Duration of Patient Age Sex Height Weight symptoms no. (in.) (lb) (yr)
Family history of atopy
Minimum Infantile Sputum or maintenance dose e c z e m a nasal swab of corticosteroids eosinophilia or A C T H in past year
i 2
9¼ F I2 M
51½ 66 60 122
7½ io
+ +
+ +
+ +
3 4
14 F x3 M
5I 53
92 83
13 Ix
+ +
+ +
o +
5 6
13½ M 14 M
48 53
98 93
I x½ 6
+ +
+ +
+ +
7
x5 M
61½
94
I3½
+
+
+
8
32
M
62½ I x9
~8
+
+
o
9
39 M
64½ 166
9
-
-
+
xo
37 M
73½ x78
3
--
-
+
ACTH 20 u day ACTH 20 u twice weekly ACTH 20 u day ACTH 20 u alternate days ACTH 20 u day ACTH 20 u alternate days ACTH 4° u 3 times weekly Prednisone I o nag day Prednisone xo mg day ACTH 40 u 3 times weekly
PYoceduY~ T h e trial e x t e n d e d o v e r t w o consecutive periods o f three weeks each. Patients c o n t i n u e d their usual m e d i c a t i o n t h r o u g h o u t the trial. T h e y received in a d d i t i o n capsules c o n t a i n i n g p o w d e r to b e i n h a l e d at six-hourly intervals f r o m a special inhaler ( ' S p i n h a l e r ' ) . T h e capsule used in the p l a c e b o p e r i o d c o n t a i n e d o.I m g isoprenaline sulphate, 5 m g s o d i u m s u l p h a t e to i m p a r t a bitter taste a n d 34"9 m g lactose. T h o s e used in the d i s o d i u m c r o m o g l y c a t e p e r i o d w e r e identical in a p p e a r a n c e b u t c o n t a i n e d o- i m g isoprenaline sulphate, t o g e t h e r w i t h 20 m g o f d i s o d i u m c r o m o g l y c a t e a n d 19. 9 m g lactose. T h e o r d e r in w h i c h patients received e a c h p r e p a r a t i o n was r a n d o m i z e d . T h e patients w e r e told t h a t two different forms o f d r u g w e r e to be used, e a c h for a t h r e e - w e e k period, a n d t h a t neither m i g h t benefit t h e m , one m i g h t benefit t h e m , or b o t h m i g h t benefit t h e m . All p a t i e n t s w e r e seen before the trial, a t the cross-over a n d at the e n d o f the trial. A t each visit a n i n d e p e n d e n t assessment o f s y m p t o m s was m a d e b y the t h r e e a u t h o r s (hereafter referred to as B, C a n d W) a n d b y a m e d i c a l social w o r k e r (hereafter referred to as M ) . Physical e x a m i n a t i o n was carried out i n d e p e n d e n t l y o n e a c h p a t i e n t b y B,
T R I AL OF DISODIUM CROMOGLYGATE IN BRONCHIAL A S T H M A
x57
C and W. The presence of rhonchi, rftles and wheezing audible to the unaided ear was recorded. Each sign was rated on a notionally continuous scale (o-4). The FEV1 was recorded by two different observers and B, C and W, and M did not learn the values recorded until the trial was over. Sputum samples or, if these were unobtainable, nasal swabs were taken for examination for eosinophils by the method of L e n d r u m (i 944). A s s e s s m e n t o f R e s p o n s e to T r e a t m e n t T h e assessment forms used are s h o w n in T a b l e II. Patients c o m p l e t e d e a c h series o f q u e s t i o n s e v e r y d a y . T h e o b s e r v e r s u s e d t h e scales s h o w n i n series xa TABLE II. SCORE CARDS Questions to be answered each day Series xa: night scores
Series l: general How would you class your chest symptoms on the whole last night ?
Score i 2 3 4 5
Very bad Bad Fair Good Very good
On waking this morning was your chest
Very tight ? Tight ? Slightly tight ? Clear ?
I 2 3 4
Was your nose stuffy last night ?
A lot A moderate amount A little Not at all
x 2 3 4
Score Kept awake at night for at least one hour
o
Woken by asthma twice or more during night
x
Woken by asthma once only
2
Not woken by asthma at all
6
How many times did you need to use your usual spray last night ? Series 2: general
Questions to be answered each night Series 2a: exercise tolerance
&ore
Scora
How has your cough been during the past 24 hours ? How much sputum did you have during the past 24 hours ? Have you had bouts of sneezing in the past 94 hours ?
Very troublesome Troublesome Slight Absent
i 2 3 4
More than I egg-cup ~-~ egg-cup A few blobs None at all
I 2 3 4 5
Lots A few None
x 2 3
~-: egg-cup
How many times did you need to use your usual spray during the day ?
Just able to move around room Able to walk slowly on the level Able to climb stairs slowly with pauses Able to walk at average speed but not to hurry Able to hurry for short periods but not as much as others of same age and sex Able to keep up with others of same age and sex in all respects
0
I58
WEINBREN~
BOUND
AND
CAPPER
( n i g h t scores) a n d 2 a ( e x e r c i s e t o l e r a n c e ) f o r t h e a s s e s s m e n t s m a d e a t e a c h v i s i t a n d e x p r e s s e d t h e i r r e s u l t s as t h e a v e r a g e f o r a w e e k . I n a l l cases scores f o r t h e first w e e k a n d t h e first w e e k a f t e r t h e c r o s s - o v e r w e r e d i s c a r d e d t o o b v i a t e a n y c a r r y - o v e r effect. T h e m a x i m u m a s y m p t o m - f r e e p a t i e n t c o u l d a l l o t h i m s e l f f o r t h e t w o w e e k s w h i c h w a s c o u n t e d as a t r i a l p e r i o d w a s 84 f o r e x e r c i s e t o l e r a n c e (series 2 a ) , 84 f o r n i g h t scores (series I a ) a n d 54o f o r t h e g e n e r a l q u e s t i o n n a i r e (series I a n d 2). T h e m a x i m u m a s y m p t o m - f r e e p a t i e n t c o u l d b e a l l o t t e d b y a n o b s e r v e r f o r t h e s a m e p e r i o d w a s 12 f o r e x e r c i s e t o l e r a n c e a n d 12 f o r n i g h t scores. Results
Observer concordance Scores allotted by observers are shown in Table III. The 'improvements' each observer found in the disodium cromoglycate period compared with the pre-test period, and the placebo period compared with the pre-test period, were calculated. The differences between observers were then compared by Student's statistic 't'. The 't' values were two-sided, corresponding to the fact that differences between observers could be positive or negative. The values found are shown in Table IV. N o s i g n i f i c a n t d i f f e r e n c e a p p e a r e d b e t w e e n t h e a s s e s s m e n t o f B, C a n d W . Their concord was least in the comparison between the placebo period and the TABLE I I I . OBSErVE'aS' SCOR~.S
Exercise tolerance Pre-test period
x
2 3 4 5 6 7 8 9 Io Mean
Dbodium cromoglycate period
Placebo period
B
C
W
M
B
C
W
M
B
8
8
7
8
6
8
7
8
IO
4 8 8 8 8 8 8 8 8
4 8 8 8 8 8 12 2 8
a 6 5 5 7 Io Io 9 8
4 8 4 4 xo IO x2 8 8
4 I2 4 8 8 8 xo 8 11
2 4 xo 8 2 4 8 5 8 7 8 IO 12 Io 2 9 1o 8 76
4 IO 4 Io Io xo Io 8 xo
IO 8 IO 12 12 8 12 I2 II
74
C W M xo I i I O 8 9 8 8 8 8 8 2 7 12 II IO 12 I2 12 8 IO I O 12 IO I 2 Io 12 I I I2 I2 I 2 Ioi
Night scores I
4
2
Io
IO
4
4
4
4
12
12
12
2 3
2 I2
2 I2
2 I2
2 I2
2 I2
2 I2
2 I2
2 I2
IO I2
IO I2
II 12
4 5 6
4 4 x2
o 2 i2
i x 6
4 4 io
4 4 12
6 2 12
4 3 6
6 8 io
i2 i2 i2
I2 i2 i2
i1 7 I2
7
2
IO
IO
IO
4
IO
IO
IO
2
IO
I0
8
8
12
12
12
8
io
I2
12
12
i2
12
9
6
6
5
4
I2
IO
IO
IO 5
io 12
I2
IO
6 9
II
IO
2 5 8 9 68
If2
I2
Mean
71
i io
I2 IO I2
6 8 12 IO I2 II I2
TRIAL OF DISODIUM CROMOGLYCATE
IN B R O N C H I A L
I59
ASTHMA
T A B L E IV. DIFFERENCES B E T W E E N O B S E R V E R S ~ O B S E R V A T I O N S
Day scores
Wight scores
Placebo period DSCG period Placeboperiod DSGG period All four sets compared with comparedwith comparedwith comparedwith of data pre-test period pre-test period pre-testperiod pre-test period together 't'
't'
't'
't'
't'
B c o m p a r e d with
1.65
0.8
I'86
1.27
0"725
B&C compared with W
o.28
I, I
I. 16
o.5
0"2
B,C&W compared with M
I-8
0"95
1-76
2-22
0"29
C
In all cases p > o.o5 pre-test. There was a systematic difference between B, C and W (the doctors) and M (the medical social worker). M recorded less difference between the placebo period and the period of treatment with disodium cromoglycate with regard to both day and night scores.
Improvement due to disodium cromoglycate In view of the concordance of observers, it was possible to compare the disodium cromoglycate and placebo periods in terms of the total scores of all four observers. The average score for exercise tolerance in the pre-test period was 74. In the placebo period the average score was 76 and this increased to IOI in the disodium cromoglycate period. The improvement in the disodium cromoglycate period was significant: ' t ' (one-sided) = 3"2o (p < o'oo5). For night-time scores the average score was 68 in the pre-test period, 71 in the placebo period and I io in the disodium cromoglycate period. The improvement was significant: ' t ' (one-sided) = 3"~ (p < o'oo5). Patients' scores These are shown in Table V. The mean score for exercise tolerance of 5o in the placebo period increased to 68 in the disodium cromoglycate period. This difference was significant: ' t ' (one-sided) = 3"1 (p < o.oi). For night disturbance the corresponding increase in score was from 54 to 79: ' t ' (onesided) = 3"4 (P < o'oo5). For the patients' detailed questionnaire the increase in score was from a mean of 373 in the placebo period to 459 in the disodium cromoglycate period: ' t ' (one-sided) = 3"3 (P < o'oo5). There was no significant difference between scores in the pre-test and placebo period.
I6O
WEINBREN~
BOUND
AND
CAPPER
T A B L E V. PATIENTS' SCORES
Patient no. i 2 3 4 5 6 7 8 9 1o Mean
Exercise tolerance 37 36 56 n2 7° 69 56 76 23 56 5°
Placebo period Night Detailed score questionnaire 38 31 84 44 35 84 51 84 2i 69 54
424 365 525 223 249 262 434 465 337 446 373
Disodium cromoglycateperiod Exercise Night Detailed tolerance score questionnaire 68 48 56 59 76 79 56 84 83 67 68
84 76 84 7° 58 84 8o 84 84 82 79
455 466 500 317 4o5 5o6 462 513 468 498 459
Physical examination N o significant difference was f o u n d b e t w e e n observers. N o significant imp r o v e m e n t o c c u r r e d in the disodium c r o m o g l y c a t e period.
Spirometry T h e results o f the F E V 1 estimations are s h o w n in T a b l e V I . T h e m e a n value for the F E V 1 in the pre-test period was I66 3 ml. T h e m e a n value for the F E V 1 in the placebo period was u n c h a n g e d (i66 5 ml) b u t it increased to 2ooo m l in the disodium c r o m o g l y c a t e period. T h u s a significant i m p r o v e m e n t o c c u r r e d in the d i s o d i u m c r o m o g l y c a t e p e r i o d : ' t ' = 2"28 (p < o'o5).
TABLE VI. VALUES OF FEVI*
Patient no. 1 2 3 4 5 6 7 8 9 io Mean
Pre-test period
Placebo period
DSCG period
12oo 173o 97o IOOO 38o 2200 215° 8oo 24°° 37oo I663
IlOO 2300 II5O 5oo 75° n35o 22oo 65o 15°° 415° 1665
13oo 2500 115o ilOO 9oo 2300 275o 8oo 3 loo 41oo 2ooo
Predicted Pre-test Placebo DSCG period normal period period °7opredicted value 070predicted 07opredicted value value value 1695 2620 165o I84O I39o 184o 28io 34oo 34oo 49oo
71 47 58 6o 21 12o 72 23 71 75
65 88 7° 27 54 128 73 19 44 85
77 95 7o 6o 64 126 98 23 91 84
* In ml
Predicted values of FEV1 for children taken from Strang (1959) and for adults from Kory et al. (196I)
TRIAL
OF
DISODIUM
CRONIOGLYCATE
IN BRONCHIAL
I6I
ASTHMA
Patients' assessment
Patient 3 declared in favour of the placebo. Patient 7, 'Felt all fight on m y injections, anyway', though his parents stated he had been much better during treatment with disodium cromoglycate. The other 8 patients and the parents of the children were and have remained unequivocally in favour of continuing treatment with disodium cromoglycate. Individual changes of symptoms (disodium cromoglycate period compared with placebo period / are shown in Figs. i a (exercise tolerance) and zb (night scores). Discussion
All the studies reporting favourably on disodium cromoglycate have relied heavily on patients' assessments of their improvements, and symptomatic improvement has always been more striking and more consistent than spirometric change. In this study quantification of symptoms by rating on a notionally continuous scale has permitted comparison of independent observers' assessments. Concordance between observers (especially that between the medical observers) was significant. This suggests that symptoms in asthma may be reliably assessed and, therefore, that weight may be attached to symptomatic improvement even when this is not matched by spirometric change.
9C
Max80
Able?okeep pace
with others of age and sex
i
•
~
•
7C
6£
Able to hurry
~
9/Z
for short periods
/
5
Z/66
*
5c
4c
2/
Ableto walkat °~ overage speed but not hurry
/
3C o
Exercise tolerance scoresduringplaceboo
/
J
/e
/
g
period
Exercisetolerance during disodium • cromoglycoteperiod
Able ?o walk
slowly on level
I
,o
2b
3b
I
4o
I
50
Patients' scores, day
~IG. I(a) VOL. LXIII 3
do
7b
8b
90 Max
162
WEINBREN~
BOUND
AND
CAPPER
9(
! - Uninterrupted night every night 8[ 70 6o
Awake once every other night
7
"~ 50
g
4c; ~, 30 ..Q o
Awoke once every night
/
/
/ ~r Awake twice or more every night
Night. scores during
~ebo--pe~o~ ......
^
o
Night. scores during disodium cromoglycate t ~leurim°bd~ ?o patients
/
Awake morethan Ihr every mvght ,i~ ~o 3'0 4o ~'o Patients' scores, night
t
,t
60 .
7'o
80
90 Max
F i o . I(b)
14C "0
"10
12C
[] ~
Placebo period Disodium c r o m o g l y c a f e period N u m b e r s refer to p a t i e n t s
IOC
P 8C
. / / i / I / / / . i
6C
i i .
I,U IL
.i
,'// ///
4C 2C
i i . "11
//'/
~IG. 2
YJ.
TRIAL
OF DISODIUM
CROMOGLYOATE
IN BRONCHIAL
ASTHMA
I6 3
The finding in this study was that severity of symptoms before treatment with disodium cromoglycate was not always proportional to the degree of reduction of the F E V below the expected normal. Patient 8 (FEV I 9 ~o of normal) was hardly woken at night, while patient 2 (FEV 88~o) was woken twice or more every night and indeed had the worst night record of any patient in the group (Fig. Ib). Patients I, 4, 5 and 9 suffered much the same amount of night waking during the placebo period. Their FEVs (as ~o of expected normals) were 65, 27, 54 and 44 respectively during this period (Table VI). Similarly with exercise tolerance: patients i, 5, 6 and 9 showed the same level of exercise tolerance during placebo treatment. Yet their FEVs were 65~o, 547o, I28~o and 44~o respectively. Nor was relief of symptoms either by day or night matched by improvement in the FEV. Patient 2 who when treated with disodium cromoglycate showed the greatest improvement in night waking (Fig. Ib) improved in FEV only from 88~o to 957o (Table VI). Patients 5, 6, 8, 9 and IO all reached an almost normal exercise tolerance on treatment with disodium cromoglycate (Fig. I a) yet only patient 9 showed an improvement of more than 2O~o in the F E V (Table VI).
Conclusion The experiment effectively demonstrates the concordance of 4 independent observers in assessing symptomatic change in a double-blind trial of disodium cromoglycate in bronchial asthma. A significant and substantial degree of symptomatic improvement was found during treatment with disodium cromoglycate. The improvement in symptoms was not always matched by improvement in the FEV. The study in general supports the conclusions of Howell and Altounyan (i967) , Kennedy (i967) , Smith and Devey (I968) and Moran et al. (1968). It is concluded that symptomatic assessment of improvement in asthma under treatment with disodium cromoglycate is reliable. The improvement must often be due to physiological changes not reflected in the FEV.
Summary A double-blind, cross-over trial of disodium cromoglycate was carried out over a period of 6 weeks in 6 children and 4 adults. The reliability of symptomatic assessment was established by demonstrating concordance between four independent observers who rated symptoms on a notionally continuous scale. Significant clinical improvement was found during disodium cromoglycate therapy. This was not necessarily matched by improvement in the F E V in individual patients. The study is in general agreement with the reports of Howell and Altounyan (x967) , Kennedy (1967) , Smith and Devey (1968) and Moran et al. (I968).
16 4
WEINBREN, BOUND AND CAPPEN
Acknowledgements We thank Mrs M. Marsden, medical social worker, for her co-operation, Dr C. C. Shah and Dr W. Annan for measuring the FEV1 and Dr J. S. G. Cox, Research Director, Fisons Pharmaceuticals Ltd, for supplying the disodium cromoglycate and placebo used in the study. We are very grateful to Dr R. E. C. Altounyan and Dr J. B. L. Howell for advice and encouragement and also to E. H. Lloyd, Professor of Mathematics, The University of Lancaster, for surveying our data and carrying out the statistical analysis.
References GRANT, I. W. B., CHANNELL, S. & DREVER, J. C. (1967) Disodium cromoglycate in asthma. Lancet, 2, 673. HOWELL, J. B. L. & ALTOUNYAN, R. E. C. (1967) A double-blind trial of disodlum cromoglycate in the treatment of allergic bronchial asthma. Lancet, 2, 539. KENNEDY, M. C. S. (1967) Disodium cromoglycate in asthma. Lancet, 2, 838. KORY, R. C., CALLAHAN, R., BOREN, H. G. & SYNER, J. C. (t96i) Clinical spirometry in normal men. Amer. 07. Med., 3o, 243. LENI)ROM, A. C. (1944) The staining of eoslnophil polymorphs and enterochromaphin cells in histological sections. 07. Path. Bact., 56, 441. MORAN, F., BANKIER, J. D. H. & BOYD, C-. (1968) Disodium cromoglycate in the treatment of allergic bronchial asthma. Lancet, 2, I37. PEPYS, J., HARGREAVE, F. ]~., CHAN, M. & McCARTHY, D. S. (1968) Inhibitory effects of disodium cromoglycate in the treatment of allergic bronchial asthma. Lancet, 2, 134. SMITH, J. M. & DEvEY, G. F. (1967) Clinical trial of disodium cromoglycate in treatment of asthma in children. Brit. med. 07., 2, 340. STRANO, L. B. (1959) The ventilatory capacity of normal children. Thorax, i4, 305 .
A Double-blind Trial of Disodium Cromoglycate in Bronchial Asthma with Assessment by Four Observers I. WEINBREN,
J.
B O U N D AN D L. CA PP ER
Departments of Medicine, Pediatrics and Chest Medicine, Victoria Hospital, Blackpool
ALTOUNYAN (I967) first described the protective effect exerted by disodium cromoglycate in preventing the development of antigen-induced asthma. His observations were made on himself--an atopic subject. This power of the drug to inhibit immediate bronchial asthma has been confirmed by P e w s et al. (i968). The clinical effectiveness of the drug has been reported by Howell and Altounyan (I967) , Kennedy (I967) , Smith and Devey (I968) and Moran et al. (i968). Grant et al. (i967) reported no worthwhile effect. In comparing their results with those of Howell and Altounyan, Grant et al. state that they placed much greater reliance on the FEV1 as an index of improvement and were much less ready to accept patients' subjective assessments of the value of the drug. Howell and Altounyan (I967) reported an improvement of the F E V 1 greater than 2o~o in only four out of ten subjects and stated there was no a priori reason why such symptoms as cough, sputum, morning tightness or intermittent attacks of dyspnoea should be reflected in a change of the F E V 1. Kennedy (i967) did not report changes of the FEV. Smith and Devey (I968) found significant improvement in spirometric results in favour of the drug in patients whose F E V 1 or F V C values were less than 8o~o of predicted value in either period. Moran et al. (I 968) relied on symptomatic assessment and found no significant improvement in the F E V 1 during treatment with the active drug. Thus the place of disodium cromoglycate in the treatment of asthma rests heavily on assessment of symptoms. In view of this and its potential importance in therapeutics, a trial has been carried out which attempts to establish the reliability of symptomatic assessment. Symptoms were assessed by four independent observers (three medical and one lay). Concordance between observers was tested and also between observer assessment and patient assessment. Patients and M e t h o d s
Patients Patients were included in the trial (i) if their asthma was severe enough to need continuous corficosteroid therapy, and (2) if they were able and willing (Receivedfor lbublication, ~anuary z969)
156
WEINBREN,
BOUND AND CAPPER
to assess a n d record s y m p t o m s twice daily o n special charts for the six weeks o f the trial. T h r e e patients failed to c o m p l e t e the trial; two defaulted for personal reasons; a n d one d e v e l o p e d a n a c u t e e x a c e r b a t i o n o f cough,, s p u t u m a n d d y s p n o e a , necessitating hospital admission soon after the trial b e g a n . Details o f the i o patients w h o c o m p l e t e d the trial are s h o w n in T a b l e I. TABLE I.
Duration of Patient Age Sex Height Weight symptoms no. (in.) (lb) (yr)
Family history of atopy
Minimum Infantile Sputum or maintenance dose e c z e m a nasal swab of corticosteroids eosinophilia or A C T H in past year
i 2
9¼ F I2 M
51½ 66 60 122
7½ io
+ +
+ +
+ +
3 4
14 F x3 M
5I 53
92 83
13 Ix
+ +
+ +
o +
5 6
13½ M 14 M
48 53
98 93
I x½ 6
+ +
+ +
+ +
7
x5 M
61½
94
I3½
+
+
+
8
32
M
62½ I x9
~8
+
+
o
9
39 M
64½ 166
9
-
-
+
xo
37 M
73½ x78
3
--
-
+
ACTH 20 u day ACTH 20 u twice weekly ACTH 20 u day ACTH 20 u alternate days ACTH 20 u day ACTH 20 u alternate days ACTH 4° u 3 times weekly Prednisone I o nag day Prednisone xo mg day ACTH 40 u 3 times weekly
PYoceduY~ T h e trial e x t e n d e d o v e r t w o consecutive periods o f three weeks each. Patients c o n t i n u e d their usual m e d i c a t i o n t h r o u g h o u t the trial. T h e y received in a d d i t i o n capsules c o n t a i n i n g p o w d e r to b e i n h a l e d at six-hourly intervals f r o m a special inhaler ( ' S p i n h a l e r ' ) . T h e capsule used in the p l a c e b o p e r i o d c o n t a i n e d o.I m g isoprenaline sulphate, 5 m g s o d i u m s u l p h a t e to i m p a r t a bitter taste a n d 34"9 m g lactose. T h o s e used in the d i s o d i u m c r o m o g l y c a t e p e r i o d w e r e identical in a p p e a r a n c e b u t c o n t a i n e d o- i m g isoprenaline sulphate, t o g e t h e r w i t h 20 m g o f d i s o d i u m c r o m o g l y c a t e a n d 19. 9 m g lactose. T h e o r d e r in w h i c h patients received e a c h p r e p a r a t i o n was r a n d o m i z e d . T h e patients w e r e told t h a t two different forms o f d r u g w e r e to be used, e a c h for a t h r e e - w e e k period, a n d t h a t neither m i g h t benefit t h e m , one m i g h t benefit t h e m , or b o t h m i g h t benefit t h e m . All p a t i e n t s w e r e seen before the trial, a t the cross-over a n d at the e n d o f the trial. A t each visit a n i n d e p e n d e n t assessment o f s y m p t o m s was m a d e b y the t h r e e a u t h o r s (hereafter referred to as B, C a n d W) a n d b y a m e d i c a l social w o r k e r (hereafter referred to as M ) . Physical e x a m i n a t i o n was carried out i n d e p e n d e n t l y o n e a c h p a t i e n t b y B,
T R I AL OF DISODIUM CROMOGLYGATE IN BRONCHIAL A S T H M A
x57
C and W. The presence of rhonchi, rftles and wheezing audible to the unaided ear was recorded. Each sign was rated on a notionally continuous scale (o-4). The FEV1 was recorded by two different observers and B, C and W, and M did not learn the values recorded until the trial was over. Sputum samples or, if these were unobtainable, nasal swabs were taken for examination for eosinophils by the method of L e n d r u m (i 944). A s s e s s m e n t o f R e s p o n s e to T r e a t m e n t T h e assessment forms used are s h o w n in T a b l e II. Patients c o m p l e t e d e a c h series o f q u e s t i o n s e v e r y d a y . T h e o b s e r v e r s u s e d t h e scales s h o w n i n series xa TABLE II. SCORE CARDS Questions to be answered each day Series xa: night scores
Series l: general How would you class your chest symptoms on the whole last night ?
Score i 2 3 4 5
Very bad Bad Fair Good Very good
On waking this morning was your chest
Very tight ? Tight ? Slightly tight ? Clear ?
I 2 3 4
Was your nose stuffy last night ?
A lot A moderate amount A little Not at all
x 2 3 4
Score Kept awake at night for at least one hour
o
Woken by asthma twice or more during night
x
Woken by asthma once only
2
Not woken by asthma at all
6
How many times did you need to use your usual spray last night ? Series 2: general
Questions to be answered each night Series 2a: exercise tolerance
&ore
Scora
How has your cough been during the past 24 hours ? How much sputum did you have during the past 24 hours ? Have you had bouts of sneezing in the past 94 hours ?
Very troublesome Troublesome Slight Absent
i 2 3 4
More than I egg-cup ~-~ egg-cup A few blobs None at all
I 2 3 4 5
Lots A few None
x 2 3
~-: egg-cup
How many times did you need to use your usual spray during the day ?
Just able to move around room Able to walk slowly on the level Able to climb stairs slowly with pauses Able to walk at average speed but not to hurry Able to hurry for short periods but not as much as others of same age and sex Able to keep up with others of same age and sex in all respects
0
I58
WEINBREN~
BOUND
AND
CAPPER
( n i g h t scores) a n d 2 a ( e x e r c i s e t o l e r a n c e ) f o r t h e a s s e s s m e n t s m a d e a t e a c h v i s i t a n d e x p r e s s e d t h e i r r e s u l t s as t h e a v e r a g e f o r a w e e k . I n a l l cases scores f o r t h e first w e e k a n d t h e first w e e k a f t e r t h e c r o s s - o v e r w e r e d i s c a r d e d t o o b v i a t e a n y c a r r y - o v e r effect. T h e m a x i m u m a s y m p t o m - f r e e p a t i e n t c o u l d a l l o t h i m s e l f f o r t h e t w o w e e k s w h i c h w a s c o u n t e d as a t r i a l p e r i o d w a s 84 f o r e x e r c i s e t o l e r a n c e (series 2 a ) , 84 f o r n i g h t scores (series I a ) a n d 54o f o r t h e g e n e r a l q u e s t i o n n a i r e (series I a n d 2). T h e m a x i m u m a s y m p t o m - f r e e p a t i e n t c o u l d b e a l l o t t e d b y a n o b s e r v e r f o r t h e s a m e p e r i o d w a s 12 f o r e x e r c i s e t o l e r a n c e a n d 12 f o r n i g h t scores. Results
Observer concordance Scores allotted by observers are shown in Table III. The 'improvements' each observer found in the disodium cromoglycate period compared with the pre-test period, and the placebo period compared with the pre-test period, were calculated. The differences between observers were then compared by Student's statistic 't'. The 't' values were two-sided, corresponding to the fact that differences between observers could be positive or negative. The values found are shown in Table IV. N o s i g n i f i c a n t d i f f e r e n c e a p p e a r e d b e t w e e n t h e a s s e s s m e n t o f B, C a n d W . Their concord was least in the comparison between the placebo period and the TABLE I I I . OBSErVE'aS' SCOR~.S
Exercise tolerance Pre-test period
x
2 3 4 5 6 7 8 9 Io Mean
Dbodium cromoglycate period
Placebo period
B
C
W
M
B
C
W
M
B
8
8
7
8
6
8
7
8
IO
4 8 8 8 8 8 8 8 8
4 8 8 8 8 8 12 2 8
a 6 5 5 7 Io Io 9 8
4 8 4 4 xo IO x2 8 8
4 I2 4 8 8 8 xo 8 11
2 4 xo 8 2 4 8 5 8 7 8 IO 12 Io 2 9 1o 8 76
4 IO 4 Io Io xo Io 8 xo
IO 8 IO 12 12 8 12 I2 II
74
C W M xo I i I O 8 9 8 8 8 8 8 2 7 12 II IO 12 I2 12 8 IO I O 12 IO I 2 Io 12 I I I2 I2 I 2 Ioi
Night scores I
4
2
Io
IO
4
4
4
4
12
12
12
2 3
2 I2
2 I2
2 I2
2 I2
2 I2
2 I2
2 I2
2 I2
IO I2
IO I2
II 12
4 5 6
4 4 x2
o 2 i2
i x 6
4 4 io
4 4 12
6 2 12
4 3 6
6 8 io
i2 i2 i2
I2 i2 i2
i1 7 I2
7
2
IO
IO
IO
4
IO
IO
IO
2
IO
I0
8
8
12
12
12
8
io
I2
12
12
i2
12
9
6
6
5
4
I2
IO
IO
IO 5
io 12
I2
IO
6 9
II
IO
2 5 8 9 68
If2
I2
Mean
71
i io
I2 IO I2
6 8 12 IO I2 II I2
TRIAL OF DISODIUM CROMOGLYCATE
IN B R O N C H I A L
I59
ASTHMA
T A B L E IV. DIFFERENCES B E T W E E N O B S E R V E R S ~ O B S E R V A T I O N S
Day scores
Wight scores
Placebo period DSCG period Placeboperiod DSGG period All four sets compared with comparedwith comparedwith comparedwith of data pre-test period pre-test period pre-testperiod pre-test period together 't'
't'
't'
't'
't'
B c o m p a r e d with
1.65
0.8
I'86
1.27
0"725
B&C compared with W
o.28
I, I
I. 16
o.5
0"2
B,C&W compared with M
I-8
0"95
1-76
2-22
0"29
C
In all cases p > o.o5 pre-test. There was a systematic difference between B, C and W (the doctors) and M (the medical social worker). M recorded less difference between the placebo period and the period of treatment with disodium cromoglycate with regard to both day and night scores.
Improvement due to disodium cromoglycate In view of the concordance of observers, it was possible to compare the disodium cromoglycate and placebo periods in terms of the total scores of all four observers. The average score for exercise tolerance in the pre-test period was 74. In the placebo period the average score was 76 and this increased to IOI in the disodium cromoglycate period. The improvement in the disodium cromoglycate period was significant: ' t ' (one-sided) = 3"2o (p < o'oo5). For night-time scores the average score was 68 in the pre-test period, 71 in the placebo period and I io in the disodium cromoglycate period. The improvement was significant: ' t ' (one-sided) = 3"~ (p < o'oo5). Patients' scores These are shown in Table V. The mean score for exercise tolerance of 5o in the placebo period increased to 68 in the disodium cromoglycate period. This difference was significant: ' t ' (one-sided) = 3"1 (p < o.oi). For night disturbance the corresponding increase in score was from 54 to 79: ' t ' (onesided) = 3"4 (P < o'oo5). For the patients' detailed questionnaire the increase in score was from a mean of 373 in the placebo period to 459 in the disodium cromoglycate period: ' t ' (one-sided) = 3"3 (P < o'oo5). There was no significant difference between scores in the pre-test and placebo period.
I6O
WEINBREN~
BOUND
AND
CAPPER
T A B L E V. PATIENTS' SCORES
Patient no. i 2 3 4 5 6 7 8 9 1o Mean
Exercise tolerance 37 36 56 n2 7° 69 56 76 23 56 5°
Placebo period Night Detailed score questionnaire 38 31 84 44 35 84 51 84 2i 69 54
424 365 525 223 249 262 434 465 337 446 373
Disodium cromoglycateperiod Exercise Night Detailed tolerance score questionnaire 68 48 56 59 76 79 56 84 83 67 68
84 76 84 7° 58 84 8o 84 84 82 79
455 466 500 317 4o5 5o6 462 513 468 498 459
Physical examination N o significant difference was f o u n d b e t w e e n observers. N o significant imp r o v e m e n t o c c u r r e d in the disodium c r o m o g l y c a t e period.
Spirometry T h e results o f the F E V 1 estimations are s h o w n in T a b l e V I . T h e m e a n value for the F E V 1 in the pre-test period was I66 3 ml. T h e m e a n value for the F E V 1 in the placebo period was u n c h a n g e d (i66 5 ml) b u t it increased to 2ooo m l in the disodium c r o m o g l y c a t e period. T h u s a significant i m p r o v e m e n t o c c u r r e d in the d i s o d i u m c r o m o g l y c a t e p e r i o d : ' t ' = 2"28 (p < o'o5).
TABLE VI. VALUES OF FEVI*
Patient no. 1 2 3 4 5 6 7 8 9 io Mean
Pre-test period
Placebo period
DSCG period
12oo 173o 97o IOOO 38o 2200 215° 8oo 24°° 37oo I663
IlOO 2300 II5O 5oo 75° n35o 22oo 65o 15°° 415° 1665
13oo 2500 115o ilOO 9oo 2300 275o 8oo 3 loo 41oo 2ooo
Predicted Pre-test Placebo DSCG period normal period period °7opredicted value 070predicted 07opredicted value value value 1695 2620 165o I84O I39o 184o 28io 34oo 34oo 49oo
71 47 58 6o 21 12o 72 23 71 75
65 88 7° 27 54 128 73 19 44 85
77 95 7o 6o 64 126 98 23 91 84
* In ml
Predicted values of FEV1 for children taken from Strang (1959) and for adults from Kory et al. (196I)
TRIAL
OF
DISODIUM
CRONIOGLYCATE
IN BRONCHIAL
I6I
ASTHMA
Patients' assessment
Patient 3 declared in favour of the placebo. Patient 7, 'Felt all fight on m y injections, anyway', though his parents stated he had been much better during treatment with disodium cromoglycate. The other 8 patients and the parents of the children were and have remained unequivocally in favour of continuing treatment with disodium cromoglycate. Individual changes of symptoms (disodium cromoglycate period compared with placebo period / are shown in Figs. i a (exercise tolerance) and zb (night scores). Discussion
All the studies reporting favourably on disodium cromoglycate have relied heavily on patients' assessments of their improvements, and symptomatic improvement has always been more striking and more consistent than spirometric change. In this study quantification of symptoms by rating on a notionally continuous scale has permitted comparison of independent observers' assessments. Concordance between observers (especially that between the medical observers) was significant. This suggests that symptoms in asthma may be reliably assessed and, therefore, that weight may be attached to symptomatic improvement even when this is not matched by spirometric change.
9C
Max80
Able?okeep pace
with others of age and sex
i
•
~
•
7C
6£
Able to hurry
~
9/Z
for short periods
/
5
Z/66
*
5c
4c
2/
Ableto walkat °~ overage speed but not hurry
/
3C o
Exercise tolerance scoresduringplaceboo
/
J
/e
/
g
period
Exercisetolerance during disodium • cromoglycoteperiod
Able ?o walk
slowly on level
I
,o
2b
3b
I
4o
I
50
Patients' scores, day
~IG. I(a) VOL. LXIII 3
do
7b
8b
90 Max
162
WEINBREN~
BOUND
AND
CAPPER
9(
! - Uninterrupted night every night 8[ 70 6o
Awake once every other night
7
"~ 50
g
4c; ~, 30 ..Q o
Awoke once every night
/
/
/ ~r Awake twice or more every night
Night. scores during
~ebo--pe~o~ ......
^
o
Night. scores during disodium cromoglycate t ~leurim°bd~ ?o patients
/
Awake morethan Ihr every mvght ,i~ ~o 3'0 4o ~'o Patients' scores, night
t
,t
60 .
7'o
80
90 Max
F i o . I(b)
14C "0
"10
12C
[] ~
Placebo period Disodium c r o m o g l y c a f e period N u m b e r s refer to p a t i e n t s
IOC
P 8C
. / / i / I / / / . i
6C
i i .
I,U IL
.i
,'// ///
4C 2C
i i . "11
//'/
~IG. 2
YJ.
TRIAL
OF DISODIUM
CROMOGLYOATE
IN BRONCHIAL
ASTHMA
I6 3
The finding in this study was that severity of symptoms before treatment with disodium cromoglycate was not always proportional to the degree of reduction of the F E V below the expected normal. Patient 8 (FEV I 9 ~o of normal) was hardly woken at night, while patient 2 (FEV 88~o) was woken twice or more every night and indeed had the worst night record of any patient in the group (Fig. Ib). Patients I, 4, 5 and 9 suffered much the same amount of night waking during the placebo period. Their FEVs (as ~o of expected normals) were 65, 27, 54 and 44 respectively during this period (Table VI). Similarly with exercise tolerance: patients i, 5, 6 and 9 showed the same level of exercise tolerance during placebo treatment. Yet their FEVs were 65~o, 547o, I28~o and 44~o respectively. Nor was relief of symptoms either by day or night matched by improvement in the FEV. Patient 2 who when treated with disodium cromoglycate showed the greatest improvement in night waking (Fig. Ib) improved in FEV only from 88~o to 957o (Table VI). Patients 5, 6, 8, 9 and IO all reached an almost normal exercise tolerance on treatment with disodium cromoglycate (Fig. I a) yet only patient 9 showed an improvement of more than 2O~o in the F E V (Table VI).
Conclusion The experiment effectively demonstrates the concordance of 4 independent observers in assessing symptomatic change in a double-blind trial of disodium cromoglycate in bronchial asthma. A significant and substantial degree of symptomatic improvement was found during treatment with disodium cromoglycate. The improvement in symptoms was not always matched by improvement in the FEV. The study in general supports the conclusions of Howell and Altounyan (i967) , Kennedy (i967) , Smith and Devey (I968) and Moran et al. (1968). It is concluded that symptomatic assessment of improvement in asthma under treatment with disodium cromoglycate is reliable. The improvement must often be due to physiological changes not reflected in the FEV.
Summary A double-blind, cross-over trial of disodium cromoglycate was carried out over a period of 6 weeks in 6 children and 4 adults. The reliability of symptomatic assessment was established by demonstrating concordance between four independent observers who rated symptoms on a notionally continuous scale. Significant clinical improvement was found during disodium cromoglycate therapy. This was not necessarily matched by improvement in the F E V in individual patients. The study is in general agreement with the reports of Howell and Altounyan (x967) , Kennedy (1967) , Smith and Devey (1968) and Moran et al. (I968).
16 4
WEINBREN, BOUND AND CAPPEN
Acknowledgements We thank Mrs M. Marsden, medical social worker, for her co-operation, Dr C. C. Shah and Dr W. Annan for measuring the FEV1 and Dr J. S. G. Cox, Research Director, Fisons Pharmaceuticals Ltd, for supplying the disodium cromoglycate and placebo used in the study. We are very grateful to Dr R. E. C. Altounyan and Dr J. B. L. Howell for advice and encouragement and also to E. H. Lloyd, Professor of Mathematics, The University of Lancaster, for surveying our data and carrying out the statistical analysis.
References GRANT, I. W. B., CHANNELL, S. & DREVER, J. C. (1967) Disodium cromoglycate in asthma. Lancet, 2, 673. HOWELL, J. B. L. & ALTOUNYAN, R. E. C. (1967) A double-blind trial of disodlum cromoglycate in the treatment of allergic bronchial asthma. Lancet, 2, 539. KENNEDY, M. C. S. (1967) Disodium cromoglycate in asthma. Lancet, 2, 838. KORY, R. C., CALLAHAN, R., BOREN, H. G. & SYNER, J. C. (t96i) Clinical spirometry in normal men. Amer. 07. Med., 3o, 243. LENI)ROM, A. C. (1944) The staining of eoslnophil polymorphs and enterochromaphin cells in histological sections. 07. Path. Bact., 56, 441. MORAN, F., BANKIER, J. D. H. & BOYD, C-. (1968) Disodium cromoglycate in the treatment of allergic bronchial asthma. Lancet, 2, I37. PEPYS, J., HARGREAVE, F. ]~., CHAN, M. & McCARTHY, D. S. (1968) Inhibitory effects of disodium cromoglycate in the treatment of allergic bronchial asthma. Lancet, 2, 134. SMITH, J. M. & DEvEY, G. F. (1967) Clinical trial of disodium cromoglycate in treatment of asthma in children. Brit. med. 07., 2, 340. STRANO, L. B. (1959) The ventilatory capacity of normal children. Thorax, i4, 305 .