Jt /7
`
`OCTOBER 1964
`
`The Journal of The British Society of Gastroenterology
`
`A-
`
`EDITOR: HAROLD C. EDWARDS
`
`EDITORIAL SECRETARY: F. AVERY JONES
`
`CONTENTS
`
`Dose response curves for the effect of gastrin II
`on acid gastric secretion in man 0. M. MAKHLOUF,
`J. P. A. MCMANUS, and w. 1. CARD (cid:9)
`page 379
`The absorption of radioactive vitamin B12 and the
`secretion of hydrochloric acid in patients with
`atrophic gastritis M. G. WHITESIDE, D. L. MOLLIN,
`N. F. COGHILL, A. WYNN WILLIAMS, and BARBARA
`ANDERSON (cid:9)
`page 385
`
`Note on the late effect of vagotomy and pyloro-
`plasty on the maximal acid response to histamine
`ALVIN M. GELB and HENRY D. JANOVVTTZ .page 400
`
`Gastric ulcers, blood groups, and acid secretion
`IL DAINTREE JOHNSON, A. II. G. LOVE, N. C. ROGERS,
`and A. P. WYATT (cid:9)
`page 402
`
`Peptic ulcer in India and its aetiology s. L.
`MALHOTRA (cid:9)
`page 412
`
`Peptic ulcer and gastric secretion in patients with
`liver disease SOAD TABAQCHALI and A. M (cid:9) DAWSON
`page 417
`
`Reduced gastric acid output in cirrhosis: Quantita-
`tion and relationships BRIAN A. SCOBIE and
`WILLIAM H. J. SUMMERSKILL (cid:9)
`page 422
`
`Spontaneous internal biliary fistulae J. L. A.
`DOWSE (cid:9)
`page 429
`
`Controlled trial of sulphasalazine in the treatment
`of ulcerative colitis A. P. DICK, M. J. GRAYSON,
`R. G. CARPENTER, and A. PETRIE (cid:9)
`page 437
`- (cid:9)
`_
`
`Motility of the pelvic colon
`Part III Motility responses in patients with
`symptoms following amoebic dysentery A. M.
`CONNELL, M. GAAFER, M. A. HASSANEIN, and M. A.
`page 443
`KHAYAL (cid:9)
`Periampullary and duodenal carcinoid tumours
`KENNETH W. WARREN, WILLIAM M. MCDONALD, and
`page 448
`C. J. HUME LOGAN (cid:9)
`Experimental production of gastric epithelium in
`page 454
`the duodenum J. RHODES (cid:9)
`Hyperplasia of Brunner's glands J. F (cid:9) STOKES,
`L. A. TURNBERG, and J. C. HAWKSLEY.. . (cid:9) page 459
`Effect of paracetamol (N-acetyl-p-aminophenol) on
`gastrointestinal bleeding KERRY GOULSTON and
`page 463
`ALAN SKYRING (cid:9)
`Fixation of sulphur in the gut by bismuth salts
`page 467
`J. T. WRIGHT and J. GUPTE (cid:9)
`Some effects of hypophysectomy on gastro-
`intestinal function and structure E. D. JACOBSON
`and T. J. MAGNANI with the technical assistance of
`page 473
`E. B. MCCLASKEY and T. J. KALLAL (cid:9)
`Hydrolysis of fat by human gastric juice S. BANK,
`L. II. KRUT, I. N. MARKS, N. BRONTE-STEWART, and
`page 480
`P. J. LE R. UYS (cid:9)
`Methods and techniques
`Peritoneoscopy as an aid to diagnosis IVAN D. A.
`page 485
`JOHNSTON and H. W. RODGERS (cid:9)
`Experience of a new procedure for faecal analysis
`W. C. WATSON and CHRISTINE DICKSON . . .page 488
`Gastroenterological Society of Australia . .page 490
`
`LO
`
`YEA,
`
`REct.L v (cid:9)
`
`-LIMY OF
`
`•Z
`251964
`
`ISSOCIATION • TAVISTOCK SQUARE W.C.1
`ID £4. 4s. ABROAD £4. 15s. SINGLE NUMBER 18s. 6D.
`
`INDEXER. —
`
`INDEX MEDIC:0
`
`Thierr?te.lal az :: pied
`et; (cid:9)
`L
`
`'kg-- L. vs
`
`Ex. 1060 - Page 1
`
`(cid:9)
`

`

`
`
`'4177:7.„
`
`Editorial Committee
`
`C. C. BOOTH
`WILFRID CARD
`EDWARD R. CULLINAN
`SIR CHARLES DODDS
`HENRY T. HOWAT
`THOMAS HUNT
`ANDREW W. KAY
`H. A. MAGNUS
`
`C. NAUNTON MORGAN
`A. E. A. READ
`HAROLD RODGERS
`E. N. ROWLANDS
`SHEILA SHERLOCK
`NORMAN C. TANNER
`GEOFFREY WATKINSON
`L. J. WITTS
`
`EDITOR British Medical Journal
`HAROLD C. EDWARDS (Editor)
`
`F. AVERY JONES (Editorial Secretary)
`
`The object of Gut is to publish original papers and reviews
`concerned with practice and research in the field of
`gastroenterology. The field is that of alimentary, hepatic,
`or pancreatic disease, and papers may cover the medical,
`surgical, radiological, or historical aspects. They may
`also deal with the basic sciences concerned with the
`alimentary tract, including experimental work. The report
`of a single case will be accepted only if it is of sufficient
`interest in relation to a wider field of research.
`There will be a section devoted to short papers on
`laboratory and surgical techniques and methods of
`investigation where these are not part of a larger survey.
`
`COMMUNICATIONS Papers should be addressed to the
`Editor, Gut, B.M.A. House, Tavistock Square,
`London, W.C.1. Papers are accepted only on the
`understanding that they are not published elsewhere
`without previous sanction of the Editorial Board.
`They should be in double-spaced typewriting on one side
`of the paper only. On the paper the name of the author
`should appear with initials (or distinguishing Christian
`name) only, and the name and address of the hospital or
`laboratory where the work was performed. A definition
`of the position held by each of the authors in the hospital
`or laboratory should be stated in a covering letter to
`the Editor. Communications should be kept short, and
`illustrations should be included when necessary; coloured
`illustrations are allowed only if monochrome will not
`satisfactorily demonstrate the condition. It is not desirable
`that results should be shown both as tables and
`graphs.
`
`ILLUSTRATIONS Diagrams should be drawn in Indian
`ink on white paper, Bristol board, or blue-squared paper.
`The legends for illustrations should be typed on a separate
`sheet and numbered to conform with the relevant illus-
`trations. Photographs and photomicrographs should
`be on glossy paper, unmounted. TABLES should not be
`included in the body of the text, but should be typed on a
`separate sheet.
`
`ABBREVIATIONS In general, symbols and abbreviations
`should be those used by British Chemical and Physio-
`logical Abstracts. In any paper concerning electrolyte
`metabolism, it is desirable that data be calculated as
`mEq./1. as well as (or alternatively to) mg./100 ml.
`
`REFERENCES These should be made by inserting The
`name of the author followed by year of publication it
`brackets. At the end of the paper, references should be
`arranged in alphabetical order of author's name. Siych
`references should give author's name, followed by initials
`and year of publication in brackets, the title of the art
`quoted, the name of the journal in which the article
`appeared, the volume number in arabic numerals, ft!,
`lowed by numbers of first and last pages of artiqe,
`Abbreviations are according to World Medical Periodic,
`(published by B.M.A. for World Medical Associati%),
`thus: Chandler, G. N., Cameron, A. D., Nunn, A.
`and Street, D. F. (1960). Early investigations of haeznate.
`mesis. Gut, 1, 6-13.
`
`REPRINTS Fifty reprints will be supplied free of charke,
`Further reprints will be available on payment of
`necessary costs; an indication of the number of repriuts
`required should be sent to the Publishing Manager on tie
`post-card provided with the proofs.
`
`NOTICE To ADVERTISERS Applications for advertisement
`space and for rates should be addressed to the Advertise.
`ment Manager, GUT, B.M.A. House, Tavistock Square,
`London, W.C.1.
`
`NOTICE TO SUBSCRIBERS The annual subscription rate is
`£4 4s. in the United Kingdom and the Republic of Ireland,
`and £4 15s. in all countries overseas. The following are
`examples of equivalents to the sterling subscription rates:
`Australia £A.5 18s 9d.; Belgium Fr. 662.00; Canada
`$14.50; Denmark Kr. 92.25; France NF 65.25; Gen:natty
`DM. 53.50; India and Pakistan R. 63.50; Italy L. 8,215;
`Japan Yen 4,775; Netherlands G. 48.00; Norway Kr,
`95.25; South Africa Rand. 9.50; Spain Pta. 800.00;
`Sweden Kr. 68.75; Switzerland Fr. 57.50; U.S.A. $13.50;
`Venezuela Bol. 60.00. Payment for overseas subscriptions
`should be made in sterling, i.e. £4 15s., and sent by Mail
`Transfer—Charges Remitter—through a Bank. Orders
`can also be placed locally with any leading subscription
`agent or bookseller.
`
`cornuoirr (0 1964 by GUT. All rights of reproduction
`are reserved in respect of all papers, articles, tables,
`illustrations, etc., published in this Journal in all countries
`of the world.
`
`Thisriat•ial (cid:9)
`attt
`
`vied
`
`Ex. 1060 - Page 2
`
`

`

`OP' -
`apt.ti4"— - (cid:9)
`
`
`
`:tf
`
`Gut, 1964, 5, 437
`
`Controlled trial of sulphasalazine in the treatment
`of ulcerative colitis
`
`A. P. DICK, M. J. GRAYSON,' R. G. CARPENTER, AND A. PETRIE
`
`From Addenbrooke's Hospital, Cambridge and the Department of Human Ecology,
`University of Cambridge
`
`EDITORIAL SYNOPSIS This paper provides further evidence that sulphasalazine is an effective agent
`in the treatment of mild or moderate colitis. There was a high incidence of gastrointestinal side-effects
`and one patient developed haemolytic anaemia.
`
`Sulphasalazine (salicylazosulphapyridine, Salazo-
`pyrin, Asulfidine) was first used by Svartz (1942) in
`the treatment of rheumatoid arthritis. Later,
`patients with arthritis associated with ulcerative
`colitis were treated with sulphasalazine with clinical
`improvement of both conditions (Svartz, 1948). The
`drug has since been used extensively in Scandinavia
`and in America in the treatment of ulcerative
`colitis, and many reports have indicated favourable
`results, some three-quarters of the patients showing
`improvement in most series (Bargen, 1949, 1956;
`Moertel and Bargen, 1959; Morrison, 1952; Svartz,
`1954, 1960). However, at the time the present
`investigation was started in 1959 no controlled
`studies had been reported.
`Lennard-Jones, Longmore, Newell, Wilson, and
`Avery Jones (1960) report the result of two consecu-
`tive trials. In the first prednisone was compared with
`an inert tablet and found to be effective in cases of
`left-sided colitis. Prednisone was then used as a
`standard with which to compare sulphasalazine and
`hydrocortisone hemisuccinate retention enemata.
`There was no doubt about the effectiveness of
`prednisone as compared with that of an inert
`tablet. The authors considered that sulphasalazine
`probably brought about remission almost as
`frequently as prednisone, although more slowly.
`Under the conditions of their trial, however, a
`statistically significant result for the effectiveness of
`sulphasalazine was not obtained. The dosage of
`sulphasalazine used was 4 g. daily and the patients
`were assessed at the end of a three-week period.
`Truelove, Watkinson, and Draper (1962) compared
`combined oral and topical corticosteroid therapy
`with sulphasalazine over a 14-day period using the
`sequential method of analysis. The combined
`
`'Al present at King's College Hospital, London.
`
`corticosteroid therapy, given as a dose of prednisone,
`20 mg. a day, and hydrocortisone hemisuccinate
`100 mg. by retention enema, was shown to be
`significantly more effective in the 14-day period of
`the trial than sulphasalazine. The latter was given
`in a dose of 8 g. a day for the first week and 4 g. a
`day for the second. At the end of the two-week
`period 78 % of the patients on combined corti-
`costeroids had shown sigmoidoscopic improvement
`as opposed to 43 % on sulphasalazine. As emphasized
`by the authors, their trial shows only that combined
`corticosteroid treatment is better than sulphasalazine
`for rapidly checking an attack of the disease.
`The only formal double-blind trial comparing
`sulphasalazine with a placebo, which has been
`reported, was carried out by Baron, Connell,
`Lennard-Jones, and Avery Jones (1962). They
`tested in addition a new drug, salicylazosulphadimi-
`dine, but this was abandoned after a short time as
`being obviously ineffective, and the trial continued
`only between sulphasalazine and an inert tablet. A
`statistically significant result was found in favour of
`sulphasalazine over a three-week period. The dosage
`used was 4 g. a day for the first week and 2 g. a day
`for the next two weeks. The patients all had mild
`active ulcerative colitis with little or no systemic
`upset and were fit to be treated as out-patients.
`
`PRESENT INVESTIGATION
`
`The present investigation comprised a double-blind trial
`of sulphasalazine against an inert tablet in cases of
`ulcerative colitis or proctitis in which the disease was of
`mild or moderate activity at the time. The trial was
`carried out by considering pairs of patients, one of whom
`was treated with sulphasalazine and the other given a
`dummy control treatment, and noting which patient
`responded most favourably over a four-week period. The
`437
`
`This mat =la! as ..c
`E-i rr
`atthe (cid:9)
`Subject US (cid:9)
`
`7 Laws
`
`Ex. 1060 - Page 3
`
`

`

`438 (cid:9)
`
`A. P. Dick, M. J. Grayson, R. G. Carpenter, and A. Petrie
`
`trial continued until a significant result was reached,
`sequential methods of analysis being used.
`No patient with severe disease or with appreciable
`systemic upset was included, as clearly it would have
`been unjustifiable to withhold corticosteroid therapy
`from such cases. All the patients were fit enough to be
`treated as out-patients during the period of the trial, and,
`to avoid introducing additional factors, only out-patients
`were included. The patients were either in an initial
`attack, in relapse after a remission, or were chronic
`cases in an exacerbation. None had received sulphasala-
`zinc, corticosteroids, or adrenocorticotrophin during the
`preceding three months. In the great majority of cases
`the disease was limited to the left side or distal colon
`although a few had total colitis. A limiting factor in
`obtaining patients suitable for inclusion, many of whom
`were drawn from rural areas, was their difficulty in
`attending weekly or fortnightly during the trial period.
`Each case was assessed on clinical and sigmoidoscopic
`criteria. The clinical state, number and consistency of
`the stools, the presence of blood, pus, or mucus, and the
`result of a full blood count and sedimentation rate were
`noted on a form. The findings on sigmoidoscopy were
`then recorded, the appearance being classified into five
`grades, as follows:-
`0 = normal mucosa
`I = faintly granular, pink mucosa without visible
`vessels, of quiescent colitis
`II — granular, reddened, oedematous and somewhat
`friable mucosa
`III --- very reddened oedematous and very friable mucosa,
`usually with actual ulceration, pus and blood often being
`present
`IV = flaming red mucosa of a fulminating case
`
`ALLOCATION OF TREATMENTS
`
`Allocation of active and dummy tablets was done by the
`hospital pharmacist without the knowledge of the doctor
`in charge of the case. Treatments were allocated strictly
`at random using random sampling numbers, and, for
`the purpose of assessing the trial, treated and control
`patients were subsequently paired at random with the
`restriction that colitis cases were paired with colitis cases
`and proctitis with proctitis.
`
`DOSAGE
`
`The optimal dosage of sulphasalazine is uncertain, but
`dosages varying from 4 to 12 g. daily have been suggested.
`In this trial an arbitrary daily dosage depending on body
`weight was given. Patients up to 9 stone received eight
`half-gram tablets per day in divided doses, patients
`weighing from 9 to 10 stone received nine tablets, 10 to
`11 stone, 10 tablets, 1 t to 12 stone, 11 tablets, and patients
`over 12 stone received 12 tablets per day in divided doses.
`The daily dosage thus varied from 4 to 6 g. of sulpha-
`salazine.
`The dummy tablets were specially prepared by the
`manufacturer to have a similar appearance to the active
`tablet and were in all respects indentical except that they
`did not have the same bitter taste.
`
`PROCEDURE
`
`After the initial assessment the patients usually attended
`weekly, sometimes every second week, when data
`regarding the clinical symptoms and stools were recorded
`and a repeat blood count and sedimentation rate were
`evaluated. A blood film was also examined for Heinz
`bodies in view of the report of Spriggs, Smith, Griffith,
`and Truelove (1958) of Heinz body anaemia occurring
`during sulphasalazine therapy. A four-week trial period
`was decided on, as previous experience had suggested
`that response to sulphasalazine was often slow.
`At the end of four weeks, each patient was assessed
`clinically, sigmoidoscopy was carried out, and an overall
`assessment made. The clinical state, sigmoidoscopic
`appearance, and overall state were in each case assessed
`as being worse, unchanged, improved, or much improved
`since the start of the trial. In the case of clinical state,
``improved' or 'much improved' was based on improve-
`ment in the patient's feeling of well-being, decrease in
`the frequency of the stools and a return towards norma l
`of their consistency, and decrease or disappearance in
`the amount of pus, mucus, and blood in the stools.
`Whether the patient was classified as 'unchanged',
``improved', or 'much improved' must clearly be to some
`extent a subjective judgment on the part of the patient
`and on the part of the observer, the only factual data
`being the alteration in the stools. The sigmoidoscopic
`appearances at the end of the month were assessed as
``worse', 'unchanged', 'improved', if they were one grade
`better, or 'much improved' if they were two grades better,
`which in some instances was equivalent to a return to
`normal. The placing of cases in a sigmoidoscopic grade
`is clearly to an appreciable extent a subjective process and
`open to observer error (Baron, Connell, and Lennard_
`Jones, 1964), but normally two observers were present
`at each examination and formed independent opinions
`of the grade before disclosing their view to the other.
`After the response had been assessed, the nature of
`the tablets with which the patient had been treated was
`then ascertained from the pharmacy. Patients on active
`treatment who had responded continued to receive
`sulphasalazine in gradually reducing doses. Any patients
`in the control group, i.e., taking inert tablets, who were
`still having symptoms were then changed over to active
`tablets for a month, the same data being recorded. These
`patients were assessed again at the end of this further
`four-week period. This month on active treatment,
`following a month on dummy tablets, is not included in
`the trial and the results are noted separately.
`
`STATISTICAL METHOD
`
`The chance that the patient of a pair receiving the active
`treatment shows more overall improvement than the
`patient receiving the dummy treatment can be denoted by
`O. It was anticipated that about one third of the patients
`receiving the placebo would show some improvement
`after four weeks, and it was felt that sulphasalazine
`would be of little clinical interest unless at least 60 % of
`the patients showed some improvement after four weeks.
`Accordingly, a paired sequential trial was planned along
`
`This Plat (cid:9)
`ate- a (cid:9)
`
`I E. E. ::aied
`E-i
`
`Ex. 1060 - Page 4
`
`

`

`Controlled trial of sulphasalazine in the treatment of ulcerative colitis (cid:9)
`
`439
`
`TABLE I
`SEVERITY OF DISEASE AND MEAN DURATION OF
`DISEASE IN TREATED AND CONTROL GROUPS
`Severity
`Mean Duration of
`Disease (mth.)
`
`Mild
`
`Moderate Total
`
`Patients
`
`the lines described by Armitage (1960) to test the null
`hypothesis that 0 = 0.5, i.e., that sulphasalazine has no
`effect, against the alternative hypothesis that 0 = 0.75,
`which corresponds to 60 % of patients responding to
`sulphasalazine and one third of the patients responding
`to control.
`This formulation presupposes only two classes of
`results, 'responded' and 'did not respond', but when
`assessing the overall response three grades were used;
`the classification 'worse' was never used. It may, however
`be shown that for the type of results we were interested in
`detecting, the formulation of the trial is unaltered by
`assessing response as no change, improved, or much
`improved.
`As the overall assessments of response fell into one of
`three categories, it was not surprising that in several
`cases both patients of a pair were assessed the same and
`so contributed nothing to the analysis. Suitable patients
`were scarce and progress was slow. We therefore
`attempted to make better use of the data collected. For
`this reason, from records of hospital in-patients suffering
`from colitis, a scoring system, based on the change in
`sigmoidoscopy gradings and changes in the number of
`stools per day, was developed to measure improvement.
`The chance of two patients having the same score on this
`system in extremely small. Details of how this response
`score was constructed may be found elsewhere (Carpenter,
`Petrie, and Dalton, 1964).
`The above hypothesis, formulated in terms of 0, can
`be reformulated in terms of the difference, d, between the
`response scores of the two patients of a pair, and tested by
`means of a sequential t test (Davies, 1956).
`
`RESULTS
`
`CLINICAL OBSERVATIONS As early results were not
`expected, the trial was left to proceed for some time
`before the results were examined. At this stage, the
`results merely indicated that the trial should continue.
`The trial then proceeded for another six months
`when it was decided to call a temporary halt and
`develop the scoring system. By this time 44 patients
`had entered the trial, 30 suffering from colitis and
`14 from proctitis. Three of the colitis patients who
`had been treated with sulphasalazine had to be
`excluded from the analysis as the tablets were
`discontinued after a short time. Two stopped taking
`the tablets after a few days because of vomiting
`while the third discontinued treatment after a
`fortnight saying she was cured. Of the remaining
`41 patients, 18 (10 with colitis and eight with
`proctitis) were treated with sulphasalazine, and 23
`(17 with colitis and six with proctitis) were treated
`with the dummy control tablets.
`Table I shows how the severity of disease differed
`between the treated and control groups and gives
`the mean duration of disease for these groups. In
`neither case is the difference statistically significant,
`and so it appears that the random allocation of
`
`Treated
`4
`14
`18
`Control
`23
`13
`10
`27
`Total
`41
`14
`x2 (with I degree of freedom) — 2.03 (cid:9)
`not significant (P>0.1) (cid:9)
`
`49.4
`60.1
`55.4
`= 0.58 not
`significant (P>0.25)
`
`active and inert treatment satisfactorily balanced the
`two groups with respect to these factors.
`All the 23 patients who were started on dummy
`tablets completed the first period of a month. Of
`these, 19 were subsequently started on sulphasalazine,
`four being excluded for diverse reasons. One had
`recovered on dummy tablets. En one, further treat-
`ment was discontinued because Crohn's disease of
`the rectum was incorrectly suspected. A third was
`started on prednisone largely because of a rheu-
`matoid-like arthritis thought not to be associated
`with the colitis, while the fourth patient felt he was
`sufficiently recovered not to wish to continue
`attending from a long distance at intervals for
`supervision. Nineteen cases thus started treatment.
`In two it had to be discontinued after seven and 14
`days respectively because of nausea and vomiting,
`while in a third patient the drug was stopped after
`three weeks because of the development of a
`haemolytic anaemia. In a further three patients
`detail was not complete, mainly owing to difficulties
`in attendance, but two of these patients appeared to
`have improved on sulphasalazine, one considerably.
`Thirteen patients were thus left who completed
`the four-week period on sulphasalazine after a
`previous four-week period on dummy tablets.
`Table II shows the various combinations of
`changes in overall state, clinical state, and sigmoido-
`scopic appearance, both for the 18 treated and 23
`control patients and also for the 13 patients who
`were subsequently given a month's treatment with
`sulphasalazine after a month's treatment with the
`dummy tablets. From Table 11 it may be seen that
`nine (39 %) of 23 patients receiving dummy tablets
`were assessed as improved or much improved
`compared with 14 (78 %) of 18 patients on sulpha-
`salazine in the trial. Among the controls sub-
`sequently treated with sulphasalazine 10 (77%) of
`13 were improved or much improved. The trial was,
`however, planned and conducted sequentially and
`hence the statistical significance of the difference
`between the treatments may only be judged by a
`sequential test.
`
`RESULTS OF SEQUENTIAL ANALYSIS Because of the
`restrictions regarding the formation of pairs it was
`
`This me:a•iai
`at::^E
`
`ied
`
`Ex. 1060 - Page 5
`
`(cid:9)
`

`

`440 (cid:9)
`
`A. P. Dick, M. J. Grayson, R. G. Carpenter, and A. Petrie
`
`TABLE II
`COMBINATIONS OF CHANGES IN OVERALL STATE, CLINICAL STATE, AND SIGMOIDOSCOPIC
`APPEARANCE FOR TREATED AND CONTROL PATIENTS AND FOR 13 CONTROL PATIENTS
`SUBSEQUENTLY TREATED WITH SULPHASALAZ1NE
`Number of Patients on
`
`Combination of Response
`
`Change in Overall (cid:9)
`State (cid:9)
`
`Change in Clinical
`State
`
`Change in Sigmohlo-
`scopic Appearance
`
`Sulphasalazine (cid:9)
`
`Dummy
`
`Sulphasalazine after
`Dummy
`
`o
`o
`
`0 (cid:9)
`+1 (cid:9)
`+1 (cid:9)
`+ (cid:9)
`+ (cid:9)
`+ (cid:9)
`+2 (cid:9)
`+2 (cid:9)
`+2 (cid:9)
`4-2 (cid:9)
`
`o
`0
`
`+1
`0
`0
`-4-1
`-I-1
`+1
`0
`-I- I
`+2
`+2
`
`—1
`0
`
`0
`+1
`+2
`0
`-4- I
`+2
`+2
`+2
`+1
`+2
`
`Total
`Mean change in overall assessment
`Mean change in clinical state
`Mean change in sigmoidoscopic appearance
`1 = worse
`
`0 = unchanged
`
`+1
`
`possible to form only 16 pairs from the 41 patients.
`Figure 1 shows the progress of the trial, as assessed
`by the response score when it was developed, and
`shows that a decision was reached in favour of
`sulphasalazine after 11 pairs of patients had entered
`the trial. Further details are given elsewhere
`(Carpenter et al., 1964). It should, however, be
`noted that had the plot of the response scores shown
`in Fig. 1 failed to cross either of the boundaries, the
`trial would have continued until a decision one way
`or the other had been reached.
`
`ACCEPT NEW TREATMENT
`
`CONTINUE
`TRIAL
`
`12 (cid:9)
`
`14 (cid:9)
`
`16 (cid:9)
`
`18 (cid:9)
`
`20
`
`REJECT NEW TREATMENT
`
`5
`
`FIG. 1. The sequential progress of the trial as judged by
`the scores measuring response to treatment.
`
`3
`1
`
`1
`1
`
`5
`1
`
`11
`
`2
`
`3
`4
`
`2
`4
`18
`1.11
`1.00
`1.17
`improved
`
`1
`23
`0.48
`0.48
`0.30
`+2 = much improved
`
`3
`
`7
`
`2
`
`13
`1.00
`0.85
`1.00
`
`By making use of the response score which was
`developed to assess the trial, it was also possible to
`investigate the effect of age, sex, and type of disease
`on the response treatment. The patients in the trial
`were divided into 12 groups by classifying there
`according to one of three age groups, sex, and
`whether they had proctitis or colitis, and an analysis
`of variance performed on the response scores of the
`treated and control patients in these 12 groups. The
`age groups chosen for this classification were less
`than 30, 30 to 49, and 50+. The analysis, which is
`given in detail in the companion paper (Carpenter
`et al., 1964), showed that patients both with proctitis
`and colitis responded similarly to both treatments,
`and that the response was unaffected by either the
`age or sex of the patients.
`
`COMPLICATIONS The incidence of gastrointestinal
`symptoms was high. Nausea, vomiting, anorexia,
`indigestion, heartburn, or abdominal discomfort
`were the usual complaints. Sometimes they began
`immediately on taking the drug, but usually after a
`few days or occasionally not until a fortnight had
`passed. The symptoms often became less severe in a
`few days but in some patients persisted. Of the
`21 patients who were started on sulphasalazine in
`the trial, eight had gastrointestinal symptoms and in
`two the drug had to be discontinued because of these.
`Of the 23 patients who were on dummy tablets
`initially, abdominal discomfort occurred in two
`while taking these tablets. One of these patients felt
`sick for the first fortnight on dummy tablets but
`took active tablets without symptoms. The other
`patient had epigastric discomfort for a few days on
`
`Thismat•Elal (cid:9)
`
`I
`
`L
`
`Ex. 1060 - Page 6
`
`

`

`Controlled trial of sulphasalazine in the treatment of ulcerative colitis (cid:9)
`
`441
`
`dummy tablets and had similar symptoms when
`started on the active preparation. Nineteen of these
`23 patients, who had taken dummy tablets for a
`month, were given sulphasalazine subsequently. Of
`these, 10 had nausea, vomiting, or heartburn,
`starting from one to 10 days after beginning the
`active preparation, and in two treatment had to be
`discontinued.
`The only other complication seen was in a woman
`aged 52, who developed a haemolytic anaemia while
`taking the drug. After four weeks on dummy tablets
`without change in her active proctosigmoiditis, her
`haemoglobin was 11.2 g. per 100 ml. She was
`started on sulphasalazine, 4 g. daily, and after one
`week her haemoglobin had fallen to 10.5 g. %. After
`two weeks it was 10.1 g. % and after three weeks
`9 g.%, at which time she was noticed to be slightly
`jaundiced but without bile in the urine. Her reticulo-
`cytes were 9 % at this stage. The drug was stopped.
`Three days later the jaundice had cleared, her
`haemoglobin was 10 g. % and reticulocytes 7.1 %.
`After a further three days her haemoglobin had risen
`to 10.3 g. %, and her reticulocytes were 3.9 %.
`Thereafter, her haemoglobin gradually returned to
`its usual level of 11 g. %. Her colitis remained
`unchanged during this period.
`
`DISCUSSION
`
`This trial has shown that sulphasalazine, in a dosage
`of between 4 and 6 g. daily, is more effective than
`dummy tablets in producing improvement in cases of
`mild or moderate active colitis and proctitis. It
`confirms the findings of Baron et al. (1962) and the
`clinical impression of many previous authors.
`About three-quarters of the patients appeared to
`derive benefit from the drug, both in the formal trial
`and again in those cases which were treated with
`sulphasalazine after an initial period on dummy
`tablets.
`Against this benefit must be set the high incidence
`of gastrointestinal side-effects, 18 out of 40 patients
`(45 %) on sulphasalazine experiencing them. Of
`these, four had to stop the drug. Only two out of 23
`patients had similar symptoms on the inert prepar-
`ation. The authors have no experience of the recently
`introduced enteric-coated tablets of sulphasalazine.
`In a further patient, treatment had to be stopped
`because of the development of a haemolytic anaemia.
`This incidence of side-effects in our patients was
`similar to that in previous series. Baron et al. (1962)
`noted that, although 16 out of 20 of their patients
`had benefited from the drug, eight had side-effects,
`consisting of nausea and vomiting, dizziness, or
`epigastric discomfort, while one patient had a
`generalized rash. Lennard-Jones et al. (1960)
`
`reported 12 out of 20 patients with unpleasant
`symptoms while on the drug, and a high incidence is
`also noted by Truelove et al. (1962). Nausea,
`anorexia, vomiting, and indigestion are much the
`most commonly reported symptoms, but dizziness,
`rashes, and diarrhoea are occasionally noted.
`Svartz (1954) states that in 5% of her patients
`treatment had to be discontinued owing to side-
`effects, usually drug fever and rash. Five out of her
`366 cases developed leucopenia. Morrison (1952)
`noted that 21 % of his patients were intolerant of the
`drug, developing headache, nausea, dermatitis, or a
`secondary anaemia.
`Haematological complications are the only
`serious ones. Spriggs et al. (1958) report three cases
`of toxic haemolytic anaemia associated with the
`presence of Heinz bodies due to sulphasalazine.
`Withdrawal of the sulphasalazine was followed by
`an immediate fall in the Heinz body count and
`cessation of the haemolytic anaemia, and they
`conclude that the anaemia was due to sulphasalazine
`intoxication. They recommend that the blood of all
`patients on sulphasalazine should be examined for
`Heinz bodies. One case in our series developed a
`haemolytic anaemia while on sulphasalazine which
`ceased as soon as the drug was stopped. No Heinz
`bodies were seen in this case, and although looked
`for routinely were not in fact seen in any patient in
`this series.
`Thirkettle, Gough, and Read (1963) reported two
`patients with agranulocytosis associated with sulpha-
`salazine therapy, both of whom died of septicaemia.
`They quote four previously reported cases from the
`literature, one of which died. They note that a
`preceding rash may occur and is an indication that
`the treatment should be stopped. In these six cases
`therapy had continued for variable periods of two
`and a half to three months, with a dosage of 3 or 4 g.
`daily, before symptoms associated with the agranulo-
`cytosis appeared. Leucopenia is mentioned as a
`complication by other writers, but agranulocytosis
`must be rare in view of the scarcity of the reported
`cases, considering how extensively the drug has been
`used.
`The place of sulphasalazine in the treatment of
`ulcerative colitis and proctitis is more deba