Oral 5 , ASA versus prednisone in short tertn treattnent of Crohn ' s disease : A tnulticentre controlled trial

A multicencre randomized controlled trial was designed to compare 
the efficacy and safety of Eudragit-L coated oral 5-aminosalicylic acid 
(5-ASA) (Salofalk; lnterfalk) 3 g per day to a 'standard' oral prednisone therapeutic 
regimen in a 12 week treatment period of uncomplicated attacks of 
Crohn's ileitis and ileocolitis. Fifty patients with active Crohn's disease (Crohn's 
disease activity index [CDAI] 200 to 450) were randomized to receive either four 
250 mg Eudragit-L-100 coated 5-ASA tablets three times a day for 12 weeks or 
oral prednisone ( 4 mg tablets) at a sustained 40 mg per day for two weeks followed 
by a 4 mg/day weekly dose reduction for the 10 subsequent weeks. Efficacy was 
determined by changes in the calculated CDAI and, as a novel assessment, the 
McMaster University quality of life index at two, four, six, eight, 10 and 12 weeks. 
Standard blood and urine values were obtained and physician's assessment 
completed at each two week visit. Clinical remission was obtained in 12 of 26 
patients (46%) in the prednisone group and in nine of 19 (47%) in the 5-ASA 
group. Treatment failure was observed in three patients in each group. All other 
patients improved during the treatment period. Patients on prednisone reduced 
their CDAI scores significantly more rapidly during the first four weeks, but the 
reduction and maintenance of CDAI scores were similar in both groups for the 
remainder of the study period. In patients with ileocolitis, prednisone was 
significantly better than 5-ASA. Quality of life assessment parallelled the changes 
in CDAI, and appear a valid index. The two therapeutic regimens appear safe 
and did not disclose any unexpected adverse events or side effects. No significant 
biological abnormalities were detected in either treatment group. In conclusion, 
in this small trial, it was found that Salofalk at a dose of 3 g per day appears 
effective treatment for active Crohn's disease, and it is proposed chat higher doses 
may be beneficial in more extensive disease (ileocolitis) and during the first four 
weeks of treatment.

T HE TREATMENT OF UNCOMPLI• cared a ttacks of Crohn's disease in an outpatien t setting is mostly pharmacological, and includes both oral and parenteral corticosteroids and sulphasalazine.T wo recent multicentre cooperative studies compared prednisone, sulphasalazine and placebo (1,2).In these stud ies, oral prednisone or 6-merhylprednisolone given for 17 weeks was most effective in treating active Crohn's ileitis and ileocolit1s.
Sulphasalazine h as been shown to have some clinical benefit in patients with small bowel disease, but due to the colonic bacterial reduction needed for the release of the active moiety, 5. aminosalicylic acid (5-ASA) (3), sulphasalaz ine is more useful in pauencs with C rohn's disease of the colon.Moreover sulphasalazine efficacy 15 dose-dependent and patients often canno t tole rate sufficient doses for an optimal therapeutic response due to the sulfapyridine mo iety's relative tox1 c1ty.
Altho ugh effective in reducing symptoms and creating a somewhat art ificial sense of general well-being in patients wi th active disease, oral corticosteroids are not devoid of several potentially dangerous side effects which are dependent on dose and duration of t herapy ( 4 ).
The first report suggesting potential therapeutic efficacy for Salofalk in the short term treatme nt of active Crohn's disease came from Ma'ier and colleagues (6).In this randomized trial, they compared Salofalk 1.5 g per day to sulphasa lazine 3 g per day in 30 patients dunng an eight week treatment period.They observed that 87% of the Salofalk patients and 80% of the sulphasa lazine patients 'improved' as determined by a mean reduction of the clinical activity scores of 61 % for Salofalk and 47°,{1 for sulphasa lazine.
The same group then performed another controlled trial comparing 3 g Salofalk daily co a combination therapy of methylprednisolone 40 g per day for one week fo llowed by a 4 mg weekly reduction plus a constant dose of 3 g per day of sulphasalazine fo r 12 weeks (7).In this clinical mal, the reported therapeutic success was remarkably high ; 83% of the patients taking Salofalk and 88% taking combination therapy were said to have achieved remission at the end of the 12 week period.
The present authors designed a multicentre clinical trial to compare the relative efficacy and safety of 3.0 g Salofalk daily to a 'standard' oral prednisone l 2 week treatment period in Orol 5-ASA versus prednisone for Crohn's pari ents with active ile1t1~ and 1leocolitb.

PATIENTS AND METHODS
Fifty patients from eight centres e ntered the study.Men and nonpregnant, nonlactating women over 18 years of age participated.Patients with ac tive, uncomplicated Crohn 's ileitis or ileocolitis were eligible 1f, at screcnmg visi t, the Crohn 's disease activity index (COAi) (8) score was between 200 and 450 pomts.Diagnostic confirmation of Crohn's disease with ileal involvement was obta med at entry or wirhm the previous 12 months by small bowel follow-through barium meal and barium enema and/or by colonoscopy and biopsy.
Patients with confirmed infectious enterocolius, 1nremal or external fistulas, esophageal, gastric or jejunal disease, C rohn's colitis alone, pnor bowel resection or clinically significant hepatic, renal, cardiovascular or respiratory disease were excluded from the study.Patients were also excluded if they had received active Crohn's disease treatment within the previous month; however, patients who were already taking oral prednisone at a maximum of 10 mg per <lay for at least on e month were a llowed in the trial providing that the dose was kept unc hanged during the trial period.
This was a 12 week, randomized, double-blind, parallel group, multicentre study.Candidate patients were fi rst seen for a screening visit.Physician's evaluation included medical history and ph ysical examination; blood and urine samples were collected for standa rd analysis and stools for culture.Selection crite ria were revised for eligibility and informed consent signed.Screened patients were then released and asked to record daily for one week the number ofliquid stools, a numerical rating of abdominal pams and of their general well-being for the calculation of the baseline CDAI score.If the criteria were met for the trial after this screening week, each patient was randomly assigned to receive either four 250 mg Eudragit-L-100 coated 5-ASA tablets (Salofalk) three times a day fo r 12 weeks or oral prednisone in 4 mg  Efficacy assessment was determined Three Salofalk patients were not included by protocol stipulations, and two prednisone patients were lost to follow-up during the first week of the study; these five patients are excluded from efficacy and safety analysis.z UJ a: 1--1

Cl
Figure 3) Mean percentage increase from baseline values of the quality of life ( QOL) index scores obtained at each two week visit in all patients in a multicentre controlled trial of 5-aminosalicylic acid versus prednisone below at the end of the 12 week study, was achieved in nine of the 19 Salofalk patients (47%) and in 12 of the 26 prednisone patients (46%).Treatment failure due to therapeutic insufficiency before or after completion of treatment was observed in three patients in each treatment group, determined either by increased or unchanged COAI values from baseline or by the physician's clinical decision.All other patients were clinically improved, confirmed by a reduction in their COAi scores compared to pretrial va lues.
The therapeutic response with respect to site of disease has been analyzed separately and the changes in COAi values are shown in Figure 2. In CAN J GASTROENTEROL VOL 4 NO 7 NOVEMBER 1990 Oral 5-ASA versus prednlsone for Crohn's patients with ileitis alone, the two therapeutic regimens were not different in reducing COAi scores over the 12 weeks.In the ileocolitis group, however, prednisone was significantly better than Salofalk in reducing COAI at almost every follow-up visit (P<0.05).
Quality of life assessment: Patients' quality of life, determined by the Mc-Master quality of life index (19), improved concomitantly with clinical improvement as expected.However, when the percentage increases in the overall scores both treatment groups we re compared, prednisone patients achieved 20 and 40% increases in the quality of life index at weeks 2 and 4. respectively, and seemed to maintain th is level of improvement for the remaining weeks of the study, while Salofalk patients had a sign ificantly more modest increase of 6 and 24% at weeks 2 and 4, respectively (Figure 3).At six weeks and thereafter until study termination, the percentage increases were not different in either treatment group (35% and 40%).When the subscores of the quality of life index (relating to bowe l symptoms, systemic symptoms, social fu nctions and emotional function) were compared, only the systemic symptoms were s ignificantly less influe ntial on the quality of life in the second week in the prednisone patients compared to the Salofalk patients (Figure 4).The somewhat artificial sense of well-being of patients on high dose prednisone during the first four weeks of the study might explain this apparent advantage of prednisone over Salofalk.Adverse events: Serious adverse events which led to early term ination were observed in three prednisone and two Salofalk patients.One predn isone patient had severe headaches after two weeks, another developed severe intercostal herpes zoster in week 4, and the last had severe Cushingoid symptoms after eight weeks.O ne Salofalk patient terminated participation early when she presented with a concomitant viral hepatitis after four weeks.The other Salofalk patient terminated participation afte r two weeks because of headaches, continuous vomiting and a COAi score of 497.Table 3 lists  .... 0 .... 0 w t..J 60 w t..J 60 en en en en ""' X ""' X w w w a: a: w 40 /"/-"1""--s/.Figure 4) Mean percentage increase from baseline values of the quality of life (QOL) index subscores relating to bowel symptams, systemic sympwm.s,emotional function and social function obtained m all patients at each two week visit in a controlled multicentre trial of 5-aminosalicylic acid versus prednisone minor side effects that were reported in both groups; none was clinically significant.

DISCUSSION
Admittedly this contro lled t rial tested too few patients to contribute any firm conclusions on the comparative therapeutic efficacy of Salofa lk 3 g per day versus 'standarc.l'therapy wi th prednisone in the short term treatment of active uncomplicated C rohn's ileitis and ileocolitis.Despite this apparent short coming, rhe study can nonetheless provide useful information about the therapeutic potential of oral 5-ASA preparations and provide several lessons for the design and conduct of future stud ies in a field of investigation where standard trial practice is far from universally established.
The major therapeutic goal of treating acute attacks of uncomplicated Crohn's disease is to achieve clinical rem ission and to improve the patient's quality of life.For almost 30 years, oral cortico~teroids have been widely used clinically to achieve remission, and two recent multicentre studies confirm their efficacy (1,2).However, in order to demonstrate the superiority or ac least equivalence of an alternate drug modality co oral corticosteroids, a minimum of 350 patients shoulc.lbe admitted to a comparative trial.The present small trial is helpful as it provic.lesuseful information on the potential optimal dose of 5-ASA with respect to initial acuv1ty and to anatomical extension of the disease.Indeed, at the end of the 12 week treat• ment period, Salofalk given at a fixed dose of 3 mg per day appeared almost equivalent to standarc.loral prednisone therapy when the overall treatment groups were comparec.l(Table 2, Figure l ); however, further analysis sugge~ts that a higher dose of 5-ASA during the first four weeks of therapy might he necessary, as it is for oral prednisone.
In addition, as the oral 5-ASA preparations are dependent for efficacy on the quantity of drug delivered at the site of inflammation, it is nor unexpected char patients with more extensive disease as in ileocolitis (Figure 2) will respond less favorably when taking TABLE 3 Minor adverse events in a multicentre controlled trial of 5-aminosalicylic acid (5-ASA) versus prednisone The apparent low remission rate obtained by both treatment modalities in the present study compared to the classic report of the National Cooperative C rohn' s Disease study (NCCDS) ( l) deserves some consideration.The remission rates achieved by prednisone and sulphasa lazine in the NCCDS report were 60 and 45%, respectively, and are con sidered by many as the 'gold standard' of efficacy for these agents in active Crohn's disease.First, in the NCCDS, the treatment period for active disease (phase I) was 17 weeks.On inspection of the results curve for remission rate at 12 weeks, the remission rate for the prednisone group was 48% compared to 28% for sulphasalazine.Second, in the NCCDS the mean pretrial CDAI scores are 17% lower than in the present treatment groups, which could obvio usly influence treatment outcome at 12 weeks.Third, the initial dose of prednisone was modulated according to pretrial severity o f the attack as determined by the pretrial COAi score and the patient's weight.Initial maximum doses, as high as 60 mg prednisone and S g sulphasalazine have been administered.In the present study, the pre-established doses of prednisone and Salofalk were applied to all patients regardless of clinical activity or weight.Therefore, the authors are convinced that their resu lts a re not out of range, and for the purpose of comparison between trials, they suggest that a new study design include the preceding consideratio ns.
A therapeutic efficacy assessment of any modality should evaluate concomitantly its effect on the quality of life of the treated patients.In the present study, a recently proposed 'quality of life index' was tested and its apparent validity confirmed inasmuch 4. Meyers S. Oral and parenteral steroids.
In Oral 5-ASA versus prednisone for Crohn's as it parallelled the clinical act1v1ty scores, and in that the comparative analysis of the subscores relating to groups of symptoms or functions were in agreement with overall evaluation.More specifically the better efficacy of higher dose prednisone during the first four weeks was reflected significantly by the quality of life index.Too few serious adverse events were observed during the study to justify conclusions or fa ir comparison of the two treatment modalities.Fewer minor side effects were reported in the Salofalk group compared to the prednisone group and the prcdnisone/ Salofalk group (Table 3), but none was of serious significance.
In conclusion, this study strongly suggests that oral 5-ASA, more specifically Salofalk at a minimum dose of 3 g per day, is efficacious in treating acute attacks of Crohn's ileitis and ileocolitis.Perhaps higher doses of the drug should be given during the first four weeks of therapy in a ll patients, and higher dose regimens should also be considered in patients with more extensive bowel involvement, namely ileocolitis.If these dose modulations are proved effective in future clinical trials, it is foreseeable that oral 5-ASA therapy could become an effective, less toxic therapeutic approach fo r active Crohn's disease than standard prednisone treatment.

Figure 1 )
Figure 1) Mean Crohn's disease acti11ity index (CDAl) score changes obtained at each two week 11isit in all studied patients in a multicentre controlled trial of 5-aminosalicylic acid 11ersus prednisone tablets at a sustained 40 mg per day for two weeks followed by a 4 mg per day weekly dose reduction for the 10 subsequent weeks.Each patient returned every two weeks for 12 weeks.At each visit, physic ian's global assessment and physical examination were completed,

Figure 2 )
Figure2) Mean Crohn's disease activity index (CDAI) score changes obtained at each two week visit in patients with ileitis and ileocolitis in a multicentre controlled trial of 5-aminosalicylic acid versus prednisone

P
Prednisone: 5-ASA+ P 5-ASA plus 10 mg or less prednisone a fixed dose of 3 g per day of Salofalk.A higher dose of 5-ASA is perhaps necessary for patients with more extensive ileocolic disease.

TABLE 1
Study population of a multicentre controlled trial of 5-ASA versus prednisone in active Crohn's disease