Description of studies

A literature search conducted on 10 June 2015 identified 1961 studies. Five additional studies were identified through searching of references. After duplicates were removed a total of 1177 reports remained for review of titles and abstracts. Two authors independently reviewed the titles and abstracts of these studies and 101 reports were selected for full text review (See Figure 1). Seventy reports of 68 studies were excluded (See Characteristics of excluded studies and additional Table 1). Thirty‐one reports of 20 studies involving a total of 2367 patients, were selected for inclusion (See Characteristics of included studies).

Figure 1

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Study flow diagram.

Two studies included more than two treatments arms (Malchow 1984; Summers 1979). Comparisons are described below.

a. Three studies compared the efficacy of sulfasalazine with placebo (Summers 1979; Van Hees 1981; Malchow 1984).
b. Two studies compared the efficacy of sulfasalazine with corticosteroids (Summers 1979; Malchow 1984).
c. Two studies examined the efficacy of sulfasalazine either alone or in combination with corticosteroids (Malchow 1984; Rijk 1991).
d. Eight studies compared the efficacy of mesalamine with placebo (Saverymuttu 1986; Rasmussen 1987; Mahida 1990; Singleton 1993; Singleton 1994; Crohn's III 1997; Tremaine 1994; Wright 1995).
e. Four studies compared the efficacy of mesalamine with conventional corticosteroids (Martin 1990; Scholmerich 1990; Gross 1995; Prantera 1999).
f. Two studies compared the efficacy of mesalamine with budesonide (Thomsen 1998, Tromm 2011).
g. Two studies compared the efficacy of mesalamine with sulfasalazine (either alone or in combination with corticosteroids) (Maier 1985; Maier 1990).

One German article was translated with the assistance of an interpreter (Maier 1985).

Risk of bias in included studies

The risk of bias results were summarized in Figure 2. Four of the 20 included studies were rated as low risk of bias for all six items (Malchow 1984; Prantera 1999; Summers 1979; Tromm 2011). The authors were unable to assess the risk of bias for 2 studies, because they were not fully published (Crohn's III 1997; Singleton 1994). The risk of bias was high for 2 studies that did not use blinding (Maier 1985; Maier 1990) or unclear for some quality items in 11 studies (due to inadequate descriptions of methods used for sequence generation and/or allocation concealment; Gross 1995; Mahida 1990; Martin 1990; Rasmussen 1987; Rijk 1991; Saverymuttu 1986; Scholmerich 1990;Singleton 1993; Tremaine 1994; Van Hees 1981; Wright 1995). Two studies (Rijk 1991; Wright 1995) scored high risk of bias for incomplete outcome data and selective reporting. In addition, six other studies were rated as high risk for attrition bias (Crohn's III 1997; Rasmussen 1987; Singleton 1993; Singleton 1994; Thomsen 1998; Tremaine 1994).

Figure 2

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Effects of interventions

See: Summary of findings for the main comparison Sulfasalazine compared to placebo for induction of remission or response in Crohn's disease; Summary of findings 2 Sulfasalazine compared to Corticosteroids for induction of remission or response in Crohn's disease; Summary of findings 3 Sulfasalazine compared to Sulfasalazine and corticosteroids for induction of remission or response in Crohn's disease; Summary of findings 4 Controlled‐release mesalamine (1 ‐ 2 g/day) compared to Placebo for induction of remission or response in Crohn's disease; Summary of findings 5 Controlled‐release mesalamine (4 g/day) compared to Placebo for Induction of remission or response in Crohn's disease; Summary of findings 6 Azo‐bonded and delayed‐release mesalamine (2 ‐ 3.2 g/day) compared to Placebo for Induction of remission or response in Crohn's disease; Summary of findings 7 Delayed‐release mesalamine (3 ‐ 4.5 g/day) compared to Corticosteroids for Induction of remission or response in Crohn's disease; Summary of findings 8 Mesalamine (4 ‐ 4.5 g/day) compared to Budesonide for Induction of remission or response in Crohn's disease; Summary of findings 9 Mesalamine compared to Sulfasalazine (alone or in combination with corticosteroids) for Induction of remission or response in Crohn's disease

Sulfasalazine

a. Sulfasalazine versus placebo

Three trials compared the efficacy of sulfasalazine with placebo (Van Hees 1981; Summers 1979; Malchow 1984). Due to a lack of available data in these trials, only per protocol results were reported in this review.

Van Hees 1981
Van Hees 1981 randomly assigned 27 patients with active Crohn's disease to receive sulfasalazine 4 to 6 g/day (n = 13) or placebo (n = 13) for 26 weeks. More sulfasalazine‐treated patients responded (≥ 25% decrease in baseline Van Hees Activity Index [VHAI]) than those assigned to placebo (61.5% [8/13] versus 7.7% [1/13], P = 0.03; RR 8; 95% CI 1.16 to 55.2), ABI = 53.8%, NNT = 2). Firm conclusions cannot be made due to the small sample size of this study.

Summers 1979
The National Cooperative Crohn's Disease Study (NCCDS) compared the efficacy of sulfasalazine, prednisone and azathioprine to placebo in a two‐part, multicenter trial (Summers 1979). Six hundred and four patients with Crohn's disease were randomized into Part I or Part II of the study. Thirty‐five randomized patients were excluded from the final analysis due to an erroneous diagnosis (20), inappropriate entry (12) or administrative error during the conduct of the trial (3). In part I of the study, data from 295 patients with active Crohn's disease, randomized to 1 g/15kg sulfasalazine (n = 74), 0.25 to 0.75 mg/kg prednisone (dose adjusted according to disease activity, n = 85), 2.5 mg/kg azathioprine (n = 59) or placebo (n = 77) for 17 weeks were analyzed. The dose of sulfasalazine ranged from 2 to 5 g/day (mean 4 g/day). Remission (CDAI < 150) was achieved in 38% (28/74) of sulfasalazine‐treated patients versus 26% (20/77) in the placebo group (P = 0.12). Patients with Crohn's colitis (with [P = 0.027] or without [P = 0.006] small bowel disease) or those who were treatment‐naive at entry (P = 0.01) were more likely to respond. These data suggest that patients who continued to have active disease despite prior treatment with steroids or sulfasalazine were unlikely to respond to further sulfasalazine therapy. There was no statistically significant difference in the proportion of patients who experienced an adverse event or serious adverse event. Fourteen per cent of patients sulfasalazine experienced at least one adverse event during the induction study compared to 6% of placebo patients (RR 2.08, 95% CI 0.75 to 5.80). There were no serious adverse events in the sulfasalazine group compared to one event in the placebo group (RR 0.35, 95% CI 0.01 to 8.38). Adverse events reported in the sulfasalazine group included skin rash, nausea and vomiting, headache and leukopenia. Adverse events reported in the placebo group included depression, abscess, candidiasis of mouth and duo ulcer (serious adverse event).

Malchow 1984
In the European Cooperative Crohn's Disease Study (ECCDS) (Malchow 1984) randomized 455 patients with Crohn's disease to receive sulfasalazine, 6‐methylprednisolone, combination therapy (sulfasalazine with 6‐methylprednisolone) or placebo. Three patients were excluded after randomization due to an incorrect diagnosis. Of 452 patients, 215 had active disease (CDAI ≥ 150) were treated with sulfasalazine 3 g/day (n = 54), 6‐methylprednisolone (48 mg/day tapered weekly to 12 mg/day, n = 47), combination therapy (n = 56) or placebo (n = 58) for 6 weeks. Patients could be re‐treated with the same drug regimen once or twice if induction therapy was not successful. Although there were significantly fewer "treatment failures and relapses" in the sulfasalazine group compared to placebo (P < .05), particularly in patients with colonic disease (P < .01), the difference in proportions of patients in remission (CDAI < 150) before the end of 18 weeks was not significant (sulfasalazine: 27/54, 50%; placebo: 22/58, 38%; P = 0.20). Common adverse events reported in the sulfasalazine group included nausea, headache, infection, hypertension, anorexia, back pain, and skin rash. Common adverse events reported in the placebo group included nausea, headache, infection, hypertension, anorexia, back pain, skin rash and acne.

Pooled analysis
In a combined analysis of three trials (n = 289), sulfasalazine was not superior to placebo for inducing remission or response at 17 to 26 weeks of follow‐up (See Analysis 1.1) Forthy‐five per cent (63/141) of sulfasalazine patients entered remission or responded compared to 29% (43/148) of placebo patients (RR 1.52; 95% CI 0.95 to 2.43; P = 0.08). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data and heterogeneity (See summary of findings Table for the main comparison). However, moderate heterogeneity was observed (test of heterogeneity chi² = 3.38, P = 0.18, I² = 41%) for this comparison. A visual inspection of the forest plot indicated that the Van Hees 1981 study was the likely source of this heterogeneity and this study employed different measures of treatment response and duration of therapy than the larger trials (Summers 1979; Malchow 1984). A sensitivity analysis combining data from only the NCCDS and ECCDS (n = 263) that employed similar efficacy measures, therapeutic endpoints and duration of therapy (See Analysis 1.2; Analysis 1.3) reduced the I² value to zero. A trend in favour of sulfasalazine over placebo for inducing remission was observed at 17‐18 weeks follow‐up (random‐effects model: RR 1.38; 95% CI 1.00 to 1.89, P = 0.05; fixed‐effect model: RR 1.38; 95% CI 1.01‐1.90; P = 0.05, ABI = 12%, NNT = 8). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (See summary of findings Table for the main comparison). A pooled analysis of three studies (n = 289 patients) found no difference in the proportion of patients who withdrew due to adverse events. Seven per cent (10/141) of sulfasalazine patients withdrew due to an adverse event compared to 6% (9/148) of placebo patients (RR 1.00, 95% CI 0.26 to 3.83).

b. Sulfasalazine versus corticosteroids

Two trials, the NCCDS (Summers 1979) and ECCDS (Malchow 1984), compared the efficacy of sulfasalazine with corticosteroids. Per‐protocol results were reported due to lack of data.

Summers 1979
In the NCCDS, 38% (28/74) of sulfasalazine‐treated patients achieved remission compared to 47% (40/85) in the prednisone group (P = 0.25). Common adverse events reported in the prednisone group included acne, ecchymosis, moon face, psychic disturbances, peptic symptoms and hypertension.

Malchow 1984
In the ECCDS, less sulfasalazine‐treated patients achieved remission compared to 6‐methylprednisolone (50% [27/54] versus 83% [39/47], P = 0.001). Common adverse events reported in the 6‐methylprednisolone group included acne, moon face, headache, hypertension and infection.

Pooled analysis
Combining results from these two trials (n = 260), sulfasalazine was clearly inferior to corticosteroids at 17 to 18 weeks of follow‐up (See Analysis 2.1). Forty‐three per cent (55/128) of sulfasalazine patients entered remission compared to 60% (79/132) corticosteroid patients (RR 0.68; 95% CI 0.51 to 0.91, P = 0.009. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (See summary of findings Table 2). A sensitivity analysis using a fixed‐effect model had minimal impact: RR 0.70; 95% CI 0.55 to 0.88. A sensitivity analysis based on duration of therapy was not carried out, as the two trials had a similar duration of treatment.

c. Sulfasalazine versus combination therapy with sulfasalazine and corticosteroids

Two trials examined the efficacy of sulfasalazine either alone or in combination with corticosteroids. Per‐protocol results were reported due to the lack of data.

Malchow 1984
In the ECCDS (Malchow 1984), 50% (27/54) of sulfasalazine‐treated patients achieved remission at 18 weeks compared with 79% (44/56) in the combination therapy group (RR 0.64; 95% CI 0.47 to 0.86; P = 0.003). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (See summary of findings Table 3). In those that achieved remission, the CDAI score decreased to approximately 32% (sulfasalazine group) and 29% (combination group) of its initial value at the end of 18 weeks (See Comparison 3, Outcome 01; Analysis 3.1). The overall final CDAI in each treatment group was not reported. Common adverse events reported in the combination therapy group included acne, moon face, headache, back pain, hypertension and infection.

Rijk 1991
Rijk 1991 randomly assigned 71 patients (11 dropouts) with active CD to receive higher doses of sulfasalazine at 4 to 6 g/day alone (n = 30) or in combination with lower doses of corticosteroids, prednisone 30 mg/day, equivalent to methylprednisolone 24 mg/day (n = 30, tapered 5 mg/2‐weeks and maintained at 10 mg/day) for 16 weeks. Therapeutic response in the initial 6 weeks (initial response) and the last 4 weeks (final response) were assessed using the Van Hees Activity Index (VHAI) and CDAI. Based on VHAI scores, a significantly greater and more rapid initial response was observed with combination therapy (median 30% decrease versus 13%, P = 0.001). This advantage remained statistically significant only in the a priori subgroup analysis of patients with severe disease at entry (VHAI ≥175) in the final response (median decrease 58% versus 30%, P = 0.02). A greater but insignificant decline in CDAI scores was seen with combination therapy (initial response: decrease of 35% versus 25%, P > 0.2; final response: decrease of 35% versus 24%, P = 0.19). The proportion of patients in remission was not reported in this trial. Although three of 11 drop‐outs withdrew due sulfasalazine‐related adverse events, adverse events were not reported on as an outcome.

Although results from these 2 trials could not be pooled together as they employed differing dosages, treatment regimens and endpoints, the results are consistent: sulfasalazine monotherapy was inferior to combination therapy with corticosteroids, particularly in patients with severe disease.

Mesalamine

a. Mesalamine versus placebo

Eight placebo‐controlled trials evaluated the efficacy of different dosages of controlled‐release mesalamine (Pentasa), delayed‐release mesalamine (Asacol) and olsalazine (Dipentum) for the treatment of mildly to moderately active Crohn's disease.

Controlled‐release Mesalamine 1 to 2 g/day

Saverymuttu 1986
Saverymuttu 1986 provided some evidence that controlled‐release mesalamine reduced gut inflammation in mildly‐moderately active Crohn's colitis. Twelve patients were randomized to receive 1.5 g/day of Pentasa (n = 6) or placebo (n = 6) for 10 days. The primary outcome of the study was assessment of disease activity at the end of the study period with fecal granulocyte excretion, CDAI and erythrocyte sedimentation rate (ESR). Fecal granulocyte excretion was significantly reduced in all Pentasa‐treated patients (5% decrease, P < 0.01) but not in the placebo group (2.1% decrease, P = NS). No significant changes in CDAI or ESR were observed in this small study. One placebo patient withdrew due to an adverse event (nausea). No other adverse events were reported.

Three subsequent published studies (Rasmussen 1987; Mahida 1990; Singleton 1993) and one unpublished studies (Singleton 1994) examined the therapeutic efficacy of controlled‐release mesalamine at 1 to 2 g/day. Results based on ITT analysis are reported in this review.

Rasmussen 1987
Sixty‐seven patients with active Crohn's disease were randomized to Pentasa 1.5 g/day (n = 30) or placebo (n = 37) for 16 weeks (Rasmussen 1987). There was no significant difference between the treatment groups in the proportion of patients who achieved remission (as defined by Tvede 1983) or improvement (Pentasa 13/30, 43.3% versus placebo 9/37, 24.3%; RR 1.78; 95% CI 0.88 to 3.59). In addition, the cumulative proportion of patients achieving a > 33% reduction in CDAI did not differ between the 2 groups: 26% (Pentasa) versus 24% (placebo), P > 0.5. Common adverse events included headache, nausea and vomiting and itching. No serious adverse events were reported.

Mahida 1990
Similarly, Mahida and colleagues (Mahida 1990) did not find any therapeutic benefit of Pentasa 1.5 g/day in a pilot trial in which 40 patients with active Crohn's disease were randomly assigned to Pentasa 1.5 g/day (n = 20) or placebo (n = 20) for 6 weeks; 40% (8/20) and 35% (7/20) in the Pentasa and placebo group achieved "improvement" respectively, defined as a reduction of Harvey Bradshaw Index (HBI) by = 2 points (P = 0.74). Seven patients in the Pentasa group withdrew due to adverse events including deteriorating Crohn's disease (4 patients), abdominal distension and pain (1 patient) and malaise (2 patients). Four patients in the placebo group withdrew due to adverse events including deteriorating Crohn's disease (3 patients) and nausea (1 patient).

Singleton 1993
In the third trial, Singleton and colleagues (Singleton 1993) compared three daily doses of Pentasa at 1 g (n = 80), 2 g (n = 75) and 4 g (n = 75) with placebo (n = 80) in 310 patients with active CD for 16 weeks. Mean CDAI reductions (baseline to final study visit) in patients taking the 1 g/day (‐8) and 2 g/day (‐29) doses did not differ significantly from placebo‐treated patients (‐21). Remission (defined as CDAI ≤ 150 with > 50‐points reduction) and therapeutic benefit (defined as ≥ 50‐points reduction) was achieved in 22.5% (18/80) and 36.3% (29/80) in the 1‐g group, 24% (18/75) and 38.7% (29/75) in the 2‐g group, 17.5% (14/80) and 40% (32/80) in the placebo group respectively (P > 0.05). Results for the higher 4 g/day dose will be discussed in the next section. Common adverse events included nausea or vomiting, headache, abdominal pain, diarrhea and rash.

Singleton 1994
In a second trial by the same investigator (Singleton 1994, not fully published), 232 patients with active Crohn's disease were randomized to receive Pentasa 2 g/day (n = 82), 4 g/day (n = 75), or placebo (n = 75) for 16 weeks. Remission rates were not reported. There were no significant differences in CDAI scores between the Pentasa 2 g, 4 g and placebo groups (P > 0.05). The actual CDAI values were not available for the 2 g group; results on the 4 g group are discussed in the next section.

Pooled analysis
Result from these three studies (Rasmussen 1987; Mahida 1990; Singleton 1993), were combined and analyzed (n =342). Pentasa at 1 to 2 g/day was not superior to placebo for inducing a therapeutic benefit defined by improvement in disease activity. Thirty‐eight per cent (79/205) of Pentasa patients improved compared to 35% (48/137) of placebo patients (RR 1.07; 95% CI 0.80 to 1.42; P = 0.65; See Analysis 4.1). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data and risk of bias (See summary of findings Table 4). For the endpoint of induction of remission, results from Rasmussen 1987 and Singleton 1993 were pooled (n = 302). Similarly, Pentasa 1 to 2 g/day was not superior to placebo at 16 weeks follow‐up (See Analysis 4.2). Twenty‐three per cent (43/185) of Pentasa patients entered remission compared to 15% (18/117) of placebo patients (RR 1.46; 95% CI 0.89 to 2.40; P = 0.14). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data and risk of bias (See summary of findings Table 4). Sensitivity analyses using a fixed‐effect model had minimal impact on point estimates with with a pooled RR of 1.08 for clinical improvement (95% CI 0.81 to 1.43) and 1.46 for clinical remission (95% CI 0.89 to 2.40) respectively. Sensitivity analysis based on duration of therapy, performed by excluding Mahida 1990, yielded similar RR of 1.08 (95% CI 0.75 to 1.54) and 1.46 (95% CI 0.89 to 2.40) respectively. A pooled analysis of two studies (342 patients) showed no statistically significant difference in the proportion of patients who had an adverse event or withdrew due to adverse events. Twenty‐eight per cent (58/205) of Pentasa patients had an adverse event compared to 23% (31/137) of placebo patients (RR 1.33, 95% CI 0.91 to 1.96). Twenty per cent (41/205) of Pentasa patients withdrew due to an adverse event compared to 15% (21/137) of placebo patients (RR 1.21, 95% CI 0.75 to 1.95).

Controlled‐release Mesalamine 4 g/day

The efficacy of higher doses of Pentasa at 4 g/day was evaluated in three similarly designed, randomized, double‐blind, placebo‐controlled trials (Singleton 1993, Singleton 1994, Crohn's III 1997). Results based on ITT analysis are reported here. The proportion of patients in remission was only available for Singleton 1993. An attempt to provide additional information regarding the efficacy of high dose controlled release 5‐ASA in a meta‐analysis was performed by Hanauer 2004 using individual patient data from the three trials. This analysis revealed a small difference in reduction of CDAI between Pentasa and placebo treated patients of only 18 points (P = 0.04).

Singleton 1993
In the first Singleton trial (described in the previous section), Pentasa 4 g/day significantly reduced baseline CDAI (‐72 versus ‐21, P = 0.005). A greater proportion of patients in the Pentasa 4 g/day group achieved remission (42.7% [32/75] versus 17.5% [14/80], P = 0.001; RR 2.44 [95% CI 1.42 to 4.20], ABI = 25% and NNT = 4) and therapeutic benefit (64% [48/75] versus 40% [32/80], P = 0.004; RR 1.6 [95% CI 1.16 to 2.20], ABI = 24% and NNT = 4) when compared to placebo. The largest CDAI reduction was observed in those with isolated ileal disease (Singleton 1993). There was no statistically significant difference in the proportion of patients who experienced an adverse event or withdrew due to an adverse event. Twenty‐seven per cent (20/75) of Pentasa 4 g/day patients had an adverse event compared to 19% (15/80) of placebo patients (RR 1.42, 95% CI 0.79 to 2.57). Twelve per cent (9/75) of Pentasa 4 g/day patients withdrew due to an adverse event compared to 19% (15/80) of placebo patients (RR 0.64, 95% CI 0.30 to 1.37). Common adverse events included nausea or vomiting, headache, abdominal pain, diarrhea and rash.

Singleton 1994
In the second Singleton trial (described in the previous section), there were no significant differences in reduction of CDAI scores between the Pentasa 4 g/day and placebo groups (Pentasa 4 g/day ‐41 versus placebo ‐35; WMD ‐6; 95% CI ‐39 to ‐27) (Singleton 1994). Remission rates were not reported.

Crohn III 1997
In this third, unpublished, trial, Hanauer and colleagues (Crohn's III 1997), randomly assigned 310 patients to receive Pentasa 4 g/day (n = 154) or placebo (n = 156) for 16 weeks. There were no statistically significant differences in CDAI scores between the Pentasa 4 g/day and placebo groups (Pentasa 4/g day ‐72 versus placebo ‐64; WMD ‐8; 95% CI ‐33 to ‐17). The proportions of patients that achieved remission or therapeutic benefit were not reported.

Pooled analysis
Data from these three studies were combined using an ITT approach (n = 615). A non‐significant mean difference (Pentasa ‐ placebo) in CDAI reduction of ‐19.8 (95% CI ‐46.2 to 6.7, P = 0.14) points was obtained (See Analysis 5.1). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to heterogeneity and risk of bias (See summary of findings Table 5). However, a sensitivity analysis based on a fixed‐effect model yielded a mean difference in CDAI reduction of ‐17.5 (95% CI ‐35 to ‐0.1, P = 0.05; See Analysis 5.2). This difference is of questionable clinical significance because the minimum detectable difference in CDAI that a patient can detect is approximately 50 points (Brant 1999; Feagan 2004).

Delayed‐release mesalamine

Tremaine 1994
Thirty‐eight patients with active Crohn's disease were randomly assigned to Asacol 3.2 g/day (n = 20) or placebo (n = 18) for 16 weeks (Tremaine 1994). On ITT analysis, more patients in the Asacol group (12/20, 60%) achieved 'complete success' (CDAI < 150 with ≥ 70‐points reduction) or 'partial success' (CDAI ≥ 150 with ≥ 70‐points reduction) compared to only 22.2% (4/18) in the placebo group (RR 2.70; 95% CI 1.06 to 6.88; P = 0.04; ABI = 37.8%; NNT = 3). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to high risk of bias due to incomplete outcome data and very sparse data (See summary of findings Table 6). The difference in proportions of patients with 'complete success' (i.e. clinical remission) was not statistically significant (Asacol: 9/20, 45%; placebo: 4/18, 22.2%; RR 2.02, 95% CI 0.75 to 5.45; P = 0.16). Given the small sample size, a type II error has to be considered (See Analysis 6.1; Analysis 6.2). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to high risk of bias due to incomplete outcome data and very sparse data (See summary of findings Table 6). Common adverse events included arthralgias, headache, abdominal cramps, nausea and dizziness.

Azo‐bonded mesalamine: Olsalazine

Wright 1995
Ninety‐one patients with active Crohn's disease were randomized to receive olsalazine 2 g/day (n = 46) or placebo (n = 45) for 16 weeks (Wright 1995). A high withdrawal rate was observed: 35 of 46 (76.1%) patients taking olsalazine and 24 of 45 (53.3%) patients taking placebo. Although withdrawal rates for uncontrolled active disease were similar (28.3% versus 33.3% respectively, P = 0.6), a significant proportion of patients in the olsalazine group withdrew because of diarrhea (22% versus 4% respectively, P = 0.015). On ITT analysis, only 17.4% (8/46) olsalazine‐treated patients entered remission or had symptomatic improvement compared with 48.8% (22/45) placebo‐treated patients (RR 0.36, 95% CI 0.18 to 0.71; P = 0.004). However, this study was limited by high withdrawal rates and the small number of patients that actually completed the study (See Analysis 6.1). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to high risk of bias due to incomplete outcome data and very sparse data (See summary of findings Table 6). Common adverse events included diarrhea, vomiting, pain, anorexia and itching rash.

b. Mesalamine versus corticosteroids

Delayed‐release mesalamine versus conventional corticosteroids

Four published trials compared delayed‐release mesalamine with a tapering dose of conventional corticosteroids.

Scholmerich 1990
In the first trial, Schölmerich and colleagues (Scholmerich 1990), randomized 62 patients with active Crohn's disease to Salofalk 2 g/day (n = 30) or 6‐methylprednisolone 48 mg/day (n = 32, tapered to 8 mg/day over 5 weeks) for 24 weeks: 73% (22/30) Salofalk‐treated patients stopped treatment due to "insufficient efficacy" compared to 34% (11/32) in the 6‐methylprednisolone group (P = 0.002), with corresponding lesser reduction in median CDAI scores (‐58 versus ‐151 respectively, P < .001).

Three subsequent trials evaluated the efficacy of higher doses of delayed‐release mesalamine (3 to 4.5 g/day) compared to conventional corticosteroids, with a total of 178 patients. Results based on ITT analysis are reported here.

Martin 1990
Martin and colleagues compared the efficacy of Salofalk 3 g/day (n = 22) with prednisone 40 mg (n = 28, 4 mg/week taper from third week) in 50 patients with active Crohn's disease (60% with isolated ileitis) over 12 weeks (Martin 1990). At week 12, remission (CDAI < 150) was achieved in 40.9% (9/22) Salofalk group and 42.9% (12/28) prednisone group (RR 0.95, 95% 0.49 to 1.85; P = 0.89). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (See summary of findings Table 7). Final mean CDAI reductions (‐144 versus ‐147 respectively) were similar, although initial CDAI reduction was more rapid int the prednisone group. Post hoc subgroup analysis revealed that prednisone was significantly better at reducing CDAI at almost all time points in patients with ileocolitis; however, no difference in efficacy was found in patients with ileitis alone. Although a higher proportion of patients in the prednisone group experienced at least one adverse event (16/28) compared to the Salofalk group (6/22), the difference was not statistically significant (P = 0.05). Adverse events reported in the Salofalk group included insomnia, headache, edema and nausea. Adverse events reported in the prednisone group included hyperactivity, insomnia, headache, tiredness, edema, acne, and candidiasis. There was no difference in the proportion of patients who experienced a serious adverse event (P = 0.85). There were two serious adverse events in the Salofalk group (one patient with viral hepatitis and one patient with headaches and continuous vomiting) compared to three in the prednisone group (one patient with severe headache, one patient with severe intercostal herpes zoster and patient with severe cushingoid symptoms).

Gross 1995
In the second trial, 34 patients with active Crohn's disease (majority ileocolitis) were randomized to Salofalk 4.5 g/day (n = 17) or 6‐methylprednisolone 48 mg/day (n = 17, 8 mg weekly taper) for 8 weeks (Gross 1995). At 8 weeks, 35.3% (6/17) and 52.9% (9/17) patients achieved remission (CDAI < 150 with ≥ 60‐points decrease) respectively (RR 0.67, 95% CI 0.30 to 1.46; P = 0.3). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to very sparse data (See summary of findings Table 7). Median change in CDAI: ‐85 (Salofalk) versus ‐122 (6‐methylprednisolone), P = 0.74. Although a trend towards higher efficacy with 6‐methyprednisolone was observed, a true difference may have been missed given the small size of this study. There was no statistically significant difference in the proportion of patients who had an adverse event. Sixty‐five per cent (11/17) of patients in the Salofalk group had an adverse event compared to 58% (10/17) of 6‐methylprednisolone patients (P = 0.72).

Prantera 1999
In the third and largest trial, 94 patients with active Crohn's disease (distal ileum or ileocecal region) were randomly assigned to treatment with Asacol tablets (n = 35) or Asacol microgranules (n = 28) at 4 g/day (tapered to 2.4 g/day), or 6‐methylprednisolone 40 mg/day (n = 31, 4mg weekly taper from third week) for 12 weeks (Prantera 1999). Stringent entry criteria led to recruitment of only 43% of the original planned sample size. At 12 weeks, remission (CDAI ≤ 150) was achieved in 60% (21/35), 78.6% (22/28) and 61.3% (19/31), with median CDAI reduction of 113.5, 123 and 154 in the Asacol tablets, Asacol microgranules and 6‐methylprednisolone groups respectively (P = 0.27 and P = 0.07). The RR for the comparison of Asacol tablets to corticosteroids was 1.00 (95% CI 1.00, 95% CI 0.61 to 1.64). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (See summary of findings Table 7). The RR for the comparison of Asacol granules to corticosteroids was 1.26 (95% CI 0.82 to 1.92). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (See summary of findings Table 7). A significantly higher proportion of adverse events was reported in the 6‐methylprednisolone group (14/31) compared to the Asacol tablets (5/35) and Asacol microgranules (3/28) groups. Adverse events thought to be related to steroids included acne, moon faces, hypertension, insomnia and excitability. Adverse events thought to be related to mesalamine included acute pancreatitis. A higher proportion of serious adverse events was reported in the 6‐methylprednisolone group (5/31) compared to the Asacol tablets (0/35) and Asacol microgranules (1/28) groups.

Pooled analysis
The results of these three trials examining higher doses of delayed‐release mesalamine were combined and analyzed (n = 178). No significant difference in efficacy between delayed‐release mesalamine and conventional steroids was found. Fifty‐seven per cent (58/102) of mesalamine patients achieved remission compared to 53% of corticosteroid patients (RR 1.04, 95% CI 0.79 to 1.36; See Analysis 7.1). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (See summary of findings Table 7). Sensitivity analysis based on the fixed effect model and duration of therapy (by excluding Gross et al) had minimal effects on the results: RR 1.00 (95% CI 0.75 to 1.31) and 1.10 (95% CI 0.82 to 1.47) respectively. When the three studies were pooled to assess adverse events there was no statistically significant difference in the proportion of patients who experienced at least one adverse event, a serious adverse event, or withdrawal due to adverse events. Twenty‐four per cent (25/102) of mesalamine patients had at least one adverse event compared to 53% (40/76) of corticosteroid patients (RR 0.49, 95% CI 0.23 to 1.05; P = 0.07). Three per cent (3/102) of mesalamine patients had a serious adverse event compared to 10% (8/76) of corticosteroid patients (RR 0.35, 95% 0.10 to 1.27; P = 0.11). Four per cent (4/102) of mesalamine patients withdrew due to an adverse event compared to 13% (10/76) of corticosteroid patients (RR 0.39, 95% 0.13 to 1.15; P = 0.09).

Mesalamine versus budesonide

Two studies evaluated the efficacy of controlled‐release (Pentasa) and delayed‐release (Salofalk) mesalamine compared with budesonide in patients with mildly to moderately active Crohn's disease.

Thomsen 1998
The first trial compared Pentasa with budesonide (Entocort®) (Thomsen 1998). One hundred and eighty‐two patients with active Crohn's disease (disease limited to distal ileum and ascending colon) were randomly assigned to receive Pentasa 4 g/day (n = 89) or budesonide 9 mg/day (n = 93) for 16 weeks. Pentasa was significantly less effective than budesonide for inducing remission (CDAI ≤ 150): 33.7% (30/89) Pentasa group versus 60.2% (56/93) budesonide group at 16 weeks (RR 0.56, 95% CI 0.40 to 0.78; P = 0.0007; See Analysis 8.1). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to high risk of bias due to incomplete outcome data and sparse data (See summary of findings Table 8). For budesonide, the calculated RR was 1.79 (95% CI 1.28‐2.50), ABI = 26.5% and a NNT = 4. Lower remission rates were observed for patients with more severe disease at entry (CDAI > 300, 11% Pentasa versus 41% budesonide, P = 0.01, RR 0.26 [95% CI 0.08 to 0.84]) and in those with colonic involvement (23% versus 56% respectively, P = 0.03, RR 0.41 [95% CI 0.21 to 0.77]) although budesonide was still more effective than Pentasa. The median time to remission was numerically but not significantly longer with mesalamine treatment (28 versus 58 days, P = 0.12) (Thomsen 2001). There was no statistically significant difference in the proportion of patients who had an adverse event or serious adverse event. Seventy‐two per cent (64/89) of Pentasa patients experienced at least one adverse event compared to 63% (59/93) of budesonide patients (RR 1.13, 95% CI 0.93 to 1.39; P = 0.22). Nineteen per cent (17/89) of Pentasa patients had a serious adverse event compared to 12% (11/93) of budesonide patients (RR 1.61, 95% CI 0.80 to 3.25; P = 0.18). Significantly more Pentasa patients withdrew due to an adverse event compared to budesonide patients. Thirty‐nine per cent (35/89) of Pentasa patients withdrew due to an adverse event compared to 14% (13/93) of budesonide patients (RR 2.81, 95% CI 1.60 to 4.96; P = 0.0003). Common adverse events included headache, abdominal pain, enteritis, nausea, back pain, dizziness. vomiting, anemia, depression and flatulence.

Tromm 2011

Tromm 2011 compared Salofalk to budesonide (Budenofalk) in a study that was originally designed to assess the superiority of budesonide over mesalamine, but was converted to a non‐inferiority study due to a higher than expected response in the mesalamine arm. Three hundred and nine patients with mildly to moderately active Crohn's disease confined to the terminal ileum and/or ascending colon (84%) or distal colon (16%) were randomly assigned to receive Salofalk 4.5 g/day (n = 153) or budesonide 9 mg/day (taken 9 mg once daily [n = 76] or 3 mg three times daily [n = 78]; 2 patients were excluded from the analysis as baseline CDAI was less than 150) for 8 weeks. Remission (CDAI ≤ 150) was achieved in 62.1% (95/153) in those who received Salofalk compared to 69.5% (107/154) in the budesonide group (RR 0.89; 95% CI 0.76 to 1.05; P = 0.17; See Analysis 8.1). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was moderate due to sparse data (See summary of findings Table 8). The median time to remission (mesalamine 16 days; budesonide 14 days) and mean change in CDAI scores from baseline (mesalamine ‐130; budesonide ‐149) also did not differ significantly between the two treatment groups. However, budesonide was more efficacious at inducing remission in patients with high baseline erythrocyte sedimentation rate (> 20 mm/hr) while a trend in favour of budesonide was also observed in patients with high baseline CRP (> 10 mg/L) and CDAI scores (> 300), suggesting that budesonide was more effective than delayed‐release mesalamine in patients with more severe inflammation. Clinical remission and response rates did not differ significantly between the two budesonide groups. There was no statistically significant difference in the proportion of patients who had an adverse event or withdrew due to adverse events. Forty‐seven per cent (72/153) of Salofalk patients experienced at least one adverse event compared to 43% (66/154) of budesonide patients (RR 1.10, 95% CI 0.86 to 1.41; P = 0.46). Five per cent (8/153) of Salofalk patients withdrew due to an adverse event compared to 3% (4/154) of budesonide patients (RR 2.01, 95% CI 0.62 to 6.55; P = 0.24). Common adverse events included abdominal pain, worsening Crohn's disease, vomiting, pyrexia, viral infection, decreased blood cortisol (in budesonide patients), back pain and headache.

As the two studies evaluated different formulations of mesalamine, results were not pooled for analysis.

c. Mesalamine versus sulfasalazine alone or in combination with corticosteroids

Two trials evaluated the efficacy of delayed‐release mesalamine compared to sulfasalazine (alone or in combination with corticosteroids).

Maier 1985
In an early small trial, Maier and colleagues (Maier 1985), randomly assigned 30 patients with active Crohn's disease to receive either Salofalk 1.5 g/day (n = 15) or sulfasalazine 3 g/day (n = 15) for 8 weeks. Compared to baseline values, mean CDAI decreased significantly in both groups (Salofalk: ‐189, P < .0001, Sulfasalazine: ‐148, P = 0.0001). There was no difference in clinical improvement rates. Eighty‐seven per cent of (13/15) Salofalk patients improved clinically compared to 73.3% (11/15) of sulfasalazine patients (RR 1.18, 95% CI 0.82 to 1.70; P = ‐0.37; See Analysis 9.1). The addition of corticosteroid therapy (Salofalk: 6; Sulfasalazine: 7) to patients who were still symptomatic after 5 days of aminosalicylates therapy, probably led to these impressive results. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to risk of bias due to blinding and very sparse data (See summary of findings Table 9). The authors reported no adverse events in the Salofalk group and four adverse events in the sulfasalazine group (RR 0.11, 95% CI 0.01 to 1.90; P = 0.13). Sulfasalazine had to be withdrawn in four patients due to intolerance.

Maier 1990
In a subsequent trial, the same authors randomized 54 patients (4 dropouts) with active Crohn's disease to Salofalk 3 g/day (n = 24) or combination therapy with sulfasalazine 3 g/day and 6‐methylprednisolone 40 mg/day (n = 26, reductions of 4 mg/week) for 12 weeks (Maier 1990). At week 12, 83.3% (20/24) Salofalk‐treated patients and 88.5% (23/26) in the combination group achieved remission (CDAI < 150) (RR 0.94, 95% 0.75 to 1.18; P = 0.61, See Analysis 9.1). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to risk of bias due to blinding and very sparse data (See summary of findings Table 9). There was a mean change in CDAI of ‐148 and ‐146 respectively (P = 0.90). There was no difference in the proportion of patients who experienced an adverse event. Twelve per cent (3/24) of Salofalk patients experienced an adverse event compared to 23% (6/26) of sulfasalazine patients (RR 0.54, 95% CI 0.15 to 1.93). It should be noted that Maier 1985 and Maier 1990 were not designed as formal equivalence or non‐inferiority trials. Future trials would require the randomization of large numbers of patients.