A defence of the small clinical trial: evaluation of three gastroenterological studies. Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Once daily versus conventional dosing of pH-dependent mesalamine long-term to maintain quiescent ulcerative colitis: Preliminary results from a randomized trial 5-Aminosalicylic acid as enemas or suppositories in distal ulcerative colitis? Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. A pilot feasibility study of once daily versus conventional dosing mesalamine for maintenance of ulcerative colitis. Topical Rosiglitazone Treatment Improves Ulcerative Colitis by Restoring Peroxisome Proliferator-Activated Receptor-γ Activity A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis. Once-daily dosing of delayed-release oral mesalamine (400-mg tablet) is as effective as twice-daily dosing for maintenance of remission of ulcerative colitis. Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Dose-ranging study of mesalamine (PENTASA) enemas in the treatment of acute ulcerative proctosigmoiditis: results of a multicentered placebo-controlled trial. The U.S. PENTASA Enema Study Group. Once daily MMX mesalazine for the treatment of mild‐to‐moderate ulcerative colitis: a phase II, dose‐ranging study [Efficacy of a daily application of mesalazine (Pentasa) suppository with progressive release, in the treatment of ulcerative proctitis. A double-blind versus placebo randomized trial]. Comparison of mesalazine suppositories in proctitis and distal proctosigmoiditis Mesalamine once daily is more effective than twice daily in patients with quiescent ulcerative colitis. Clinical trial: A novel high‐dose 1 g mesalamine suppository (salofalk) once daily is as efficacious as a 500‐mg suppository thrice daily in active ulcerative proctitis
Emphasis has been placed on the importance of ? , the type II error , in clinical trials and the corresponding necessity of including large numbers of subjects in a study .1 Large trials are in fashion and small trials?even when they yield statistically significant results ? are regarded with suspicion ; a small trial which does not show a conventional statistically significant difference is often thought worthless . Interpretation of the small trial has increasingly been recognised to be dangerous , and the argument that lack of a significant difference between two treatments must mean that they have equal efficacy is recognised to be false . The need for large trials is undeniable in diseases such as cancer and cardiovascular prob ? lems where earlier trials have excluded large advantages for new treatments and small differences in outcome are still clinical ly and socially important . The unfortunate consequence of the emphasis on large trials in these setting s is that small trials conducted in other diseases where only large differences in outcome are relevant have illogically become unacceptable in many people 's minds . With appropriate statistical analysis , including calculation of the confidence limits for the likely " true " difference , small controlled trials can provide clinical ly useful information . We present three such small clinical trials?none of which show Objectives : To determine the therapeutic equivalence and safety of once daily ( OD ) versus three times daily ( TID ) dosing of a total daily dose of 3 g Salofalk ( mesalazine ) granules in patients with active ulcerative colitis . Design : A r and omised , double-blind , double-dummy , parallel group , multicentre , international , phase III non-inferiority study . Setting : 54 centres in 13 countries . Patients : 380 patients with confirmed diagnosis of established or first attack of ulcerative colitis ( clinical activity index (CAI)>4 and endoscopic index ⩾4 at baseline ) were r and omised and treated . Interventions : 8-week treatment with either 3 g OD or 1 g TID mesalazine granules . Main outcome measures : Clinical remission ( CAI⩽4 ) at study end . Results : 380 patients were evaluable for efficacy and safety by intention-to-treat ( ITT ) ; 345 for per protocol ( PP ) analysis . In the ITT population , 79.1 % in the OD group ( n = 191 ) and 75.7 % in the TID group ( n = 189 ) achieved clinical remission ( p<0.0001 for non-inferiority ) . Significantly more patients with proctosigmoiditis achieved clinical remission in the OD group ( 86 % ; n = 97 ) versus the TID group ( 73 % ; n = 100 ; p = 0.0298 ) . About 70 % of patients in both treatment groups achieved endoscopic remission , and 35 % in the OD group and 41 % in the TID group achieved histological remission . About 80 % of all patients preferred OD dosing . Similar numbers of adverse events occurred in 55 patients ( 28.8 % ) in the OD group and in 61 patients ( 32.3 % ) in the TID group , indicating that the two dosing regimens were equally safe and well tolerated . Conclusions : OD 3 g mesalazine granules are as effective and safe as a TID 1 g schedule . With respect to the best possible adherence of patients to the treatment , OD dosing of mesalazine should be the preferred application mode in active ulcerative colitis . Clinical Trials.gov Identifier : The efficacy and safety of 4-g 5-aminosalicylic acid enemas were assessed in 153 patients with ulcerative colitis involving up to 50 cm of distal colon . Seventy-six patients received active medication and 77 received a placebo .  There were 20 dropouts ( 6 in the active group and 14 in the placebo group ) during the study because of insufficient efficacy . After 6 wk of therapy , 48 of the 76 patients ( 63 % ) receiving 5-aminosalicylic acid were considered to be " much improved " by the study physician compared to 22 of the 77 patients ( 29 % ) on placebo ( p = 0.001 ) . A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy . Mean disease activity index declined 55 % for patients on 5-aminosalicylic acid and 24 % for patients on placebo ( p = 0.0001 ) . Analysis of subgroups indicated that patients most likely to respond were those with disease confined to the 20 - 40 cm from the anus . Response was not affected by concurrent sulfasalazine , but patients requiring concurrent oral steroids had a diminished response . Rapid onset of efficacy was shown by a significant reduction in rectal bleeding within 3 days of treatment initiation . 5-Aminosalicylic acid enemas are well tolerated and are of benefit in the treatment of ulcerative colitis confined to the distal colon Background and Aims Multiple studies have demonstrated the efficacy of aminosalicylates in maintaining remission in ulcerative colitis ( UC ) . A newer formulation of mesalamine can be administered once daily . We aim ed to examine the efficacy and tolerability of pH-dependent mesalamine for long-term maintenance , and compare the rates of medication consumption between groups over a prolonged period . Methods Subjects whose UC had been quiescent for at least 4 months , and who had been receiving mesalamine for maintenance only , were r and omized to once daily or conventional dosing for 12 months .  Disease activity and medication consumption was assessed every 3 months . The primary endpoint was the percentage of those with quiescent disease at 12 months . Results We enrolled 20 patients , 12 to once daily and 8 to conventional dosing . Six of the 12 patients ( 50 % ) in the once daily group compared with 5 of the 8 patients ( 62.5 % ) in the conventional group experienced a flare ( p = 0.31 ) . Only 5 of the 12 ( 42 % ) patients in the once daily group were adherent compared with 3 of 8 patients ( 37.5 % ) in the conventional dosing group ( p = NS ) . Median amount consumed in the once daily group was 63 % ( range 0%–100 % ) and in the conventional group 55 % ( range 0%–100 % ) , ( p > 0.5 ) . None of the adherent subjects in the once daily group experienced a flare , while 6 out of 7 ( 86 % ) who were non-adherent experienced a flare ( p < 0.01 ) . In the conventional dosing group , 1 in 3 adherent patients ( 33 % ) experienced a flare compared with 4 out of 5 ( 80 % ) in the non-adherent group ( p < 0.01 ) . Conclusion Adherence , rather than medication regimen , appeared to be important in disease outcome at 12 months Thirty-nine patients with documented active distal proctitis ( less than 20 cm ) received either 5-aminosalicylic acid ( 5-ASA ) enemas ( 2 g in 100 ml ) or suppositories 1 g b.i.d . , in a controlled study . Twenty patients received enemas , while 19 patients received suppositories , for 30 days . No difference could be observed in terms of efficacy ; however , it was the patients ' opinion that treatment with suppositories was easier than that with enemas ( p less than 0.01 ) BACKGROUND & AIMS SPD476 ( MMX mesalamine ) , a novel , once-daily mesalamine formulation , uses MMX Multi Matrix System ( MMX ) technology to delay and extend delivery of active drug throughout the colon . We performed a r and omized , double-blind , parallel-group , placebo-controlled , multicenter phase III study in patients with mild to moderately active ulcerative colitis . METHODS Two hundred eighty patients with mild to moderately active ulcerative colitis received MMX mesalamine 2.4 g/day given twice daily ( n = 93 ) , 4.8 g/day given once daily ( n = 94 ) , or placebo ( n = 93 ) for 8 weeks . The primary end point was the percentage of patients in clinical and endoscopic remission ( modified ulcerative colitis disease activity index score of < or = 1 , with a score of 0 for rectal bleeding and stool frequency , and at least a 1-point reduction in sigmoidoscopy score ) at week 8 . Patients with mucosal friability were not considered to have achieved this end point . RESULTS Clinical and endoscopic remission at week 8 was achieved by 34.1 % and 29.2 % of patients receiving MMX mesalamine 2.4 g/day given twice daily and MMX mesalamine 4.8 g/day given once daily , respectively , versus 12.9 % receiving placebo ( P < .01 ) . MMX mesalamine was generally well-tolerated . CONCLUSIONS MMX mesalamine given once or twice daily is well-tolerated and , compared with placebo , demonstrated efficacy for the induction of clinical and endoscopic remission in mild to moderately active ulcerative colitis PURPOSE We conducted a prospect i ve study to determine the effects of nonadherence with mesalamine among patients with quiescent ulcerative colitis . METHODS We followed a cohort of 99 consecutive patients who had ulcerative colitis in remission for more than 6 months and who were taking maintenance mesalamine .  Medication adherence rates were calculated based on pharmacy records and a vali date d formula . Nonadherence was defined as refilling less than 80 % of prescribed medication . Patients were followed prospect ively and evaluated either in clinic or via telephone at 6 , 12 , and 24 months . The primary outcome was clinical recurrence of ulcerative colitis . Proportional hazards models were used to adjust for confounders . RESULTS At 6 months , 12 patients ( 12 % ) had clinical recurrence of disease symptoms , all of whom were nonadherent with medication . At 12 months , 19 of 86 patients had recurrent disease , 13 ( 68 % ) of whom were nonadherent . Patients who were not adherent with medication had more than a fivefold greater risk of recurrence than adherent patients ( hazard ratio = 5.5 ; 95 % confidence interval : 2.3 to 13 ; P < 0.001 ) . CONCLUSION Nonadherence with medication increases the risk of clinical relapse among patients with quiescent ulcerative colitis . Future research should be directed at behavioral interventions to improve adherence BACKGROUND & AIMS This study was conducted to assess , in a small sample , the short-term outcomes of once-daily mesalamine versus conventional dosing in maintaining quiescent ulcerative colitis ( UC ) and to assess adherence rates with both regimens . METHODS Consecutive patients were r and omly assigned to either a once-daily regimen , or they continued current conventional regimen ( twice daily or 3 times daily ) . Patients were assessed at 3 months and 6 months . At each point , a clinical symptom disease score was obtained using patient question naires , and medication rates via pharmacy data . Adherence was defined as consumption of > 80 % of prescribed medication . Information was collected by an investigator blinded to treatment regimen . RESULTS Twenty-two patients were enrolled in the study , 12 in the once-daily group ( QD ) and 10 in the conventional group ( CD ) . At 3 months , no patients had experienced a relapse . All of the patients in the QD group and 70 % of patients in the CD group were adherent ( P = 0.04 ) . The average amount of medication consumed in the QD group was significantly higher than in the CD group ( 90 % vs. 75 % , P = 0.02 ) . At 6 months , 2 patients ( 1 patient from each group ) experienced a clinical relapse ( P = 0.76 ) . Seventy-five percent vs. 70 % of patients were adherent ( P = 0.8 ) ; the amount of medication taken approached significance ( 90 % vs. 76 % , P = 0.07 ) . All patients in the QD group reported being either " very satisfied " or " satisfied " with their regimen . CONCLUSIONS In this r and omized pilot trial , patients taking once-daily mesalamine had outcomes similar to those for patients on conventional regimens . A larger trial is warranted to assess whether true differences between regimens exist OBJECTIVES : Impaired epithelial expression of peroxisome proliferator-activated receptor-γ ( PPARγ ) has been described in animal colitis models and briefly in patients with ulcerative colitis , but the functional significance in humans is not well defined . We examined PPARγ expression and functional activity in human colonic epithelium and explored the potential of topical treatment with rosiglitazone ( a PPARγ lig and ) in patients with ulcerative colitis . METHODS : Spontaneous and rosiglitazone-mediated PPARγ and adipophillin expression ( a gene transcriptionally activated by PPARγ ) were measured by reverse transcriptase PCR in colonic biopsies and isolated epithelial cells from patients with ulcerative colitis and controls . Fourteen patients with active distal ulcerative colitis were r and omized to either rosiglitazone ( 4 mg ) or mesalazine ( 1 g ) enema treatment once daily for 14 days . RESULTS : PPARγ expression was fourfold reduced in epithelial cells from inflamed compared with uninflamed mucosa and controls . Adipophillin levels were decreased in parallel . Rosiglitazone induced a concentration-dependent increase in adipophillin levels and restored PPARγ activity in epithelial cells from inflamed mucosa in vitro . Rosiglitazone enema treatment was well tolerated and reduced the Mayo ulcerative colitis score from 8.9 to 4.3 ( P<0.01 ) , similar to the effect of mesalazine . Rosiglitazone  increased adipophillin levels in the epithelial cells of the patients , indicating PPARγ activation in vivo . CONCLUSIONS : Roziglitasone enemas improve impaired PPARγ activity in inflamed colonic epithelium and have beneficial clinical effect in patients with active distal ulcerative colitis . These findings raise interest in further studies of PPARγ lig and s that exhibit their anti-inflammatory effect locally in the gut to avoid possible systemic side effects OBJECTIVES The aim of this study was to compare the efficacy of mesalamine rectal suspension enema ( Rowasa ) alone , oral mesalamine tablets ( Asacol ) alone , and the combination of mesalamine enema and mesalamine tablets in patients with active mild-to-moderate distal ulcerative colitis . METHODS Sixty out patients with ulcerative colitis at least 5 cm above the anal verge and not more than 50 cm , inclusive , and a total disease activity index ( DAI ) score between 4 and 10 , inclusive , were r and omized to either mesalamine rectal enema ( n = 18 ) once nightly , oral mesalamine 2.4 g/day ( n = 22 ) , or a combination of both treatments ( n = 20 ) . Placebo capsules and enemas were used to maintain a blind procedure . Total DAI scores and abbreviated DAI scores were evaluated at wk 3 and 6 , and wk 1 and 2 , respectively . Patients recorded the amount of blood in stools , urgency , straining at stools , and abdominal pain in daily diaries . Physicians and patients rated overall improvement at each visit . RESULTS At wk 6 , combination therapy produced a greater improvement ( -5.2 ) in total DAI scores than did either mesalamine enema ( -4.4 ) or mesalamine tablet ( -3.9 ) therapy alone ; similar treatment differences were observed at wk 3 . Compared with patients given mesalamine enemas or mesalamine tablets , combination-therapy patients reported an absence of blood in stools significantly sooner and , at all visits , the combination therapy group had the highest percentage of patients who reported no blood in their stools . Physicians ' and patients ' ratings of improvement indicated that combination therapy significantly improved disease status , compared with mesalamine tablet therapy alone . All treatments were well tolerated . CONCLUSIONS The combination of oral and rectal mesalamine therapy was well tolerated and produced earlier and more complete relief of rectal bleeding than oral or rectal therapy alone BACKGROUND & AIMS The practice of dosing mesalamines in divided doses for the treatment of ulcerative colitis ( UC ) began with sulfasalazine and was driven by sulfapyridine toxicity . This convention and the assumption that dosing multiple times a day is necessary to treat UC had not been challenged until recently . This study was conducted to determine the efficacy and safety of once-daily dosing of delayed-release mesalamine ( Asacol 400-mg tablets ) compared with twice-daily dosing for maintaining remission in UC patients . METHODS A multicenter , r and omized , investigator-blinded , 12-month , active-control trial was conducted to assess the noninferiority of delayed-release mesalamine 1.6 - 2.4 g/day administered once daily compared with twice daily in patients with mild-to-moderate UC currently in clinical remission . The primary end point was maintenance of clinical remission at month 6 . RESULTS A total of 1023 patients were r and omized and dosed . The primary objective of noninferiority was met . At month 6 , 90.5 % of patients receiving once-daily dosing had maintained clinical remission , compared with 91.8 % of patients receiving twice-daily dosing ( 95 % confidence interval for twice daily - once daily , -2.3 to 4.9 ) . At month 12 , 85.4 % of patients receiving once-daily dosing had maintained clinical remission , compared with 85.4 % of patients receiving twice-daily dosing ( 95 % confidence interval for twice daily - once daily , -4.6 to 4.7 ) . Both regimens had low rates of withdrawals as a result of adverse events and serious adverse events . CONCLUSIONS Once-daily dosing of delayed-release mesalamine at doses of 1.6 - 2.4 g/day was shown to be as effective as twice-daily dosing for maintenance of clinical remission in patients with UC BACKGROUND & AIMS SPD476 ( LIALDA in the US ; MEZAVANT in the EU ; otherwise known as MMX mesalamine ; Shire Pharmaceuticals Inc. , Wayne , PA , under license from Giuliani SpA , Milan , Italy ) is a novel , once-daily , high-strength ( 1.2 g/tablet ) formulation of mesalamine , utilizing MMX Multi Matrix System ( MMX ) technology design ed to deliver the active drug throughout the colon . We performed a double-blind , multicenter study , comparing MMX mesalamine vs placebo for the treatment of active ulcerative colitis . A delayed-release oral mesalamine ( ASACOL ; Procter & Gamble , Cincinnati , OH ) reference arm was included . METHODS Three hundred forty-three patients with active , mild-to-moderate ulcerative colitis received MMX mesalamine 2.4 g/day or 4.8 g/day given once daily , ASACOL 2.4 g/day given in 3 divided doses , or placebo for 8 weeks . The primary end point was the proportion of patients in clinical and endoscopic remission ( modified ulcerative colitis disease activity index of < or = 1 with rectal bleeding and stool frequency scores of 0 , no mucosal friability , and a > or = 1-point reduction in sigmoidoscopy score from baseline ) . RESULTS A significantly greater proportion of patients receiving MMX mesalamine 2.4 g/day given once daily ( 40.5 % ; P = .01 ) and 4.8 g/day given once daily ( 41.2 % ; P = .007 ) achieved clinical and endoscopic remission at week 8 , vs placebo ( 22.1 % ) . The clinical and endoscopic remission rate for ASACOL ( 32.6 % ; P = .124 ) was not significantly superior to placebo . All active treatments were well-tolerated . CONCLUSIONS Once-daily MMX mesalamine was efficacious and well-tolerated for the induction of clinical and endoscopic remission . MMX mesalamine offers effective and convenient mesalamine therapy , potentially improving treatment compliance The safety and efficacy of mesalamine enemas were determined ina dose-ranging study enrolling 287 patients with ulcerative proctitis and proctosigmoiditis in a double-blind , placebo-controlled , multicenter trial . Patients were r and omized to receive placebo , 1 , 2 , or 4 g in 100 ml mesalamine ( PENTASA ) enemas h.s . for 8 weeks . Efficacy was assessed by clinical , sigmoidoscopic , and histologic improvement , as well as by induction of remission . Sixty-seven percent , 65 % , and 75 % of patients receiving 1- , 2- , and 4-g enemas were markedly improved according to the physician 's global assessment compared with 27 % of patients treated with placebo . The mean improvement in sigmoidoscopic index was 5.8 , 5.9 , and 6.4 points ( on a 15-point scale ) for the 1- , 2- , and 4-g enema groups compared with a decrease of 1.8 points for the placebo group . Improvement in biopsy scores was observed in 47 , 55 , and 59 % of 1- , 2- , and 4-g groups contrasted with 27 % of the placebo-treated patients . All three doses were significantly more effective than placebo in reducing symptoms and trips to the toilet compared with placebo . No dose-response relation was demonstrated . The safety profile was similar to that of placebo . In conclusion , mesalamine enemas are effective as a single agent in the short-term treatment of distal ulcerative colitis without an apparent dose response between 1 and 4 g nightly Background SPD476 ( MMX ™ mesalazine ) , is a novel , once daily , high‐strength mesalazine formulation ( 1.2 g/tablet ) that utilizes Multi Matrix System ™ ( MMX ) technology to delay and extend delivery of the active drug throughout the colon Therapeutic efficacy of mesalazine controlled-release suppository 1 g once daily was compared with that of a placebo during 2 weeks in 50 patients ( 26 in the mesalazine group , 24 in the placebo group ) with ulcerative proctitis , in a double-blind r and omized trial .  Endoscopic and clinical remission was seen in 69 and 65 % of mesalazine-treated patients and in 33 and 25 % of placebo-treated patients respectively ( P < or = 0.01 ) . No side effects were seen . It is concluded that a once-a-day administration of 1 g mesalazine controlled-release suppository is effective for topical treatment of patients with ulcerative proctitis Mesalazine suppositories at 500 mg b.d . are a safe and effective treatment for patients with ulcerative proctitis or distal proctosigmoiditis . Recently a mesalazine 1 g suppository ( Pentasa ) has been developed BACKGROUND & AIMS Oral mesalamine ( 5-aminosalicylate ) is the current st and ard of care for mild-to-moderate ulcerative colitis . We investigated the efficacy and safety of once daily administration of prolonged-release mesalamine granules in maintenance of remission in patients with quiescent ulcerative colitis , compared with the well established twice daily dosing regimen . METHODS In this multicenter , r and omized , single blind , noninferiority trial , 362 patients with quiescent ulcerative colitis were r and omly assigned ( 1:1 ) to groups that were given oral mesalamine 2 g , once daily , or 1 g , twice daily , for 12 months . The primary objective was to compare remission rates at 1 year , based on the ulcerative colitis disease activity index score , using Kaplan-Meier methodology . RESULTS At 1 year , 70.9 % of the group given 2 g mesalamine once daily remained in remission vs 58.9 % of the group given 1 g mesalamine twice daily ; this difference was statistically significant ( P = .024 ) , indicating the increased efficacy of once daily , compared with twice daily , dosing . Self-reported adherence to therapy , measured by visual analog scale score after 4 , 8 , and 12 months , was significantly greater in the group given 2 g mesalamine once daily , compared with twice daily , at all but 1 study visit ( P < .05 ) . Compliance measured by medication taken was not significantly different between the groups . The difference between the 2 groups in overall incidence of adverse events was not statistically significant ( P = .23 ) . CONCLUSIONS Patients with ulcerative colitis given prolonged-release oral mesalamine 2 g once daily had better remission rates , acceptability , and self-reported adherence to therapy compared with patients given oral mesalamine 1 g twice daily Background : Mesalamine suppositories are first‐line therapy in active ulcerative proctitis ; the st and ard regime still recommends multiple doses per day . The primary objective of this study was to show the noninferiority of once‐daily administration of a novel 1 g mesalamine suppository versus thrice‐daily administration of the 0.5 g mesalamine suppository . Methods : This was a single‐blind ( investigator‐blinded ) , r and omized , multicenter , comparative , Phase III clinical trial . Patients with mild to moderately active ulcerative proctitis inserted either one mesalamine 1 g suppository at bedtime or one mesalamine 0.5 g suppository thrice daily over a 6‐week period . The primary endpoint was rate of remission ( Disease Activity Index below 4 ) . Results : In all , 354 patients were evaluable for safety and per‐ protocol analysis . The new regimen demonstrated noninferiority : The percentage of patients with remission was 87.9 % for the once‐daily 1 g mesalamine suppository and 90.7 % for the thrice‐daily 0.5 g mesalamine suppository . Each regimen result ed in prompt cessation of clinical symptoms ( e.g. , median time to ≤3 stools per day ( all without blood ) : 5 days in the 1 g mesalamine once‐daily and 7 days in the 0.5 g mesalamine thrice‐daily group ) . Patients preferred applying suppositories once a day . Conclusions : In active ulcerative proctitis the once‐daily administration of a 1 g mesalamine suppository is as effective and safe , yet considerably more convenient , than the st and ard thrice‐daily administration of a 0.5 g mesalamine suppository . ( Inflamm Bowel Dis 2010
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