- Email: [email protected]
Efficacy of mesalamine rectal gel in distal ulcerative colitis. A pilot study
bfllximab MainteaLq~ T r e l ~
Enl~lld Eady Reduction aid Blmlr
GmuI) I Bllellne r ~1 14 yr ~ t0 rag/day for ' 3 too* 4(28.6%) No emtlcoltlm~s for ' 3 me 3(21.4%) I~mel~ corttcolmrokls > 1 yr < 10 raG/day for * 3 too* NOcorUcoltli~Ids for a 3
mo
and safety of mesalamine gel in a limited number of patients with mild to moderate distal UC. All patients were included on the basis of a disease activity index (DAI) > 3, assessed 8 days before the first dose. Patients with known hypersensitivity to mesafamine or related drugs were excluded as well as pregnant or breast-feeding women. Patients who were taking oral mesalamine stopped it at least 5 days before receiving their first dose of rectal gel. No other medications for UC were taken during the trial. Three men and three women with mean age of 42.7 (s.d. 7.0, range 35-55) years received a single rectal dose of 4 g of mesalamine in 60 mL gel HS and, starting 48 hours after their first dose, 4 g / 60 mL HS x 4 consecutive days. Patients went to bed immediately after each dose, at 22:00, stayed in bed for at least 8 hours, and consequently slept overnight at the research center. The DAI was also assessed 14 ( + 1) hours after administration of the last dose. DAIs at baseline were 5, 4, 6, 6, 9, and 9 (mean 6.5, s.d. 2.1) for patients 1 to 6 respectively. They were 2, 2, 3, 3, 4, and 4 (mean 3.0, s.d. 0.9) at the end of study for patients 1 to 6 respectively. Exploratory statistics by paired t-test showed a statistically significant difference between baseline and end-of-treatment DAIs (p=0.0009). Reported adverse events (# patients), regardless of relationship to study medication, were: abdominal pain (5), headache (3), mouth ulcer (2), dizziness (2), flatulence, sinus discomfort, nausea, gastro-esophageal reflux, and rectorragia (1 each). We conclude that mesalarnine rectal gel provided, in these patients, a clinically and statistically (despite their limited number) stgnificant amelioration of UC, within 4 days. The associated safety profile is good. These results support the conduct of Phase III studies to confirm efficacy and safety of the North American mesalamine rectal gel.
of St~oldl: Week 54 Relultl
Groep II
Group II
11
11
G r ~ I It and Ill 22
6(54.5%)
7(63.6%)
13(59.1%)
5(45.5%)
6 (54,5%)
11 (50,6%)
39
44
44
88
5 (12,6%)
15 (341%)"
22(50.6%)#
37 (42.0%)#
4 (10.3%)
12 (27,3%)~
18 (40.9%)#
30 (34.1%)#
9p < 0.05 #p < 0.01
M1589 Meaalazine (5-ASA) Micrnpellets Show Comparable Efficacy and Tolerability as Mesalazine Tablets in Patients with Ulcerative Colitis. a Prospective, MultiNational, Randomised, Double-Blind, Active-Controlled Clinical Phase II Study Chr/stoph Behrens, Peter Bias, Helmut Malchow, Andreas Raedler Non-inferiority of a new sustained-release inesalazine micropellet formulation was studied in comparison to registered mesalazine tablets with regard to efficacy and safety/tolerability in patients with recurrent active mild to moderate ulcerative colitis (UC). A total of 362 patients (ITT = 357, ATP = 322) were enrolled CA11-7>4, EI>4, extent of UC>12 cm, > 18 blood stools/week) at 38 active European study centres. Eligible patients were randomised to take orally up to 8 weeks (A) mesalazine micropellets 1.5g b.i.d, or (B) mesalazine tablets 1.0g t.i.d.. Assessments were carned out after 2, 4, 6 and 8 weeks of treatment. Primary efficacy variable was clinical remission (CR) within 8 weeks of treatment, defined as CA114<2. Secondary efficacy variables were: CAI 1-7, endoscopic index (EI), endoscopic remission (El<2), histological evaluation, additional symptom evaluation, global assessment of efficacy. Secondary safety variables were AEs, clinically relevant laboratory changes, global assessment of tolerability. Results: With statistical significance micropellets showed noninferiority compared to tablets regarding CR and all secondary efficacy endpoints. The cumulative numbers of patients with CR (CAI 1-4< 2) within 8 weeks show up as for ATP population: micropellets/ tablets (160/162) = 64.4%/64.2% and as for ITT population: micropellets/tablets (179/ 178) = 67.0%/62.9%. Regarding secondary efficacy endpoints non-inferiority of the micropellets was shown for CR within 8 weeks in the ITT population and within 6 weeks in both analysis populations. No major safety differences between treatment groups were observed. All SAEs reported were not related to the intake of micropellets. The efficacy of micropellets was judged as very good and good by a total of 89.3% of treated patients and by 91.6% of the investigators. Conclusion: The mesalazine micropellet formulation was demonstrated to show a non-inferior effecacy compared to the reference, to be safe, and well tolerable in mild to moderate active ulcerative colitis.
M1592 Prevention of Recurrence by Mesalamine (Pcutasa) In Pediatric Crohn's Disease. A Muhicentric Double Blind Trial Jean Pierre Cezard, A. Munck, O. Mouterde, A. Morali, C. Lenaerts, A. Lachattx, D. Turck, J. Schmitz, C. Maurage, J. P. Girardet, D. Belfi, T. Lamireau, J. Sarles, J. P. Chouraqui, B. Descos, A. Dabadi, M. Meyer, J. P. Olives, J. Crand, J. Y. Mary In a previously reported study (1), a trend in relapse prevention has been observed in children receiving maintenance treatment with Mesalazine (Me) as compared to placebo (P), with 59% vs 37% of children still in remission at 1 year (R1) after successful treatment of a flare-up of their Crohn's disease (CD). Therefore, it was decided to re-start patient recruitment in the same protocol conditions up to 120 evaluable children. Material and methods : during both periods (1991-1993 and 1996-1999), 122 patients aged 12 +/- 3 yrs (mean +/- SD) were randomized with stratification according to flare-up treatment, including nutrition (N, n = 41) or drugs only (D, n = 81) ; Relapse was defined by a Harvey Bradshaw > 5. Time to relapse curves were estimated through Kaplan-Meier method and analysed according to treatment, stratum and period through Cox model. Results : No significant difference was observed between treatment groups, Me(n = 60) and P (n = 62) for clinical and biological features measured at flare-up or at randomization as well as for side effects recorded during the study. 29 patients et 35 patients experience a relapse during the follow up in the Me et P groups. Globally, R1 was 43 +/- 7% and 37 +/- 7%, median time to recurrence 10.7 +/- 2.1 and 6.2 +/- 1.8 months, in Me and P groups, respectively. Time to relapse analysis provided a significant model with 3 groups showing different remission rates (p = 0.01) as follows : a positive effect of Me during the first period (R1 = 59 +/- 11%, n = 26), a possibly negative effect of Me during the second period in stratum N (R1 = 14 +/- 12%, n = 12), an absence of effect of Me during the second period in stratum D as compared to placebo group in both strata and periods (R1 = 38 +/- 6%, n = 80). Ahhrough some characteristics of children were clearly different from one period to another, pronostic factors of relapse could not explain the variation of the effect of Me between the 2 periods. Conclusion : Me appears to be possibly an effective maintenance treatment for relapse prevention in pediatric CD after successful treatment of flare-up. Nevertheless, conditions for efficacy remained to be elucidated. 1. JP Cezard and al. J. Ped. Gastroenterol. Nutr 1996 ; 22 : 86. Supported by Ferring SAS.
M1590 Is Better Methodology In the Design of Randomized Controlled Trials Rewarded by Publication In Higher Quality Journals? Alexander I. Aspinall, Avni Hutton, Feng X. Li, Lloyd R. Sutherland
Introduction: The last two decades have seen an emphasis on improved conduct of RCT. We hypothesized that better methodology is rewarded by publication in higher quality journals. Alternatively, novelty rather than methodology might be important.
Methods: Using MEDLINE and bibliographic searches, we identified 111 RCT for ulcerative colitis published between 1972 and 2001. We restricted our analysis to induction of remission trials with treatment arms using 5-ASA. Fifty-five such RCT were identified with 25 published prior to 1990, and 30 published between 1990-2001. Impact factors from Journal CitaFLon Reportsfor 2001 were used as an indteator of journal quality. Markers of good methodology included quality of randomization (adequate vs marginal), blinding and sample size.
M1593 Infliximab Does Not Result in Increased Abscess Development in Fistulizing Crohn's Disease: Results from ACCENT II Sander J. Van Deventer, Marion Blank, Steve Waldschmidt, Bruce Sands
Results: RCT with better randomization were published in journals with impact factor 6.6 +2.0 (vs 4.3 -+0.6; p=n/s). Data were stratified by publication prior to or after 1990. Prior to 1990, RCT with adequate randomization were published in journals with a higher mean impact factor of 11.3 _+4.8 vs 4.4 _+0.9 (p=0.03). However, after 1990, the impact factors for papers with better randomization did not differ from the few with poor randomization (4.0 + 1.0 vs 4.1 -+ 0.7). Trials with a sample size greater than the median (61 patients) were published in journals of higher impact factor (6.1 -+ 1.1 vs 317 -+0.6; p=0.058). Blinding, regardless of level, did not predict publication in a journal of higher impact factor.
Background: Frequencies of perianal abscesses in Crohn's disease (CD) are reported to be between 44% and 61%. Concern exists that mfliximab, which has been demonstrated to induce and maintain fistula closure in CD, promotes abscess formation behind superficially closed fistulas. Data on the incidence of fistula-related abscesses in the 54-week study of infliximab in fistulizing CD (ACCENT If) are presented. Methods: In ACCENT II, patients with 1 or more draining fistula received 5 mg/kg infliximab at weeks 0, 2, and 6 (induction phase). At week 14, patients were randomized to receive either 5 mg/kg infliximab or placebo maintenance therapy every 8 weeks (q8 wks) through week 46. Starting at week 22, patients who did not maintain at least a 50% reduction in the number of draining fistulas relative to baseline could cross over to treatment with infliximab q 8 wks at a dose 5 mg/kg higher than their assigned maintenance dose. If present, abscesses should have been drained more than 3 weeks prior to screening. Setons present at screening had to be removed at week 2. Results: Of 282 randomized patients followed for an average of 51 weeks, 42 (14.9%) patients reported at least one newly-developed fistula-related abscess; 17 (12.3%) in the 5 mg/kg infliximab maintenance group compared with 25 (17.4%) in the placebo maintenance group. Ten of the 42 abscesses were reported during the induction phase, and 32 were reported during the maintenance phase; 13 in the 5mg/kg infiiximab group and 19 in the placebo group. Three of the 32 abscesses reported in the maintenance phase occurred after cross over from 5 to 10mg/kg infiiximab and 4 after cross over from placebo to 5mg/kg infliximab. Abscesses were considered to be serious infections in 7 patients; 2 in infliximab and 5 in placebo. Conclusion: In ACCENT If, the largest study to date of medical therapy of fistulizing CD, infliximab maintenance therapy promoted fistula closure with no increase in risk of new abscess development.
Conclusions: The landmark papers for 5-ASA therapy in UC were published prior to 1990 in higher impact journals during that time period. This implies that novelty was an important determinant in publishing in high impact factor journals. Improvement in the conduct of RCT during the 1990s did not necessarily predict publication in a higher impact journal, as it did in the previous decade. Using this representative database of UC trials, adequate randomLzation and sample size, but not blinding, correlated with publication in journals with a high impact factor. M1591 Efficacy of Mesalamine Rectal Gel in Distal Ulcerative Colitis. A Pilot Study Guy Aumais, Marc Lefebwe, Julie Massicotte, Claude Tremblay, Katcha Pierre, Cynthia Cardinal, Jean Spenard Mesalamine enema in a gas-propelled gel form has been used for many years in Europe for the treatment of distal ulcerative colitis (UC). A North American version of this treatment, easier to administer than the current aqueous suspension enema, is now under development (Canasa| - Axcan). This study, part of a pharmacokinetic assessment, looked at the efficacy
A-379
AGA Abstracts
Enl~lld Eady Reduction aid Blmlr
GmuI) I Bllellne r ~1 14 yr ~ t0 rag/day for ' 3 too* 4(28.6%) No emtlcoltlm~s for ' 3 me 3(21.4%) I~mel~ corttcolmrokls > 1 yr < 10 raG/day for * 3 too* NOcorUcoltli~Ids for a 3
mo
and safety of mesalamine gel in a limited number of patients with mild to moderate distal UC. All patients were included on the basis of a disease activity index (DAI) > 3, assessed 8 days before the first dose. Patients with known hypersensitivity to mesafamine or related drugs were excluded as well as pregnant or breast-feeding women. Patients who were taking oral mesalamine stopped it at least 5 days before receiving their first dose of rectal gel. No other medications for UC were taken during the trial. Three men and three women with mean age of 42.7 (s.d. 7.0, range 35-55) years received a single rectal dose of 4 g of mesalamine in 60 mL gel HS and, starting 48 hours after their first dose, 4 g / 60 mL HS x 4 consecutive days. Patients went to bed immediately after each dose, at 22:00, stayed in bed for at least 8 hours, and consequently slept overnight at the research center. The DAI was also assessed 14 ( + 1) hours after administration of the last dose. DAIs at baseline were 5, 4, 6, 6, 9, and 9 (mean 6.5, s.d. 2.1) for patients 1 to 6 respectively. They were 2, 2, 3, 3, 4, and 4 (mean 3.0, s.d. 0.9) at the end of study for patients 1 to 6 respectively. Exploratory statistics by paired t-test showed a statistically significant difference between baseline and end-of-treatment DAIs (p=0.0009). Reported adverse events (# patients), regardless of relationship to study medication, were: abdominal pain (5), headache (3), mouth ulcer (2), dizziness (2), flatulence, sinus discomfort, nausea, gastro-esophageal reflux, and rectorragia (1 each). We conclude that mesalarnine rectal gel provided, in these patients, a clinically and statistically (despite their limited number) stgnificant amelioration of UC, within 4 days. The associated safety profile is good. These results support the conduct of Phase III studies to confirm efficacy and safety of the North American mesalamine rectal gel.
of St~oldl: Week 54 Relultl
Groep II
Group II
11
11
G r ~ I It and Ill 22
6(54.5%)
7(63.6%)
13(59.1%)
5(45.5%)
6 (54,5%)
11 (50,6%)
39
44
44
88
5 (12,6%)
15 (341%)"
22(50.6%)#
37 (42.0%)#
4 (10.3%)
12 (27,3%)~
18 (40.9%)#
30 (34.1%)#
9p < 0.05 #p < 0.01
M1589 Meaalazine (5-ASA) Micrnpellets Show Comparable Efficacy and Tolerability as Mesalazine Tablets in Patients with Ulcerative Colitis. a Prospective, MultiNational, Randomised, Double-Blind, Active-Controlled Clinical Phase II Study Chr/stoph Behrens, Peter Bias, Helmut Malchow, Andreas Raedler Non-inferiority of a new sustained-release inesalazine micropellet formulation was studied in comparison to registered mesalazine tablets with regard to efficacy and safety/tolerability in patients with recurrent active mild to moderate ulcerative colitis (UC). A total of 362 patients (ITT = 357, ATP = 322) were enrolled CA11-7>4, EI>4, extent of UC>12 cm, > 18 blood stools/week) at 38 active European study centres. Eligible patients were randomised to take orally up to 8 weeks (A) mesalazine micropellets 1.5g b.i.d, or (B) mesalazine tablets 1.0g t.i.d.. Assessments were carned out after 2, 4, 6 and 8 weeks of treatment. Primary efficacy variable was clinical remission (CR) within 8 weeks of treatment, defined as CA114<2. Secondary efficacy variables were: CAI 1-7, endoscopic index (EI), endoscopic remission (El<2), histological evaluation, additional symptom evaluation, global assessment of efficacy. Secondary safety variables were AEs, clinically relevant laboratory changes, global assessment of tolerability. Results: With statistical significance micropellets showed noninferiority compared to tablets regarding CR and all secondary efficacy endpoints. The cumulative numbers of patients with CR (CAI 1-4< 2) within 8 weeks show up as for ATP population: micropellets/ tablets (160/162) = 64.4%/64.2% and as for ITT population: micropellets/tablets (179/ 178) = 67.0%/62.9%. Regarding secondary efficacy endpoints non-inferiority of the micropellets was shown for CR within 8 weeks in the ITT population and within 6 weeks in both analysis populations. No major safety differences between treatment groups were observed. All SAEs reported were not related to the intake of micropellets. The efficacy of micropellets was judged as very good and good by a total of 89.3% of treated patients and by 91.6% of the investigators. Conclusion: The mesalazine micropellet formulation was demonstrated to show a non-inferior effecacy compared to the reference, to be safe, and well tolerable in mild to moderate active ulcerative colitis.
M1592 Prevention of Recurrence by Mesalamine (Pcutasa) In Pediatric Crohn's Disease. A Muhicentric Double Blind Trial Jean Pierre Cezard, A. Munck, O. Mouterde, A. Morali, C. Lenaerts, A. Lachattx, D. Turck, J. Schmitz, C. Maurage, J. P. Girardet, D. Belfi, T. Lamireau, J. Sarles, J. P. Chouraqui, B. Descos, A. Dabadi, M. Meyer, J. P. Olives, J. Crand, J. Y. Mary In a previously reported study (1), a trend in relapse prevention has been observed in children receiving maintenance treatment with Mesalazine (Me) as compared to placebo (P), with 59% vs 37% of children still in remission at 1 year (R1) after successful treatment of a flare-up of their Crohn's disease (CD). Therefore, it was decided to re-start patient recruitment in the same protocol conditions up to 120 evaluable children. Material and methods : during both periods (1991-1993 and 1996-1999), 122 patients aged 12 +/- 3 yrs (mean +/- SD) were randomized with stratification according to flare-up treatment, including nutrition (N, n = 41) or drugs only (D, n = 81) ; Relapse was defined by a Harvey Bradshaw > 5. Time to relapse curves were estimated through Kaplan-Meier method and analysed according to treatment, stratum and period through Cox model. Results : No significant difference was observed between treatment groups, Me(n = 60) and P (n = 62) for clinical and biological features measured at flare-up or at randomization as well as for side effects recorded during the study. 29 patients et 35 patients experience a relapse during the follow up in the Me et P groups. Globally, R1 was 43 +/- 7% and 37 +/- 7%, median time to recurrence 10.7 +/- 2.1 and 6.2 +/- 1.8 months, in Me and P groups, respectively. Time to relapse analysis provided a significant model with 3 groups showing different remission rates (p = 0.01) as follows : a positive effect of Me during the first period (R1 = 59 +/- 11%, n = 26), a possibly negative effect of Me during the second period in stratum N (R1 = 14 +/- 12%, n = 12), an absence of effect of Me during the second period in stratum D as compared to placebo group in both strata and periods (R1 = 38 +/- 6%, n = 80). Ahhrough some characteristics of children were clearly different from one period to another, pronostic factors of relapse could not explain the variation of the effect of Me between the 2 periods. Conclusion : Me appears to be possibly an effective maintenance treatment for relapse prevention in pediatric CD after successful treatment of flare-up. Nevertheless, conditions for efficacy remained to be elucidated. 1. JP Cezard and al. J. Ped. Gastroenterol. Nutr 1996 ; 22 : 86. Supported by Ferring SAS.
M1590 Is Better Methodology In the Design of Randomized Controlled Trials Rewarded by Publication In Higher Quality Journals? Alexander I. Aspinall, Avni Hutton, Feng X. Li, Lloyd R. Sutherland
Introduction: The last two decades have seen an emphasis on improved conduct of RCT. We hypothesized that better methodology is rewarded by publication in higher quality journals. Alternatively, novelty rather than methodology might be important.
Methods: Using MEDLINE and bibliographic searches, we identified 111 RCT for ulcerative colitis published between 1972 and 2001. We restricted our analysis to induction of remission trials with treatment arms using 5-ASA. Fifty-five such RCT were identified with 25 published prior to 1990, and 30 published between 1990-2001. Impact factors from Journal CitaFLon Reportsfor 2001 were used as an indteator of journal quality. Markers of good methodology included quality of randomization (adequate vs marginal), blinding and sample size.
M1593 Infliximab Does Not Result in Increased Abscess Development in Fistulizing Crohn's Disease: Results from ACCENT II Sander J. Van Deventer, Marion Blank, Steve Waldschmidt, Bruce Sands
Results: RCT with better randomization were published in journals with impact factor 6.6 +2.0 (vs 4.3 -+0.6; p=n/s). Data were stratified by publication prior to or after 1990. Prior to 1990, RCT with adequate randomization were published in journals with a higher mean impact factor of 11.3 _+4.8 vs 4.4 _+0.9 (p=0.03). However, after 1990, the impact factors for papers with better randomization did not differ from the few with poor randomization (4.0 + 1.0 vs 4.1 -+ 0.7). Trials with a sample size greater than the median (61 patients) were published in journals of higher impact factor (6.1 -+ 1.1 vs 317 -+0.6; p=0.058). Blinding, regardless of level, did not predict publication in a journal of higher impact factor.
Background: Frequencies of perianal abscesses in Crohn's disease (CD) are reported to be between 44% and 61%. Concern exists that mfliximab, which has been demonstrated to induce and maintain fistula closure in CD, promotes abscess formation behind superficially closed fistulas. Data on the incidence of fistula-related abscesses in the 54-week study of infliximab in fistulizing CD (ACCENT If) are presented. Methods: In ACCENT II, patients with 1 or more draining fistula received 5 mg/kg infliximab at weeks 0, 2, and 6 (induction phase). At week 14, patients were randomized to receive either 5 mg/kg infliximab or placebo maintenance therapy every 8 weeks (q8 wks) through week 46. Starting at week 22, patients who did not maintain at least a 50% reduction in the number of draining fistulas relative to baseline could cross over to treatment with infliximab q 8 wks at a dose 5 mg/kg higher than their assigned maintenance dose. If present, abscesses should have been drained more than 3 weeks prior to screening. Setons present at screening had to be removed at week 2. Results: Of 282 randomized patients followed for an average of 51 weeks, 42 (14.9%) patients reported at least one newly-developed fistula-related abscess; 17 (12.3%) in the 5 mg/kg infliximab maintenance group compared with 25 (17.4%) in the placebo maintenance group. Ten of the 42 abscesses were reported during the induction phase, and 32 were reported during the maintenance phase; 13 in the 5mg/kg infiiximab group and 19 in the placebo group. Three of the 32 abscesses reported in the maintenance phase occurred after cross over from 5 to 10mg/kg infiiximab and 4 after cross over from placebo to 5mg/kg infliximab. Abscesses were considered to be serious infections in 7 patients; 2 in infliximab and 5 in placebo. Conclusion: In ACCENT If, the largest study to date of medical therapy of fistulizing CD, infliximab maintenance therapy promoted fistula closure with no increase in risk of new abscess development.
Conclusions: The landmark papers for 5-ASA therapy in UC were published prior to 1990 in higher impact journals during that time period. This implies that novelty was an important determinant in publishing in high impact factor journals. Improvement in the conduct of RCT during the 1990s did not necessarily predict publication in a higher impact journal, as it did in the previous decade. Using this representative database of UC trials, adequate randomLzation and sample size, but not blinding, correlated with publication in journals with a high impact factor. M1591 Efficacy of Mesalamine Rectal Gel in Distal Ulcerative Colitis. A Pilot Study Guy Aumais, Marc Lefebwe, Julie Massicotte, Claude Tremblay, Katcha Pierre, Cynthia Cardinal, Jean Spenard Mesalamine enema in a gas-propelled gel form has been used for many years in Europe for the treatment of distal ulcerative colitis (UC). A North American version of this treatment, easier to administer than the current aqueous suspension enema, is now under development (Canasa| - Axcan). This study, part of a pharmacokinetic assessment, looked at the efficacy
A-379
AGA Abstracts