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T1149 Response to Certolizumab Pegol Induction Is Not Steroid-Dependent in Patients with Active Crohn's Disease
AGA Abstracts
CXCL10-induced proteins previously identified in our laboratory. This study was Investigational Review Board approved and subjects provided informed consent prior to participation. Results: There were no serious adverse events or clinically significant infusion reactions reported in any cohort. Drug related adverse events (AEs; n=17) were reported in 10 subjects and all but one were Grade 1 or 2. The most common drug related AEs were somnolence, cough and dyspnea. One subject with a baseline absolute neutrophil count (ANC) of 3.0 developed Grade 3 toxicity when his ANC fell to 0.9 on Day 22. The subject was asymptomatic and the ANC spontaneously recovered to baseline levels by Day 43. MDX-1100 displayed a dose proportional PK profile. The mean Cmax and T1/2 ranged from 1.9-202.9 µg/ml and 22.4-201.9 hours, respectively, over the doses administered. DTH testing demonstrated no evidence of gross T cell dysfunction and no effect on PBMC subsets was detected by flow cytometry. Post-infusion PBMC CXCL10 mRNA was decreased in the 10 mg/kg cohort but not at lower dose levels or in placebo subjects. No anti-MDX-1100 antibody responses were detected. Conclusion: A single dose of a CXCL10 neutralizing mAb, MDX-1100, at up to 10 mg/kg, was well tolerated in healthy volunteers. MDX-1100 displayed dose proportionality and no obvious effect on DTH reactions or PBMC subset distribution was observed. A potential PD signal was evident at the highest dose tested. Together these data support the continued development of MDX-1100 for the treatment of inflammatory diseases including IBD.
balsalazide achieved greater improvements in total QoL and individual QoL components than those who received placebo. These QoL benefits achieved with a convenient, twicedaily oral dosing regimen make balsalazide 1.1-g tablets an important new treatment option for improving clinical outcomes in UC. T1148 Safety and Tolerability of Twice-Daily Balsalazide Tablets: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Ronald E. Pruitt, Alan A. Rosen, Lawrence Wruble, Shahriar Sedghi, Roland D. Shepard, Shadreck M. Mareya, Shirley Huang, Audrey L. Shaw, William P. Forbes Background: Balsalazide 1.1-g tablets are a new high-potency formulation of the azo-bonded 5-ASA prodrug balsalazide disodium, in clinical trials for first-line treatment of mild-tomoderate active ulcerative colitis (UC). Key endpoints for the phase 3, randomized, doubleblind, multicenter study included evaluation of safety and tolerability of balsalazide tablets 6.6 g/d for 8 weeks compared with placebo. Methods: Adults with mild-to-moderate active UC were randomized (2:1) to receive balsalazide tablets 6.6 g/d (3 tablets twice daily) or placebo for 8 weeks. Safety evaluations involved clinical laboratory assessments (eg, hematology, blood chemistry) at baseline and weeks 2 and 8 with vital sign measurements and adverse event (AE) and concomitant medication documentation at baseline and weeks 1, 2, 4, and 8. Eligible patients were offered enrollment in an open-label extension study to receive active treatment. Results: A total of 250 patients (median age, 43 y) were randomized, with 247 included in the safety population (168 balsalazide, 79 placebo). No clinically significant differences in laboratory assessments or vital signs were observed between groups. The proportion of patients who experienced any AE was lower in the balsalazide group (55%) than in the placebo group (68%). The majority of AEs experienced by either group were mild or moderate in severity, and the only AEs that occurred in ≥5% of patients were headache (6%:14%, balsalazide:placebo) and exacerbation of UC (7%:14%, balsalazide:placebo). Gastrointestinal AEs were experienced by a lower proportion of patients in the balsalazide group (26%) than the placebo group (37%). Serious AEs (SAEs) were experienced by a lower proportion of patients in the balsalazide group (2%) than the placebo group (5%), and no SAEs were considered drug related. Discontinuations due to AEs were observed in 10% and 13% of patients receiving balsalazide and placebo, respectively. No deaths were reported in either group. A total of 216 patients received ≥1 dose of balsalazide (mean drug exposure = 118 days), including 142 patients enrolled into the open-label extension; AEs and AE severity were consistent with those in the 8-week study. Common AEs included exacerbation of UC (10%), headache (6%), diarrhea (6%), and abdominal pain (5%). Conclusions: Balsalazide 1.1-g tablets administered at 6.6 g/d (3 tablets twice daily) were safe and well tolerated, with AE profiles equal to or better than placebo. The development of safe and effective high-potency oral 5-ASA agents with convenient, twice-daily dosing regimens stands to improve patient adherence to therapy and, thus, clinical outcomes in the treatment of UC.
T1146 Maintenance Therapy with Once-Daily 2g Mesalazine (Pentasa) Treatment Improves Remission Rates in Subjects with Ulcerative Colitis Compared to Twice Daily 1g Mesalazine: Data from a Randomised Controlled Trial Axel U. Dignass, Bernd Bokemeyer, H. E. Adamek, Michael R. Mross, Lars Vinter-Jensen, N. Boerner, Jouni Silvennoinen, T. G. Tan, M. Oudkerk-Pool, Theo Stijnen, Peter Dietel, Tobias Klugmann, Henri Veerman Introduction and Aims: Ulcerative colitis (UC) is a debilitating disease. Non-compliance with treatment results in a failure to achieve optimally effective clinical outcome with therapies such as mesalazine. The purpose of this study was to determine if good clinical outcome with mesalazine therapy can be further improved using a once daily (od) versus a twice daily (bd) treatment regimen in subjects with quiescent disease. Methods: This was a multi-centre, single-blinded, randomised controlled trial. Subjects were recruited with mild to moderate UC who had experienced at least one clinical relapse within the previous year. They were randomised to once daily treatment with a single sachet of 2g mesalazine granules, or twice-daily treatment with 2 x 1g sachets. Disease activity was assessed using the UCDAI score. The study was designed to demonstrate clinical non-inferiority, defined as a difference in remission rates of not more than 10% using the UCDAI score following 12 months of treatment in both ITT and PP analysis. Results:362 patients were randomised (54.3% male; mean age 48.7 years). At 12 months the percentage of subjects in remission was 73.8% for the once daily and 63.6% for the twice daily regimen, respectively. Kaplan Meier analysis demonstrated an 11.9% higher probability to remain in remission during 12 months after randomisation for patients randomized to the od group (P=0.024). There were 72.3% and 62.5% of subjects, respectively, with no evidence of physician assessed active disease at end of study. Subjects undergoing once daily treatment had a reduced likelihood of rectal bleeding (20.4% vs. 29.3%;, and also had increased rates of normal stool frequency (81.5% vs. 61.7%). No differences in the frequency of side effects were observed between both groups Conclusion:Both alternative mesalazine regimens were effective in preventing remission in subjects with mild to moderate ulcerative colitis; however, once daily therapy with 2g mesalazine was superior to twice daily therapy with 1g mesalazine. Furthermore, once daily therapy improved a range of other important clinical parameters.
T1149 Response to Certolizumab Pegol Induction Is Not Steroid-Dependent in Patients with Active Crohn's Disease Daniel W. Hommes BACKGROUND Recently, it was shown that Crohn's disease (CD) can be effectively treated with a combination of immunesuppressives and infliximab without the use of corticosteroids (Hommes et al, DDW 2006). However, data suggests that the anti-TNF adalimumab used concomitantly with a corticosteroid during induction may optimize its clinical efficacy in Crohn's disease (CD). Certolizumab pegol, a PEGylated Fab' anti-TNF agent has demonstrated efficacy and tolerability in patients with CD in the PRECiSE studies.1,2 We investigated the effect of steroids on response (reduction in CDAI ≥100 points) to induction with certolizumab pegol. METHODS Induction response rates at Week 6 were analyzed by corticosteroid use in one phase II (Study 005, n=292) and two phase III (PRECiSE 1 [(P1) n=659] and 2 [(P2) n=668]) studies. P1 and P2, induction treatment comprised three subcutaneous doses of certolizumab pegol at Weeks 0, 2 and 4. Concomitant corticosteroid treatment was permitted provided the dose had been stable for ≥2 weeks at study entry. Any increase from the entry dose was deemed a treatment failure and the patient was withdrawn. RESULTS Across studies, the No Steroids had longer disease duration (especially P1), more resections (P2) and more Immunosuppressants (P1). However, the Steroid group did have a slightly higher CDAI baseline (10 point difference).Response rates were not correlated with the use of corticosteroid at entry, but with a trend towards a better response in patients without steroids (table). For patients with either a history of corticosteroid use or current use, Week 6 response rates varied from 36.3% in PRECiSE 1 to 44.0% in Study 005 (400 mg group). Corresponding values for non-corticosteroid users were 34.8% and 45.5%, respectively. Similarly, corticosteroid use was not found to affect remission rates (data not shown). CONCLUSIONS Response to certolizumab pegol induction treatment is apparently not affected by concomitant administration of corticosteroids. This steroid -independent response could be advantageous in a clinical setting where patients are suffering from steroids side effects. 1.Sandborn W et al. N Engl J Med 2007;357:228-238. 2. Schreiber S et al. N Engl J Med 2007;357:239-250.
T1147 Twice-Daily Balsalazide Tablets Improve Patient Quality of Life After 2 and 8 Weeks of Treatment: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study David T. Rubin, Alan A. Rosen, Shahriar Sedghi, Roland D. Shepard, Shadreck M. Mareya, Shirley Huang, Audrey L. Shaw, William P. Forbes Background:In addition to symptom relief and inducing remission, treatment goals for ulcerative colitis (UC) include improving patient quality of life (QoL). Balsalazide 1.1-g tablets are a new formulation of the azo-bonded 5-ASA prodrug balsalazide disodium, approved for treatment of mild-to-moderate active UC. Key efficacy evaluations of a phase 3, randomized, double-blind, multicenter study included QoL assessment among patients who received twice-daily balsalazide tablets compared with placebo. Methods:Adults with mild-to-moderate UC received balsalazide 6.6 g/d (3 tablets twice daily) or placebo for 8 weeks. Patient QoL was assessed by administering the inflammatory bowel disease questionnaire (IBDQ) at baseline, week 2, and week 8 (or last treatment). The IBDQ comprises 32 questions grouped into 4 components: bowel symptoms, systemic symptoms, emotional function, and social function. At the end of the study, patients were interviewed to assess satisfaction with treatment. Results:A total of 250 patients (median age, 43 y) were randomized to the study, and QoL data were contributed by 172 patients who received balsalazide (n= 115) or placebo (n=57). After 2 weeks of treatment, patients who received balsalazide reported significantly greater improvement over placebo in mean bowel symptom score (9.7 vs 6.3 points, respectively; P=0.0044), mean emotional function score (11.1 vs 8.2 points, respectively; P=0.0105), mean social function score (3.5 vs 2.4 points, respectively; P= 0.0043), and mean total QoL score (27.9 vs 20.1 points, respectively; P=0.0064). After 8 weeks (or at last treatment), patients who received balsalazide reported significantly greater improvements over placebo in mean emotional function score (12.0 vs 10.5 points, respectively; P=0.0192), mean social function score (4.7 vs 4.1 points, respectively; P=0.0055), and mean total QoL score (32.7 vs 29.7 points, respectively; P=0.0302). Patients who received balsalazide also had numerically greater improvements over placebo in mean bowel symptom score at week 8 and in mean systemic symptom score at weeks 2 and 8. Significantly more patients who received balsalazide reported they were satisfied or very satisfied with treatment than those who received placebo (73% vs 56% of all patients, respectively; P= 0.0230). Conclusions:As early as 2 weeks into treatment, patients who received twice-daily
AGA Abstracts
A-494
CXCL10-induced proteins previously identified in our laboratory. This study was Investigational Review Board approved and subjects provided informed consent prior to participation. Results: There were no serious adverse events or clinically significant infusion reactions reported in any cohort. Drug related adverse events (AEs; n=17) were reported in 10 subjects and all but one were Grade 1 or 2. The most common drug related AEs were somnolence, cough and dyspnea. One subject with a baseline absolute neutrophil count (ANC) of 3.0 developed Grade 3 toxicity when his ANC fell to 0.9 on Day 22. The subject was asymptomatic and the ANC spontaneously recovered to baseline levels by Day 43. MDX-1100 displayed a dose proportional PK profile. The mean Cmax and T1/2 ranged from 1.9-202.9 µg/ml and 22.4-201.9 hours, respectively, over the doses administered. DTH testing demonstrated no evidence of gross T cell dysfunction and no effect on PBMC subsets was detected by flow cytometry. Post-infusion PBMC CXCL10 mRNA was decreased in the 10 mg/kg cohort but not at lower dose levels or in placebo subjects. No anti-MDX-1100 antibody responses were detected. Conclusion: A single dose of a CXCL10 neutralizing mAb, MDX-1100, at up to 10 mg/kg, was well tolerated in healthy volunteers. MDX-1100 displayed dose proportionality and no obvious effect on DTH reactions or PBMC subset distribution was observed. A potential PD signal was evident at the highest dose tested. Together these data support the continued development of MDX-1100 for the treatment of inflammatory diseases including IBD.
balsalazide achieved greater improvements in total QoL and individual QoL components than those who received placebo. These QoL benefits achieved with a convenient, twicedaily oral dosing regimen make balsalazide 1.1-g tablets an important new treatment option for improving clinical outcomes in UC. T1148 Safety and Tolerability of Twice-Daily Balsalazide Tablets: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Ronald E. Pruitt, Alan A. Rosen, Lawrence Wruble, Shahriar Sedghi, Roland D. Shepard, Shadreck M. Mareya, Shirley Huang, Audrey L. Shaw, William P. Forbes Background: Balsalazide 1.1-g tablets are a new high-potency formulation of the azo-bonded 5-ASA prodrug balsalazide disodium, in clinical trials for first-line treatment of mild-tomoderate active ulcerative colitis (UC). Key endpoints for the phase 3, randomized, doubleblind, multicenter study included evaluation of safety and tolerability of balsalazide tablets 6.6 g/d for 8 weeks compared with placebo. Methods: Adults with mild-to-moderate active UC were randomized (2:1) to receive balsalazide tablets 6.6 g/d (3 tablets twice daily) or placebo for 8 weeks. Safety evaluations involved clinical laboratory assessments (eg, hematology, blood chemistry) at baseline and weeks 2 and 8 with vital sign measurements and adverse event (AE) and concomitant medication documentation at baseline and weeks 1, 2, 4, and 8. Eligible patients were offered enrollment in an open-label extension study to receive active treatment. Results: A total of 250 patients (median age, 43 y) were randomized, with 247 included in the safety population (168 balsalazide, 79 placebo). No clinically significant differences in laboratory assessments or vital signs were observed between groups. The proportion of patients who experienced any AE was lower in the balsalazide group (55%) than in the placebo group (68%). The majority of AEs experienced by either group were mild or moderate in severity, and the only AEs that occurred in ≥5% of patients were headache (6%:14%, balsalazide:placebo) and exacerbation of UC (7%:14%, balsalazide:placebo). Gastrointestinal AEs were experienced by a lower proportion of patients in the balsalazide group (26%) than the placebo group (37%). Serious AEs (SAEs) were experienced by a lower proportion of patients in the balsalazide group (2%) than the placebo group (5%), and no SAEs were considered drug related. Discontinuations due to AEs were observed in 10% and 13% of patients receiving balsalazide and placebo, respectively. No deaths were reported in either group. A total of 216 patients received ≥1 dose of balsalazide (mean drug exposure = 118 days), including 142 patients enrolled into the open-label extension; AEs and AE severity were consistent with those in the 8-week study. Common AEs included exacerbation of UC (10%), headache (6%), diarrhea (6%), and abdominal pain (5%). Conclusions: Balsalazide 1.1-g tablets administered at 6.6 g/d (3 tablets twice daily) were safe and well tolerated, with AE profiles equal to or better than placebo. The development of safe and effective high-potency oral 5-ASA agents with convenient, twice-daily dosing regimens stands to improve patient adherence to therapy and, thus, clinical outcomes in the treatment of UC.
T1146 Maintenance Therapy with Once-Daily 2g Mesalazine (Pentasa) Treatment Improves Remission Rates in Subjects with Ulcerative Colitis Compared to Twice Daily 1g Mesalazine: Data from a Randomised Controlled Trial Axel U. Dignass, Bernd Bokemeyer, H. E. Adamek, Michael R. Mross, Lars Vinter-Jensen, N. Boerner, Jouni Silvennoinen, T. G. Tan, M. Oudkerk-Pool, Theo Stijnen, Peter Dietel, Tobias Klugmann, Henri Veerman Introduction and Aims: Ulcerative colitis (UC) is a debilitating disease. Non-compliance with treatment results in a failure to achieve optimally effective clinical outcome with therapies such as mesalazine. The purpose of this study was to determine if good clinical outcome with mesalazine therapy can be further improved using a once daily (od) versus a twice daily (bd) treatment regimen in subjects with quiescent disease. Methods: This was a multi-centre, single-blinded, randomised controlled trial. Subjects were recruited with mild to moderate UC who had experienced at least one clinical relapse within the previous year. They were randomised to once daily treatment with a single sachet of 2g mesalazine granules, or twice-daily treatment with 2 x 1g sachets. Disease activity was assessed using the UCDAI score. The study was designed to demonstrate clinical non-inferiority, defined as a difference in remission rates of not more than 10% using the UCDAI score following 12 months of treatment in both ITT and PP analysis. Results:362 patients were randomised (54.3% male; mean age 48.7 years). At 12 months the percentage of subjects in remission was 73.8% for the once daily and 63.6% for the twice daily regimen, respectively. Kaplan Meier analysis demonstrated an 11.9% higher probability to remain in remission during 12 months after randomisation for patients randomized to the od group (P=0.024). There were 72.3% and 62.5% of subjects, respectively, with no evidence of physician assessed active disease at end of study. Subjects undergoing once daily treatment had a reduced likelihood of rectal bleeding (20.4% vs. 29.3%;, and also had increased rates of normal stool frequency (81.5% vs. 61.7%). No differences in the frequency of side effects were observed between both groups Conclusion:Both alternative mesalazine regimens were effective in preventing remission in subjects with mild to moderate ulcerative colitis; however, once daily therapy with 2g mesalazine was superior to twice daily therapy with 1g mesalazine. Furthermore, once daily therapy improved a range of other important clinical parameters.
T1149 Response to Certolizumab Pegol Induction Is Not Steroid-Dependent in Patients with Active Crohn's Disease Daniel W. Hommes BACKGROUND Recently, it was shown that Crohn's disease (CD) can be effectively treated with a combination of immunesuppressives and infliximab without the use of corticosteroids (Hommes et al, DDW 2006). However, data suggests that the anti-TNF adalimumab used concomitantly with a corticosteroid during induction may optimize its clinical efficacy in Crohn's disease (CD). Certolizumab pegol, a PEGylated Fab' anti-TNF agent has demonstrated efficacy and tolerability in patients with CD in the PRECiSE studies.1,2 We investigated the effect of steroids on response (reduction in CDAI ≥100 points) to induction with certolizumab pegol. METHODS Induction response rates at Week 6 were analyzed by corticosteroid use in one phase II (Study 005, n=292) and two phase III (PRECiSE 1 [(P1) n=659] and 2 [(P2) n=668]) studies. P1 and P2, induction treatment comprised three subcutaneous doses of certolizumab pegol at Weeks 0, 2 and 4. Concomitant corticosteroid treatment was permitted provided the dose had been stable for ≥2 weeks at study entry. Any increase from the entry dose was deemed a treatment failure and the patient was withdrawn. RESULTS Across studies, the No Steroids had longer disease duration (especially P1), more resections (P2) and more Immunosuppressants (P1). However, the Steroid group did have a slightly higher CDAI baseline (10 point difference).Response rates were not correlated with the use of corticosteroid at entry, but with a trend towards a better response in patients without steroids (table). For patients with either a history of corticosteroid use or current use, Week 6 response rates varied from 36.3% in PRECiSE 1 to 44.0% in Study 005 (400 mg group). Corresponding values for non-corticosteroid users were 34.8% and 45.5%, respectively. Similarly, corticosteroid use was not found to affect remission rates (data not shown). CONCLUSIONS Response to certolizumab pegol induction treatment is apparently not affected by concomitant administration of corticosteroids. This steroid -independent response could be advantageous in a clinical setting where patients are suffering from steroids side effects. 1.Sandborn W et al. N Engl J Med 2007;357:228-238. 2. Schreiber S et al. N Engl J Med 2007;357:239-250.
T1147 Twice-Daily Balsalazide Tablets Improve Patient Quality of Life After 2 and 8 Weeks of Treatment: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study David T. Rubin, Alan A. Rosen, Shahriar Sedghi, Roland D. Shepard, Shadreck M. Mareya, Shirley Huang, Audrey L. Shaw, William P. Forbes Background:In addition to symptom relief and inducing remission, treatment goals for ulcerative colitis (UC) include improving patient quality of life (QoL). Balsalazide 1.1-g tablets are a new formulation of the azo-bonded 5-ASA prodrug balsalazide disodium, approved for treatment of mild-to-moderate active UC. Key efficacy evaluations of a phase 3, randomized, double-blind, multicenter study included QoL assessment among patients who received twice-daily balsalazide tablets compared with placebo. Methods:Adults with mild-to-moderate UC received balsalazide 6.6 g/d (3 tablets twice daily) or placebo for 8 weeks. Patient QoL was assessed by administering the inflammatory bowel disease questionnaire (IBDQ) at baseline, week 2, and week 8 (or last treatment). The IBDQ comprises 32 questions grouped into 4 components: bowel symptoms, systemic symptoms, emotional function, and social function. At the end of the study, patients were interviewed to assess satisfaction with treatment. Results:A total of 250 patients (median age, 43 y) were randomized to the study, and QoL data were contributed by 172 patients who received balsalazide (n= 115) or placebo (n=57). After 2 weeks of treatment, patients who received balsalazide reported significantly greater improvement over placebo in mean bowel symptom score (9.7 vs 6.3 points, respectively; P=0.0044), mean emotional function score (11.1 vs 8.2 points, respectively; P=0.0105), mean social function score (3.5 vs 2.4 points, respectively; P= 0.0043), and mean total QoL score (27.9 vs 20.1 points, respectively; P=0.0064). After 8 weeks (or at last treatment), patients who received balsalazide reported significantly greater improvements over placebo in mean emotional function score (12.0 vs 10.5 points, respectively; P=0.0192), mean social function score (4.7 vs 4.1 points, respectively; P=0.0055), and mean total QoL score (32.7 vs 29.7 points, respectively; P=0.0302). Patients who received balsalazide also had numerically greater improvements over placebo in mean bowel symptom score at week 8 and in mean systemic symptom score at weeks 2 and 8. Significantly more patients who received balsalazide reported they were satisfied or very satisfied with treatment than those who received placebo (73% vs 56% of all patients, respectively; P= 0.0230). Conclusions:As early as 2 weeks into treatment, patients who received twice-daily
AGA Abstracts
A-494