Maintaining Remission in Patients With Ulcerative Colitis
Two separate randomised, double-blind, placebo-controlled studies of identical design evaluated the use of MG 1.5 g once-daily vs. placebo for maintaining remission in patients with UC for up to 6 months. The patients, procedures and other details have been described previously and are summarised below.
Men and nonpregnant, nonlactating women, ≥18 years of age were eligible for the studies if they had a confirmed diagnosis of mild to moderate UC in remission (rectal bleeding score of 0 and mucosal appearance score of 0 or 1) for ≥1 month and ≤12 months, a history of ≥1 flare with symptoms within the past 1–12 months requiring therapeutic intervention and had not taken steroids or immunosuppressive agents within 30 days prior to screening. Patients using 5-ASA formulations to maintain remission were allowed in the study and switched to study drug on the day of randomisation.
Exclusion criteria included significant medical conditions; evidence of impaired immune function; positive serology results for human immunodeficiency virus or hepatitis (B or C); received immunosuppressive therapy or corticosteroids within 30 days prior to screening; clinically significant renal disease (≥1.5 times the upper limit of normal for serum creatinine or blood urea nitrogen levels); calculated creatinine clearance level of ≤60 mL/min; prior bowel surgery (except appendectomy) and liver disease manifested by values twice the upper limit of normal for alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase or total bilirubin.
Salix Pharmaceuticals, Inc. sponsored two separate, but identical Phase III randomised, double-blind, placebo-controlled 6-month trials (Salix protocols MPUC3003 and MPUC3004), respectively, registered under ClinicalTrials.gov (http://clinicaltrials.gov/ct2/) identifiers NCT00744016 and NCT00767728. Forty-eight centres participated in study MPUC3003 and 40 in MPUC3004. Both trials started in December 2004 and were completed in April 2007. The protocols were approved by institutional review boards or ethics committees and conducted in accordance with ICH guidelines and other applicable laws and regulations. All patients provided written informed consent.
Encapsulated MG and matching placebo were supplied to the study sites by Salix. The investigators, subjects and research staff members(including project biostatisticians) were blinded to study medication assignment until after database lock at the end of each study.
The studies consisted of a screening phase, a treatment phase (up to 6 months) and a follow-up visit (2 weeks after the end-of-treatment visit). Eligible patients received a consecutively assigned ID number, allocated in the order of enrolment, and those who continued to meet eligibility criteria at Visit 1 [Baseline/Randomisation (Day 1)] were assigned a Treatment ID number using a randomisation schedule, which provided an allocation ratio of 2:1 to MG 1.5 g once-daily (dosed as four capsules, 0.375 g mesalazine each) or placebo for up to 6 months during the treatment phase. Patients self-administered study medication on an out-patient basis; four capsules were taken together once daily. Prohibited medications included immunosuppressants, chronic nonsteroidal anti-inflammatory drugs, corticosteroids, oral antibiotics (except as 7- to 10-day courses for conditions unrelated to UC), psyllium-containing compounds and other 5-ASA formulations.
The treatment phase consisted of four scheduled clinic visits to assess disease activity and monitor adverse events (AEs): Visit 1 (Baseline)/Randomisation (Day 1), Visit 2 (Month 1), Visit 3 (Month 3) and Visit 4/end of treatment (Month 6). Per protocol, if at any time during the study a patient experienced a UC flare, including rectal bleeding, an unscheduled visit occurred. Patients meeting relapse criteria based on the physician's assessment were withdrawn from the study and treated per standard of care.
A complete UC disease activity assessment using a revised Sutherland Disease Activity Index (SDAI) including a flexible sigmoidoscopy was performed at screening and at Month 6 or end of treatment. The revision to the SDAI was the deletion of 'friability' from a mucosal appearance score equal to 1 to clarify the definition of remission. The revised SDAI evaluated each of the following four parameters on a scale of 0 to 3, with a maximum total score of 12: (i) stool frequency (i.e. 0 to >4 stools/day more than normal); (ii) rectal bleeding (i.e. none to mostly blood); (iii) mucosal appearance (i.e. intact mucosa with preserved or distorted vessels to blood in lumen, gross ulceration, exudates) and (iv) physician's rating of disease activity (i.e. normal to severe).
An abbreviated SDAI assessment, excluding mucosal appearance, was performed at Baseline/Day 1, Month 1 and Month 3. For patients who discontinued therapy prior to Month 6, a sigmoidoscopy, UC disease activity assessments and safety assessments were performed at the Early Termination visit, if possible. A total revised SDAI score was calculated at baseline by carrying forward the mucosal appearance (sigmoidoscopy) score from screening. Adverse events and serious AEs were monitored throughout the treatment period, and clinical laboratory evaluations and vital signs were assessed at each visit and at follow-up.
The population for efficacy analysis included patients in the MPUC3003 and MPUC3004 combined intent-to-treat (ITT) population who switched from other 5-ASA formulations. The prior daily doses of the oral formulations ranged from 1.6 to 4.8 g/day. These patients were treated with either once-daily MG 1.5 g or placebo. The ITT population was defined as randomised patients who received ≥1 dose of study drug. Safety data were analysed from randomised patients in the 5-ASA subgroup who received ≥1 dose of study medication, with ≥1 dose post baseline safety assessment.
The primary efficacy endpoint was the proportion of patients who remained relapse-free after 6 months of treatment with MG vs. placebo. Relapse or treatment failure was defined as the following revised SDAI component scores: Rectal bleeding score of 1 or more and mucosal appearance score of 2 or more; or initiation of medication used previously to treat a UC flare; or early study termination, if the reason for termination was lack of efficacy or discontinuation due to a UC-related adverse event. The last SDAI assessment was used to determine relapse status for patients who withdrew for other reasons. The primary efficacy endpoint was analysed using a Cochran-Mantel-Haenszel test, controlling for country, to determine if there was a significant difference between the treatment groups in the proportions of relapse-free patients at the end of 6 months of treatment. The null hypothesis of no treatment difference was rejected if the resulting P-value was less than 0.05.
Secondary efficacy endpoints were: the percentages of patients with each level of change from baseline in rectal bleeding score, mucosal appearance score, physician's rating of disease activity and stool frequency on the SDAI at Months 1, 3 and 6/end of treatment; mean change from baseline in the SDAI at Month 6/end of treatment; the percentage of patients classified as treatment successes, defined as maintaining the SDAI total score ≤2 with no individual component >1 and rectal bleeding score of 0 at Month 6/end of treatment; and relapse-free duration, defined as the number of days between the start of study medication and the date of first relapse or premature withdrawal from the study plus 1 day. The last-observation-carried-forward methodology was used for imputing missing values for secondary efficacy endpoints for patients who prematurely withdrew from the study.
Statistical tests for treatment differences among the secondary endpoints were performed in a hierarchical fashion. All specified analyses and significance tests of these endpoints were conducted. Ordered P-values were considered significant until the first P-value >0.05 was encountered. Differences between treatment groups were tested with a Cochran-Mantel-Haenszel test controlled for country for the categorical variables and with rank analysis of covariance adjusted for baseline value and country for mean change from baseline in the SDAI at Month 6 or end of treatment.
Relapse-free duration was computed as the number of days between the start of double-blind study drug and the date that relapse was first detected, or the date of early termination from the study, plus 1 day. Patients who completed the 6-month treatment period or who terminated early without evidence of relapse were censored at the time of their final evaluation, and their censoring time was calculated as the date of their final evaluation minus the start of double-blind study drug, plus 1 day. A Cox proportional hazards regression model was used to assess differences in relapse-free duration between treatment groups, adjusting for country. The hazard ratio and associated 95% confidence interval was obtained from this model. Finally, cumulative relapse-free probability estimates were calculated for each treatment group at Months 1, 3 and 6 using Kaplan–Meier methods. Chi-squared tests were used to identify the week at which MG separated from placebo with respect to relapse-free probability. Greenwood's formula for estimation of standard errors (S.E.s) was used to estimate S.E.s at this time point, and 95% confidence intervals (CIs) were provided.
Demographic, baseline disease characteristics and safety data were summarised with descriptive statistics.
Overall mean per cent compliance was calculated for the subpopulation using pill counts and the following equation:
Patients were considered compliant per protocol if they took at least 70% of the study drug.
Methods
Two separate randomised, double-blind, placebo-controlled studies of identical design evaluated the use of MG 1.5 g once-daily vs. placebo for maintaining remission in patients with UC for up to 6 months. The patients, procedures and other details have been described previously and are summarised below.
Patients
Men and nonpregnant, nonlactating women, ≥18 years of age were eligible for the studies if they had a confirmed diagnosis of mild to moderate UC in remission (rectal bleeding score of 0 and mucosal appearance score of 0 or 1) for ≥1 month and ≤12 months, a history of ≥1 flare with symptoms within the past 1–12 months requiring therapeutic intervention and had not taken steroids or immunosuppressive agents within 30 days prior to screening. Patients using 5-ASA formulations to maintain remission were allowed in the study and switched to study drug on the day of randomisation.
Exclusion criteria included significant medical conditions; evidence of impaired immune function; positive serology results for human immunodeficiency virus or hepatitis (B or C); received immunosuppressive therapy or corticosteroids within 30 days prior to screening; clinically significant renal disease (≥1.5 times the upper limit of normal for serum creatinine or blood urea nitrogen levels); calculated creatinine clearance level of ≤60 mL/min; prior bowel surgery (except appendectomy) and liver disease manifested by values twice the upper limit of normal for alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase or total bilirubin.
Procedures
Salix Pharmaceuticals, Inc. sponsored two separate, but identical Phase III randomised, double-blind, placebo-controlled 6-month trials (Salix protocols MPUC3003 and MPUC3004), respectively, registered under ClinicalTrials.gov (http://clinicaltrials.gov/ct2/) identifiers NCT00744016 and NCT00767728. Forty-eight centres participated in study MPUC3003 and 40 in MPUC3004. Both trials started in December 2004 and were completed in April 2007. The protocols were approved by institutional review boards or ethics committees and conducted in accordance with ICH guidelines and other applicable laws and regulations. All patients provided written informed consent.
Encapsulated MG and matching placebo were supplied to the study sites by Salix. The investigators, subjects and research staff members(including project biostatisticians) were blinded to study medication assignment until after database lock at the end of each study.
The studies consisted of a screening phase, a treatment phase (up to 6 months) and a follow-up visit (2 weeks after the end-of-treatment visit). Eligible patients received a consecutively assigned ID number, allocated in the order of enrolment, and those who continued to meet eligibility criteria at Visit 1 [Baseline/Randomisation (Day 1)] were assigned a Treatment ID number using a randomisation schedule, which provided an allocation ratio of 2:1 to MG 1.5 g once-daily (dosed as four capsules, 0.375 g mesalazine each) or placebo for up to 6 months during the treatment phase. Patients self-administered study medication on an out-patient basis; four capsules were taken together once daily. Prohibited medications included immunosuppressants, chronic nonsteroidal anti-inflammatory drugs, corticosteroids, oral antibiotics (except as 7- to 10-day courses for conditions unrelated to UC), psyllium-containing compounds and other 5-ASA formulations.
The treatment phase consisted of four scheduled clinic visits to assess disease activity and monitor adverse events (AEs): Visit 1 (Baseline)/Randomisation (Day 1), Visit 2 (Month 1), Visit 3 (Month 3) and Visit 4/end of treatment (Month 6). Per protocol, if at any time during the study a patient experienced a UC flare, including rectal bleeding, an unscheduled visit occurred. Patients meeting relapse criteria based on the physician's assessment were withdrawn from the study and treated per standard of care.
A complete UC disease activity assessment using a revised Sutherland Disease Activity Index (SDAI) including a flexible sigmoidoscopy was performed at screening and at Month 6 or end of treatment. The revision to the SDAI was the deletion of 'friability' from a mucosal appearance score equal to 1 to clarify the definition of remission. The revised SDAI evaluated each of the following four parameters on a scale of 0 to 3, with a maximum total score of 12: (i) stool frequency (i.e. 0 to >4 stools/day more than normal); (ii) rectal bleeding (i.e. none to mostly blood); (iii) mucosal appearance (i.e. intact mucosa with preserved or distorted vessels to blood in lumen, gross ulceration, exudates) and (iv) physician's rating of disease activity (i.e. normal to severe).
An abbreviated SDAI assessment, excluding mucosal appearance, was performed at Baseline/Day 1, Month 1 and Month 3. For patients who discontinued therapy prior to Month 6, a sigmoidoscopy, UC disease activity assessments and safety assessments were performed at the Early Termination visit, if possible. A total revised SDAI score was calculated at baseline by carrying forward the mucosal appearance (sigmoidoscopy) score from screening. Adverse events and serious AEs were monitored throughout the treatment period, and clinical laboratory evaluations and vital signs were assessed at each visit and at follow-up.
Endpoints and Data Analysis
The population for efficacy analysis included patients in the MPUC3003 and MPUC3004 combined intent-to-treat (ITT) population who switched from other 5-ASA formulations. The prior daily doses of the oral formulations ranged from 1.6 to 4.8 g/day. These patients were treated with either once-daily MG 1.5 g or placebo. The ITT population was defined as randomised patients who received ≥1 dose of study drug. Safety data were analysed from randomised patients in the 5-ASA subgroup who received ≥1 dose of study medication, with ≥1 dose post baseline safety assessment.
The primary efficacy endpoint was the proportion of patients who remained relapse-free after 6 months of treatment with MG vs. placebo. Relapse or treatment failure was defined as the following revised SDAI component scores: Rectal bleeding score of 1 or more and mucosal appearance score of 2 or more; or initiation of medication used previously to treat a UC flare; or early study termination, if the reason for termination was lack of efficacy or discontinuation due to a UC-related adverse event. The last SDAI assessment was used to determine relapse status for patients who withdrew for other reasons. The primary efficacy endpoint was analysed using a Cochran-Mantel-Haenszel test, controlling for country, to determine if there was a significant difference between the treatment groups in the proportions of relapse-free patients at the end of 6 months of treatment. The null hypothesis of no treatment difference was rejected if the resulting P-value was less than 0.05.
Secondary efficacy endpoints were: the percentages of patients with each level of change from baseline in rectal bleeding score, mucosal appearance score, physician's rating of disease activity and stool frequency on the SDAI at Months 1, 3 and 6/end of treatment; mean change from baseline in the SDAI at Month 6/end of treatment; the percentage of patients classified as treatment successes, defined as maintaining the SDAI total score ≤2 with no individual component >1 and rectal bleeding score of 0 at Month 6/end of treatment; and relapse-free duration, defined as the number of days between the start of study medication and the date of first relapse or premature withdrawal from the study plus 1 day. The last-observation-carried-forward methodology was used for imputing missing values for secondary efficacy endpoints for patients who prematurely withdrew from the study.
Statistical tests for treatment differences among the secondary endpoints were performed in a hierarchical fashion. All specified analyses and significance tests of these endpoints were conducted. Ordered P-values were considered significant until the first P-value >0.05 was encountered. Differences between treatment groups were tested with a Cochran-Mantel-Haenszel test controlled for country for the categorical variables and with rank analysis of covariance adjusted for baseline value and country for mean change from baseline in the SDAI at Month 6 or end of treatment.
Relapse-free duration was computed as the number of days between the start of double-blind study drug and the date that relapse was first detected, or the date of early termination from the study, plus 1 day. Patients who completed the 6-month treatment period or who terminated early without evidence of relapse were censored at the time of their final evaluation, and their censoring time was calculated as the date of their final evaluation minus the start of double-blind study drug, plus 1 day. A Cox proportional hazards regression model was used to assess differences in relapse-free duration between treatment groups, adjusting for country. The hazard ratio and associated 95% confidence interval was obtained from this model. Finally, cumulative relapse-free probability estimates were calculated for each treatment group at Months 1, 3 and 6 using Kaplan–Meier methods. Chi-squared tests were used to identify the week at which MG separated from placebo with respect to relapse-free probability. Greenwood's formula for estimation of standard errors (S.E.s) was used to estimate S.E.s at this time point, and 95% confidence intervals (CIs) were provided.
Demographic, baseline disease characteristics and safety data were summarised with descriptive statistics.
Overall mean per cent compliance was calculated for the subpopulation using pill counts and the following equation:
Patients were considered compliant per protocol if they took at least 70% of the study drug.
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