Delayed-Release Oral Mesalamine 4.8 g/day (800-mg Tablet) Is Effective for Patients With Moderately Active Ulcerative Colitis

Article Outline

• Abstract
• Materials and Methods
  • Patients
  • Study Design
  • Patient Schedule and Efficacy/Safety Evaluations
  • Statistical Analysis
• Results
  • Characteristics and Disposition of the Patients
  • Efficacy
  • Safety
• Discussion
• Acknowledgments
• Supplementary Data
• Supplementary data
• References
• Copyright

Background and Aims

It is not clear what induction dose of mesalamine is optimal for treating patients with mildly and moderately active ulcerative colitis (UC). This study was conducted to determine the efficacy and safety of mesalamine 4.8 g/day compared with 2.4 g/day for the treatment of moderately active UC.

Methods

A multicenter, randomized, double-blind, 6-week, active-control study (ASCEND III) was conducted to assess the noninferiority of delayed-release mesalamine 4.8 g/day (Asacol HD, 800-mg tablet; Procter & Gamble, Pharmaceuticals, Inc, Mason, Ohio) with 2.4 g/day (Asacol, 400-mg tablet; Procter & Gamble Pharmaceuticals, Inc) in 772 patients with moderately active UC. The primary endpoint was treatment success (overall improvement) at week 6, defined as improvement in the Physician's Global Assessment (based on clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy), with no worsening in any individual clinical assessment.

Results

The primary objective of noninferiority was met. Seventy percent (273 of 389) of patients who received 4.8 g/day of mesalamine achieved treatment success at week 6, compared with 66% (251 of 383) of patients receiving 2.4 g/day (95% confidence interval for 2.4 g/day minus 4.8 g/day, −11.2 to 1.9). In addition, 43% of patients who received 4.8 g/day mesalamine achieved clinical remission at week 6 compared with 35% of patients who received 2.4 g/day (P = .04). A therapeutic advantage for the 4.8 g/day dose was observed among patients previously treated with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications. Both regimens were well-tolerated with similar adverse events.

Conclusions

Delayed-release mesalamine 4.8 g/day (800-mg tablet) is efficacious and well-tolerated in patients with moderately active UC.

Abbreviations used in this paper: AE, adverse event, CFT, contact friability test, ITT, intent-to-treat, PFA, Patient's Functional Assessment, PGA, Physician's Global Assessment, UC, ulcerative colitis, UCDAI, xxx

Medications that deliver 5-aminosalicylate (mesalamine) as the active moiety are effective for induction and maintenance treatment in patients with mildly and moderately active ulcerative colitis (UC).¹, ² Based on favorable efficacy and safety profiles, mesalamine and its derivatives are recommended in multiple national treatment guidelines as first-line therapy for UC.³, ⁴, ⁵ Nevertheless, the dose-response of mesalamine in patients with active UC remains uncertain. The first drug used to deliver mesalamine was sulfasalazine, a pro-drug comprised of sulfapyridine linked to mesalamine by an azo-bond, which contained 40% mesalamine. Early clinical trials demonstrated that induction therapy with sulfasalazine was limited to doses of 4−6 g/day (contains 1.6−2.4 g/day mesalamine) because of side effects from sulfapyridine.⁶, ⁷ In order to reduce the side effects of sulfasalazine, new sulfa-free formulations were developed that delivered mesalamine directly to the distal small bowel and colon.⁸ Two placebo-controlled dose-ranging trials were performed with delayed-release mesalamine (Asacol, 400-mg tablet; Procter & Gamble Pharmaceuticals, Inc, Mason, Ohio) at doses of 1.6−4.8 g/day.⁹, ¹⁰ In the first trial, delayed-release mesalamine 4.8 g/day (400-mg tablet) was superior to placebo and 1.6 g/day.⁹ In the second trial, delayed-release mesalamine doses of 1.6 g/day and 2.4 g/day were both superior to placebo (with only a slight nonsignificant advantage for 2.4 g/day over 1.6 g/day).¹⁰ Results of these trials indicated that delayed-release mesalamine doses of 2.4 and 4.8 g/day were consistently more effective than 1.6 g/day and led to regulatory (US Food and Drug Administration) approval for induction therapy at the 2.4 g/day dose, but did not provide information regarding the relative efficacy of a 4.8 g/day dose to 2.4 g/day. Subsequent dose-ranging studies have been conducted to further explore this question.¹¹, ¹² The ASCEND I trial (Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA [4.8 g/day, 800-mg tablet]) compared delayed-release mesalamine 4.8 g/day (800-mg tablet, sold as Asacol HD in the United States; Procter & Gamble Pharmaceuticals, Inc) with 2.4 g/day (Asacol, 400-mg tablet) in patients with mildly to moderately active UC.¹¹ Treatment success occurred in 56% of patients (76 of 136) who received delayed-release mesalamine 4.8g/day and 51% of patients (77 of 150) who received 2.4 g/day (P = .441). A prespecified subgroup analysis of 169 patients with moderately active UC demonstrated treatment success in 72% of patients (55 of 76) treated with delayed-release mesalamine 4.8 g/day and 57% (53 of 93) of patients treated with 2.4 g/day (P = .038). When results of the ASCEND I trial became available, a second trial, ASCEND II, was still in the recruitment phase. The protocol for the ongoing blinded ASCEND II trial was amended to limit the entry criteria to patients with moderately active UC. Only patients with moderate disease were included in the analysis for the primary endpoint, and the sample size of moderate patients was increased.¹² Treatment success occurred in 72% of patients (89 of 124) treated with 4.8 g/day and 59% of patients (77 of 130) treated with 2.4 g/day (P = .036).

Here we present results of the ASCEND III trial, a 6-week noninferiority study designed to demonstrate that delayed-release mesalamine 4.8 g/day (800-mg tablet) is effective and safe as compared with delayed-release mesalamine 2.4 g/day (400-mg tablet) in patients with moderately active UC.

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Materials and Methods 

Patients 

This multicenter, randomized, double-blind, double-dummy, active-controlled trial was conducted at 113 sites in 14 countries (Belarus, Canada, Croatia, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Russian Federation, Serbia and Montenegro, Ukraine, and United States [including Puerto Rico]) between July 2006 and June 2007. The Institutional Review Board or Ethics Committee at each site approved the protocol, and all patients gave written informed consent.

Criteria for eligibility were male or female patients 18 to 75 years of age with a diagnosis of moderately active UC that extended proximally beyond 15 cm from the anal verge, as confirmed by flexible sigmoidoscopy or colonoscopy. Moderately active UC was defined as a Physician's Global Assessment (PGA) equal to 2 points, with a score of ≥1 point in both the stool frequency and rectal bleeding clinical assessments and a score of ≥2 points in the sigmoidoscopy assessment with a positive friability assessment. Patients were excluded from study participation if they had UC confined to the rectum, short bowel syndrome, renal or hepatic disease, or a stool examination positive for Clostridium difficile, bacterial pathogens, or ova and parasites. Additional exclusion criteria were a history of allergy or hypersensitivity to salicylates, aminosalicylates, or any component of the delayed-release mesalamine tablets, a history of HIV infection or AIDS, or a history of alcohol or drug abuse. Patients were also excluded if they had received an oral 5-aminosalicylate−containing product at a dose >1.6 g/day of mesalamine by any route within the last 7 days; taken any corticosteroids (oral, intravenous, intramuscular, or rectal) within the last 30 days; taken immunosuppressive drugs (including azathioprine, 6-mercaptopurine, methotrexate) within the last 90 days; received any antidiarrheal and/or antispasmodic drugs within the previous 3 days; received aspirin (except for cardioprotective indications up to a maximum dose of 325 mg/day) or other nonsteroidal anti-inflammatory drugs within the last 7 days; used antibiotics (other than topical antibiotics) or any product containing omega-3 fatty acids within the last 7 days; received infliximab, adalimumab, or other biologic treatment of UC within the last 90 days; or participated in any drug or device clinical study within the last 30 days. Pregnant and/or lactating women were excluded from study participation.

Following randomization, patients were prohibited from taking aspirin (for any indication other than cardioprotection, where the maximum allowed dose was 325 mg/day) or other nonsteroidal anti-inflammatory drugs; other medications containing 5-aminosalicylate as the active moiety; corticosteroids; immunomodulatory agents; metronidazole; antibiotics (other than topical antibiotics) for >10 days throughout the study; antidiarrheal and/or antispasmodic medications; and any products containing omega-3 fatty acids or any investigational or marketed drug that might interfere with the evaluation of the study medication.

Study Design 

Eligible patients were randomized (in a 1:1 ratio) to receive either oral delayed-release mesalamine 2.4 g/day (Asacol, 400-mg tablet) or delayed-release mesalamine 4.8 g/day (Asacol HD, 800-mg tablet; Procter & Gamble Pharmaceuticals, Inc) for 6 weeks. The study was locally randomized at each site, and treatment allocation was stratified by gender. A double-blind, double-dummy trial design was utilized. The investigator or designated representative telephoned the Interactive Voice Response System for patient randomization and allocation of study medication once the patient was determined to be eligible for the study. The treatment each patient received was not disclosed to the investigator, study-center personnel, patients, contracted monitors, contracted vendors, or the sponsor (except for selected clinical supplies, bioanalytical, or pharmacovigilance personnel). Patients randomized to 2.4 g/day received two 400-mg tablets and 2 placebo tablets 3 times daily (placebo tablets were identical in appearance to the 800-mg tablets), and patients randomized to 4.8 g/day received two 800-mg tablets and 2 placebo tablets 3 times daily (placebo tablets were identical in appearance to the 400-mg tablets).

Patient Schedule and Efficacy/Safety Evaluations 

Patients were assessed at screening and weeks 0 (baseline), 3, and 6. PGA score was used for assessment of disease severity and efficacy. Components of the PGA scoring system included stool frequency, rectal bleeding, and sigmoidoscopy with contact friability test (CFT) assessments (see Supplementary Table 1). Stool frequency and rectal bleeding were rated on a scale from 0 to 3, indicating normal to severe activity. These clinical assessments were completed by the investigator at visits at weeks 0, 3, and 6 and were based on the patient's recall of these symptoms during the previous 3 days. A novel approach to sigmoidoscopy assessment was used in this study that featured review of digital images by a central reader. Sigmoidoscopic disease activity was rated on a scale from 0 to 3, indicating normal to severe activity (see Supplementary Table 2). The sigmoidoscopy scoring system was modified from previous studies⁹, ¹⁰, ¹¹, ¹² to exclude friability from the definition of a score of 1 (mild). In addition, the sigmoidoscopy assessment was further modified to include a CFT, where investigators touched the most severely affected area of the sigmoid colon with closed biopsy forceps.¹³ Results of this mandatory friability test were incorporated into the sigmoidoscopy score, which was required to be a score of 2 if the friability test was positive. The sigmoidoscopy with CFT was performed in all patients at baseline and week 6 or exit from the study. All sigmoidoscopy procedures were recorded on videotape and reviewed by a central reader who was blinded to treatment group to monitor for consistency. Investigators were made aware of any discrepancies between their score and the central reader's score. Investigator's assessment of sigmoidoscopy with CFT was used for assessment of the primary and secondary endpoints of the study. The PGA score was determined based on the assessment scores and investigator's clinical judgment at weeks 0 and 6.

Treatment success was defined as either a complete response (remission) or a partial response (improvement) to treatment from baseline at week 6. A complete response was defined as PGA score equal to 0 points (ie, complete resolution or normalization of all of the following: stool frequency, rectal bleeding, and sigmoidoscopy with CFT Assessment Score). A partial response was defined as improvement from baseline in the PGA score and no worsening in any of the 3 component scores. Clinical remission was defined as a stool frequency score of 0 and a rectal bleeding score of 0. The Patient's Functional Assessment (PFA) was assessed at weeks 0, 3, and 6 and was rated on a scale of 0−3 indicating normal function to severe impairment. The Mayo score (Ulcerative Colitis Disease Activity Index [UCDAI] score)⁹ was also calculated at weeks 0 and 6.

At each visit, adverse events (AEs) and concomitant medications were recorded. Safety evaluations included physical examinations and serum creatinine. Differences in creatinine levels from screening to week 6 and between treatment groups were evaluated using graphical methods.

Statistical Analysis 

The primary endpoint was treatment success (partial response plus complete response) at week 6 in the intent-to-treat (ITT) population. The ITT population included all patients who were randomized and took 1 or more doses of study medication. For patients whose treatment outcomes were missing at week 6, their treatment outcomes at week 6 were set to treatment failure. Two sensitivity analyses were performed to assess the robustness of the primary efficacy result: (1) ITT patients with a known week-6 treatment outcome and (2) per-protocol analysis, which included all patients who had a week-6 treatment outcome and no major protocol violations. Secondary endpoints included clinical remission at weeks 3 and 6; improvement in stool frequency, rectal bleeding, and PFA assessments at weeks 3 and 6; improvement in the sigmoidoscopy with CFT, PGA, and UCDAI assessments at week 6; and treatment success in patients with left-sided disease at week 6.

The study was initially designed to determine whether delayed-release mesalamine 4.8 g/day (800-mg tablet) was superior to 2.4 g/day (400-mg tablet) for treatment success at week 6 with a sample size of 470 patients. While the ASCEND III study was still blinded and still recruiting, another delayed-release mesalamine formulation received regulatory approval for both 2.4 g/day and 4.8 g/day for the treatment of mildly to moderately active UC, despite the absence of a dose-response between the 2.4 g/day and 4.8 g/day doses.¹⁴, ¹⁵, ¹⁶ The ASCEND III study design was amended (while the study was still blinded and recruiting) to a noninferiority design. The amended primary efficacy analysis was designed to assess whether delayed-release mesalamine 4.8 g/day (800-mg tablet) was noninferior to 2.4 g/day (400-mg tablet) for treatment success at week 6. The noninferiority margin was set at 10% with a one-sided hypothesis test at α = .025 level of significance. A two-sided 95% confidence interval for the difference between the 2.4 g/day and the 4.8 g/day groups was computed. Noninferiority of 4.8 g/day was established if the upper boundary of the 95% confidence interval was <10%. In addition, if noninferiority was established between 4.8 g/day and 2.4 g/day, then superiority of 4.8 g/day compared with 2.4 g/day was to be evaluated by constructing a 95% two-sided confidence interval for the difference between the treatment groups and determining if this interval excludes zero. The P value for testing the treatment difference between the 2 treatment groups using the Cochran–Mantel Haenszel chi-square test, with gender as the stratum variable, was also calculated.

After the decision was made to change to a noninferiority design, the sample size was increased from 470 to 770 patients. It was assumed that the true rate of treatment success for the 2.4 g/day dose at week 6 would be 55%, and the true difference in treatment success rates between Asacol 2.4 g/day and 4.8 g/day was 3.0% in favor of the 4.8 g/day dose. Based on these assumptions, in order to establish noninferiority for treatment success at a two-sided upper confidence bound of 95% with 90% power, 306 patients per treatment group were required to be analyzable for the primary endpoint. Assuming that approximately 20% of enrolled patients were not analyzable, we planned to enroll 385 patients per group, or a total of 770 patients.

Subgroup analyses were conducted for the primary endpoint of overall improvement to evaluate the consistency of treatment effects across various patient populations. Predefined subgroup analyses included demographic parameters (eg, age, gender, race, smoking status), disease history (anatomic extent of disease, length of disease history, prior UC medication use, relapse frequency), and baseline disease activity measures (stool frequency, rectal bleeding, PFA score, and sigmoidoscopy score). A retrospective subgroup analysis to determine the treatment effect of prior multiple UC medication use (including oral mesalamines, rectal therapies, steroids, or immunomodulators) was also performed. For all subgroup analyses the Cochran–Mantel-Haenszel chi-square test was used to determine the overall treatment effect, and the 95% confidence intervals for the treatment difference between the treatment groups were also computed.

An exploratory post-hoc substudy was performed in which a subset of the sigmoidoscopies were reread with the CFT edited out of the videotape to determine whether the changes in sigmoidoscopy methodology used in this study (inclusion of a CFT in the sigmoidoscopy scoring system and use of a central reader) had an effect on the rate of improvement in the sigmoidoscopy score. Sixty patients from each dose group out of the pool of ITT patients that had both a baseline and week 6 sigmoidoscopy CFT score were randomly selected to be reread. Because changes in the sigmoidoscopy result also impact the response and remission rates, we also performed an exploratory post-hoc substudy in which the response and remission rates for the subset of patients on which sigmoidoscopy rereads were determined according to the definitions used in the infliximab ACT 1 and ACT 2 trials.¹⁷ Clinical response/improvement was defined as decrease from baseline in the total UCDAI score (Mayo score) of ≥3 points and at least 30% with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1 point. Remission was defined as a UCDAI score (Mayo score) of ≤2 points with no individual subscore >1 point. In order to determine whether the original definition of treatment success (which was based in part on sigmoidoscopy with CFT results) or the response and remission definitions that did not include CFT in the sigmoidoscopy results were the preferred outcome measure, we also defined response and remission from the patients' perspective, based on PFA scores, and then determined the agreement between the two outcome measures and PFA response and remission. PFA remission was defined as a PFA score of 0, and PFA response was defined as reduction from baseline in the PFA score ≥1 point.

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Results 

Characteristics and Disposition of the Patients 

Seven-hundred and seventy-two patients were randomized to treatment and dosed (2.4 g/day, n = 383; 4.8 g/day, n = 389). A summary of patient disposition is provided in Figure 1. Baseline characteristics were similar in the 2 treatment groups (Table 1).

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• Figure 1. 

  Patient disposition. Patients (n = 772) with moderately active ulcerative colitis were randomized to treatment and dosed with delayed-release mesalamine 2.4 g/day or 4.8 g/day.

Table 1. Baseline Characteristics of Patients with Moderate Ulcerative Colitis

Parameter	Mesalamine treatment groups
	2.4 g/day (n = 383)		4.8 g/day (n = 389)
	n	%	n	%
Mean age (y)	42.4		44.1
<65 years	355	92.7	355	91.3
≥65 years	28	7.3	34	8.7
Gender
Male	216	56.4	217	55.8
Female	167	43.6	172	44.2
Race
Caucasian	368	96.1	378	97.2
African American	6	1.6	3	0.8
Other	9	2.3	8	2.1
Smoking history
Current nonsmoker	342	89.3	352	90.5
Currently smokes	41	10.7	37	9.5
Disease extent at baseline
Proctosigmoiditis	183	48.3	185	48.2
Left-sided colitis	136	35.9	138	35.9
Pancolitis	60	15.8	61	15.9
Length of disease history
<1 y	111	29.0	98	25.2
1 to 5 y	131	34.2	148	38.0
>5 to 10 y	72	18.8	82	21.1
>10 y	69	18.0	61	15.7
Prior treatment
Steroids (oral or IV)	157	41.0	157	40.4
Immunomodulators	17	4.4	16	4.1
Any oral 5-ASA	323	84.3	338	86.9
Rectal therapies	188	49.1	192	49.4
Relapse frequency
Newly diagnosed	76	19.8	69	17.7
More than once a month	21	5.5	12	3.1
Once every 6 months	108	28.2	121	31.1
Once every 6−12 months	122	31.9	118	30.3
Less than once a year	56	14.6	69	17.7
Mean UCDAI (standard deviation)	7.8(0.68)		7.8(0.68)

5-ASA, 5-aminosalicylic acid; IV, intravenous; UCDAI, Ulcerative Colitis Disease Activity Index.

Efficacy 

The primary objective of noninferiority was met. At week 6, 70.2% (273 of 389) of patients receiving delayed-release mesalamine 4.8 g/day (800-mg tablet) achieved treatment success at week 6, compared with 65.5% (251 of 383) of those who received 2.4 g/day (400-mg tablet) (95% CI for 2.4 g/day minus 4.8 g/day treatment success rates, −11.2 to 1.9) (Figure 2A). The comparison of 4.8 g/day to 2.4 g/day for superiority was not significant (P = .17). Results of the sensitivity analyses (analyzable and per protocol) were consistent with these results (data not shown).

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• Figure 2. 

  (A) Treatment success at week 6. The 4.8 g/day dose was noninferior to delayed-release mesalamine 2.4 g/day for the endpoint of treatment success (overall improvement). Treatment success was defined as either a complete response (remission) or a partial response (improvement) to treatment from baseline at week 6. A complete response was defined as complete resolution or normalization of all of the following: stool frequency, rectal bleeding, and sigmoidoscopy with contact friability test assessment score. A partial response was defined as improvement from baseline in the Physician's Global Assessment score and no worsening in any of the 3 component scores. The complete response rates in the 4.8 g/day and 2.4 g/day groups were 2.6% and 5.0%, respectively. The partial response rates in the 4.8 g/day and 2.4 g/day groups were 67.6% and 60.6%, respectively. (B) Clinical remission at weeks 3 and 6. Significantly more patients who received 4.8 g/day compared to 2.4 g/day achieved clinical remission at week 3 (P = .02) and week 6 (P = .04).

Significantly more patients who received 4.8 g/day compared to 2.4 g/day achieved clinical remission at week 3 (P = .02) and week 6 (P = .04) (Figure 2B). Rates of improvement for individual assessments, including stool frequency, rectal bleeding, PFA, and PGA (week 6 only) were greater at weeks 3 and 6 in the 4.8 g/day group, but these differences were not consistently statistically significant (Figures 3 and 4). At week 6, 30.2% (105 of 348) of patients receiving 4.8 g/day achieved improvement in the sigmoidoscopy with CFT score, compared with 30.7% (106 of 345) of those who received 2.4 g/day (P = .88) (Figure 4). The mean change from baseline in UCDAI was statistically significant for both the 4.8 g/day group (−3.3 points) and the 2.4 g/day group (−3.1 points) compared to baseline (P < .0001); however, the difference between the 2 treatment groups was not significant (−0.2 points, P = .20). At week 6, rates of treatment success in patients with left-sided disease (including patients with proctosigmoiditis and left-sided colitis) were 72.1% (233 of 323) of patients receiving 4.8 g/day compared with 67.4% (215 of 319) of patients receiving 2.4 g/day (P = .19).

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• Figure 3. 

  Improvement in individual clinical assessments at week 3. Significantly more patients who received 4.8 g/day compared to 2.4 g/day achieved improvement in stool frequency (P = .002). The 4.8 g/day treatment group showed numerically higher improvement rates than 2.4 g/day for rectal bleeding and Patient's Functional Assessment, but these differences were not statistically significant.

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• Figure 4. 

  Improvement in individual clinical assessments at week 6. Improvement in stool frequency, rectal bleeding, Patient's Functional Assessment, and Physician's Global Assessment was numerically greater for patients who received 4.8 g/day compared to 2.4 g/day, but these differences were not statistically significant. Approximately 30% of patients in both treatment groups had improvement in sigmoidoscopy with contact friability test.

Treatment success at week 6 in favor of 4.8 g/day was generally consistent among most subgroups (Figure 5A and B). Of particular note were subgroup analyses that demonstrated an advantage for 4.8 g/day in patients previously treated with corticosteroids (P = .05), oral mesalamine (P = .07), rectal therapies (P = .06), or multiple UC medications (P = .01) (Figure 6).

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• Figure 5. 

  (A) and (B) Treatment outcome by subgroups at week 6. Treatment success in favor of 4.8 g/day was generally consistent among most subgroups.

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• Figure 6. 

  Treatment success at week 6 in patients having taken previous ulcerative colitis (UC) therapy. An advantage of 4.8 g/day versus 2.4 g/day was observed with patients previously treated with oral mesalamines (P = .07), rectal therapies (P = .06), corticosteroids (P = .05), or multiple UC medications (P = .01).

Results of the exploratory post-hoc analyses of the sigmoidoscopy reread substudy and the recalculation of remission and clinical response/improvement using the ACT study definitions and PFA definitions (described previously) are incorporated in Supplementary Table 3. Using the definitions from the infliximab ACT 1 and ACT 2 trials,¹⁷ remission was achieved in 19.4% and 19.5% of patients in the 2.4 g/day and 4.8 g/day arms, respectively. Rates of sigmoidoscopy improvement without CFT increased by approximately 40% relative to rates of sigmoidoscopy improvement with CFT, to absolute sigmoidoscopy improvement rates of >70% for both dose groups when CFT is edited out. There was greater overall agreement between PFA-based definitions and response and remission definitions that did not incorporate CFT than between response and remission definitions that did incorporate CFT (see Supplementary Table 3).

Safety 

The percent of patients with AEs was the same for both treatment groups (20.6%). A majority of AEs were assessed by the investigators as mild or moderate in severity and doubtfully related to the study drug. A incidence of the most common AEs (Medical Dictionary for Regulatory Activities−preferred terms: headache, ulcerative colitis, nasopharyngitis, nausea) in patients was similar in the 2.4 g/day and 4.8 g/day groups (Table 2). The most commonly identified causally related AEs were UC, nausea, and headache, and they were similar between treatment groups. Thirty patients were withdrawn from the study because of AEs [15 patients (3.9%) in each treatment group]. The most common cause for discontinuation was gastrointestinal symptoms associated with UC. The percent of patients with serious AEs was slightly higher in the 2.4 g/day group than the 4.8 g/day group (1.6% and 1.0%, respectively). There were a total of 10 patients with serious AEs; 6 in the 2.4 g/day group (UC, n = 3; lower abdominal pain, n = 1; enterocolitis, n = 1, gastroenteritis, n = 1) and 4 in the 4.8 g/day group (UC, n = 1; drug hypersensitivity, n = 1; colon cancer, n = 1; vasovagal syncope, n = 1). No deaths occurred during the study. Overall both treatments were well-tolerated, with a mean of 0.4 and 0.3 AEs per patient in the 4.8 g/day and 2.4 g/day groups, respectively. There were no meaningful differences in serum creatinine from baseline to week 6 within each treatment group or between the 2 treatment groups at week 6.

Table 2. Adverse Events Occurring in ≥2% in Either Treatment Group by MedDRA-Preferred Terms

	Mesalamine treatment groups
MedDRA-preferred term	2.4 g/day (n = 383)		4.8 g/day (n = 389)
	n	%	n	%
Headache	13	3.4	12	3.1
Colitis ulcerative	12	3.1	10	2.6
Nasopharyngitis	4	1.0	8	2.1
Nausea	11	2.9	5	1.3

MedDRA, Medical Dictionary for Regulatory Activities.

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Discussion 

Results of the ASCEND III trial show that delayed-release mesalamine 4.8 g/day (800-mg tablet) is safe and effective for the treatment of moderately active UC. Specifically, the trial demonstrated that 4.8 g/day (800-mg tablet) is noninferior to delayed-release mesalamine 2.4 g/day (400-mg tablet) for the endpoint of treatment success. Subgroup analyses demonstrated a generally consistent advantage in favor of the 4.8 g/day dose, with borderline significant or significant differences in patients previously treated with corticosteroids (P = .05), oral mesalamines (P = .07), rectal therapies (P = .06), or multiple UC medications (P = .01). It should be noted that 70% of patients who received the 4.8 g/day dose (800-mg tablet) achieved treatment success, consistent with the response rates observed with the 4.8 g/day dose (800-mg tablet) in 2 previous studies. In contrast, the treatment success rate of 66% achieved with the 2.4 g/day dose (400-mg tablet) in this study was higher than the treatment success rate of 55% achieved with the 2.4 g/day dose (400-mg tablet) in 2 previous studies.¹¹, ¹² Secondary analyses demonstrated an advantage for the 4.8 g/day dose over the 2.4 g/day dose for the endpoint of clinical remission, and no difference between the 2 doses for the endpoints of sigmoidoscopy with CFT improvement and treatment success in patients with left-sided disease at 6 weeks. At 3 weeks there was demonstrated superiority of the 4.8 g/day dose over the 2.4 g/day dose for the endpoints of clinical remission and stool frequency improvement. There were no significant differences in AEs between the 2 doses. These are clinically important results because symptom relief and a favorable safety profile are important considerations for UC patients and physicians.

The optimal induction dose of mesalamine for the treatment of mildly and moderately active UC has been unclear. The ASCEND I and II trials demonstrated that 2.4 and 4.8 g/day doses of delayed-release mesalamine have similar efficacy in patients with mildly active UC, and suggested that the 4.8 g/day dose might have a therapeutic advantage of 13% to 15% in patients with moderately active UC.¹¹, ¹² The larger ASCEND III trial demonstrated that the magnitude of the therapeutic advantage in patients with moderate disease is actually somewhat smaller (5%) and not significant. Taken together, the findings from these trials indicate that both 2.4 and 4.8 g/day doses of mesalamine are effective, and thus the lower 2.4 g/day dose may be preferred for patients with mild disease and some patients with moderate disease.

From a clinical practice perspective, some patients may benefit from initial therapy with the 4.8 g/day dose and other patients who fail to respond to initial induction therapy with 2.4 g/day may benefit from dose escalation up to 4.8 g/day without compromising safety. Subgroup analysis of the combined data set for the ASCEND I and II trials,¹⁸ as well as the ASCEND III trial, indicate that patients who have previously been treated with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications may have incremental benefit from receiving initial therapy with the 4.8 g/day dose. A study with another delayed-release mesalamine formulation demonstrated that some patients who fail to achieve remission with 2.4 g/day administered over 8 weeks may respond to dose escalation to 4.8 g/day administered for an additional 8 weeks.¹⁹ Thus, treatment with a 4.8 g/day dose will continue to play an important role in the clinical care of selected patients with UC.

Although response rates for rectal bleeding and stool frequency in the ASCEND III study were generally similar to those reported in previous studies, the absolute rates of sigmoidoscopy improvement observed (approximately 30%) are somewhat lower than those that have been reported in other recent induction studies with mesalamine¹¹, ¹², ¹⁴, ¹⁵ and other agents.¹⁷ This was most likely an artifact of technique and definition.²⁰ We incorporated a CFT performed with closed biopsy forceps passed through the therapeutic channel of a flexible sigmoidoscope into our definition of sigmoidoscopy improvement. CFT has not been performed in studies evaluating sigmoidoscopy improvement/mucosal healing in the modern era, and the technique that we utilized may have had the effect of overestimating friability (and thus underestimating sigmoidoscopy improvement) as compared with the usual technique of assessing contact friability caused by normal passage of the flexible sigmoidoscope. For this reason, rates of sigmoidoscopy improvement reported in the ASCEND III trial cannot be compared with those reported in other UC studies.

Results of the post-hoc sigmoidoscopy reread substudy demonstrated that inclusion of the CFT had an important impact on the sigmoidoscopy results, with the rate of sigmoidoscopy improvement increasing from 30% with the CFT included to >70% when it was edited out. The sigmoidoscopy with CFT also impacted the operating characteristics of the PGA subscore and overall UCDAI instrument, but the difference between treatment groups remained similar. These recalculations demonstrate that when response and remission are measured in a similar way, rates of response and remission are generally similar to those reported in previous mesalamine studies. There was better overall agreement between PFA-based response and remission definitions and outcome measures that did not incorporate CFT, indicating that in future clinical trials CFT should likely not be included as part of the sigmoidoscopy assessment.

Both doses of delayed-release mesalamine were well-tolerated and had low rates of serious AEs. There was no dose-related toxicity in patients administered delayed-release mesalamine at 4.8 g/day. Additionally, there were no significant differences in serum creatinine from baseline to week 6 in either of the 2 dose groups, or between the dose groups at week 6.

In conclusion, delayed-release mesalamine 4.8 g/day (800-mg tablet) is a safe and effective therapeutic option for treatment of moderately active UC. Patients with moderately active UC receiving delayed-release mesalamine 4.8 g/day (800-mg tablet) had a similar likelihood of achieving treatment success at week 6 as patients receiving delayed-release mesalamine 2.4 g/day (400-mg tablet). Moderate patients treated previously with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications may benefit from induction therapy with the 4.8 g/day dose.

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Acknowledgments 

Editorial and writing support were provided by Judith M. Pepin, an employee of Procter & Gamble Pharmaceuticals. The ASCEND (Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA) III Steering Committee of academic investigators (WJS, JR, BGF, EB, NJ, ML, SBH) were involved in the design and execution of the study; interpretation of results; and drafting and final approval of the manuscript. Procter & Gamble Pharmaceutical scientists (BY, PK, C-H Y, CAM) were involved with the conception and design of the study; assembly, analysis, and interpretation of data; and drafting and final approval of the manuscript. Data were collected by Procter & Gamble Pharmaceuticals and a clinical research organization, and analyzed by Procter & Gamble Pharmaceuticals. WJS wrote the first draft of the manuscript and the ASCEND III Steering Committee made the decision to publish. The academic authors had full access to and vouch for the veracity and completeness of the data and data analyses.

The authors wish to thank the ASCEND III Investigators who participated in this study, as listed here in alphabetical order: Olga Alexeeva (Nizhny Novogrod, Russian Federation), Istvan Altorjay (Debrecen, Hungary); Stephen Amann (Tupelo, MS), Frank Anderson (Vancouver, BC, Canada), Greg Anderson (Cincinnati, OH), Jeffrey Aron, MD (San Francisco, CA), Jeffrey Axler (Toronto, ON, Canada), Jeffrey Baker, MD (Toronto, ON, Canada), Marko Banic (Zagreb, Croatia), Scott Becker, MD (Austin, TX), Elena Belousova (Moscow, Russian Federation), Paul Bermanski, MD (Huntington, NY), Pierre Boucher, MD (Longueuil, QC, Canada), Marc Bradette (Quebec, QC, Canada), Robert Braun, MD (Topeka, KS), Eugeniusz Butruk (Warszawa, Poland), Tawfik Chami, MD (Zephyrhills, FL), Naoki Chiba (Guelph, ON, Canada), Irena Ciecko-Michalska (Krakow, Poland), Maria Czerwinska (Krakow, Poland), John Dalena, MD (Cedar Knolls, NJ), Chrystian Dallaire (Quebec, QC, Canada), Olexiy Datsenko (Kharkiv, Ukraine), Glen Davis (Little Rock, AR), Goda Denapiene (Vilnius, Lithuania), Jelena Derova (Riga, Latvia), Gerald Dryden (Louisville, KY), Marko Duvnjak (Zagreb, Croatia), Fred Fowler, MD (Charlotte, NC), Philip Ginsburg (Hamden, CT), John Griffin (Murray, UT), Flavio Habal (Toronto, ON, Canada), Ljiljana Hadnadjev (Novi Sad, Serbia and Montenegro), Richard Hansen (Littleton, CO), Robert Hardi, MD (Chevy Chase, MD), Douglas Homoky (Kingsport, TN), Ivo Horny (Strakonice, Czech Republic), Marek Horynski (Sopot, Poland), Anthony Infantolino (Philadelphia, PA), Zofia Jamrozik-Kruk (Czestochowa, Poland), Gilles Jobin (Montreal, QC, Canada), Njegica Jojic (Belgrade, Serbia and Montenegro), Waldemar Karnafel (Warszawa, Poland), Miroslava Katicic (Zagreb, Croatia), Oleg Khrustalev (Yaroslavl, Russian Federation), Robert Kindel (Cincinnati, OH), Mariusz Klin (Panama City, FL), Michal Konecny (Olomouc, Czech Republic), Asher Kornbluth (New York, NY), Darius Kriukas (Panevezys, Lithuania), Miodrag Krstic (Beograd, Serbia and Montenegro), Stephen Kuehn (Jacksonville, FL), Piyush Kumar, MD (Encinitas, CA), Limas Kupcinskas (Kaunas, Lithuania), Olena Levchenko (Odessa, Ukraine), Scott Levenson, MD (San Carlos, CA), Milan Lukas (Praha 2, Czech Republic), A.J. Magana, MD (Scottsbluff, NE), Ewa Malecka-Panas (Lodz, Poland), Pramod Malik, MD (Chesapeake, VA), Mircea Manuc (Bucuresti, Romania), Jury Marakhouski (Minsk, Belarus), Benno Margus (Tallinn, Estonia), Elena Mikhailova (Gomel, Belarus), Tatyana Mikhailova (Moscow, Russian Federation), Nikola Milinic (Beograd, Serbia and Montenegro), P. Miller (Birmingham, AL), Sam Moussa, MD (Tucson, AZ), Tudor Nicolaie (Bucharest 1, Romania), Zbigniew Pawlak (Wloclawek, Poland), Pierre Pare (Quebec City, QC, Canada), Oliviu Pascu (Cluj-Napoca, Romania, Canada), Sergei Pimanov (Vitebsk, Belarus), Henryk Pluta (Abbotsford, BC, Canada), Arthur Poch (Shreveport, LA), Juris Pokrotnieks (Riga, Latvia), Yaser Rayyan (Bismarck, ND), Triin Remmel (Tallinn, Estonia), Branka Roganovic (Beograd, Serbia and Montenegro), Peter Rosenberg, MD (Pasadena, CA), Janusz Rudzinski (Bydgoszcz, Poland), Valerii Rusinovich (Minsk, Belarus), Grazyna Rydzewska (Warszawa, Poland), Michael Safdi, MD (Cincinnati, OH), Riina Salupere, (Tartu, Estonia), William Sandborn (Rochester, MN), Jerrold Schwartz (Arlington Heights, IL), Chris Shepela (Minneapolis, MN), Natallia Silivontchik (Minsk, Belarus), Vladimir Simanenkov (St. Petersburg, Russian Federation), Teresa Sligh (Burbank, CA), Carol Stanciu (Iasi, Romania), David Stanton, MD (Orange, CA), Jiri Stehlik (Usti nad Labem, Czech Republic), Michal Stepka (Pruszkow, Poland), Davor Stimac (Rijeka, Croatia), Anatolii Svintsitskyi (Kyiv, Ukraine), Richmond Sy (Ottawa, ON, Canada), Tomasz Sylwestrowicz (Saskatoon, SK, Canada), Tibor Szaloki (Vac, Hungary), Gyorgy Szekely (Budapest, Hungary), Judit Szicsek (Budapest, Hungary), Tadeusz Tacikowski (Warszawa, Poland), Jawahar Taunk, MD (Palm Harbor, FL), Robert Tepper, MD (Great Neck, NY), Esther Torres (San Juan, PR), Zsolt Tulassay (Budapest, Hungary), Raimonda Vanagaitiene (Vilnius, Lithuania), Tomas Vanasek (Hradec Kralove, Czech Republic), Aliaksandr Varabei (Minsk Region, Belarus), Willem de Villiers, MD (Lexington, KY), Mihail Radu Voiosu (Bucuresti, Romania), and Mykhailo Zakharash (Kyiv, Ukraine). ClinicalTrials.gov Identifier NCT00350415.

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Supplementary Data 

Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at doi:10.1053/j.gastro.2009.08.069.

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Supplementary data 

Supplementary Table 1. Physician's Global Assessment

Supplementary Table 2. Sigmoidoscopy Assessment Score and Friability Assessment

Sigmoidoscopy assessment scorea
0Normal	Intact vascular pattern, no friability or granularity
1Mild	Erythema; diminished or absent vascular markings; mild granularity
2Moderate	Marked erythema, granularity; absent vascular markings; bleeds with minimal trauma; no ulcerations
3Severe	Spontaneous bleeding, ulcerations
Friability assessmentb
Negative	No bleeding after light touch to the worst affected mucosa
Positive	Bleeding after light touch to the worst affected mucosa between 15 cm and 60 cm from the anal verge

Supplementary Table 3. ASCEND III Trial Results by Various Endpoints

Endpoints	ITT patients				Sigmoidoscopy re-reada patients
					Sigmoidoscopy original scoresb				Sigmoidoscopy re-read resultsc
	2.4 g/day (n = 383)		4.8 g/day (n = 389)		2.4 g/day (n = 60)		4.8 g/day (n = 60)		2.4 g/day (n = 60)		4.8 g/day (n = 60)
	N	n(%)	N	n(%)	N	n(%)	N	n(%)	N	n(%)	N	n(%)
Sigmoidoscopy improvement	345	106(30.7)	348	105(30.2)	60	17(28.3)	60	17(28.3)	59d	43(72.9)	57d,e	40(70.2)
Remissionf	345	67(19.4)	348	68(19.5)	60	11(18.3)	60	13(21.7)	59d	22(37.3)	58e	23(39.7)
Clinical response/improvementf	345	249(72.2)	348	268(77.0)	60	40(66.7)	60	40(66.7)	59d	39(66.1)	57d,,e	40(70.2)
PFA remissiong	336h	165(49.1)	334h	189(56.6)	58h	30(51.7)	58h	35(60.3)	58h	30(51.7)	58h	35(60.3)
PFA response/improvementg	336h	243(72.3)	334h	254(76.0)	58h	45(77.6)	58h	46(79.3)	58h	45(77.6)	58h	46(79.3)

NOTE. Remission defined as Ulcerative Colitis Disease Activity Index (UCDAI) score ≤2 with no individual subscore >1.¹⁷ Clinical response/improvement defined as decrease from baseline in the total UCDAI score of ≥3 points and at least 30% with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1.¹⁷ PFA remission defined as Patient Functional Assessment (PFA) score = 0. PFA response/improvement defined as reduction from baseline in the PFA score of ≥1 point.

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