American Journal of Gastroenteroloey (cid:9)
`© 2005 by Am. Coll. of Gastroenterology (cid:9)
`Published by Blackwell Publishing
`
`ISSN 0002-9270
`doi: 10.1111/j.1572-0241.2005.00248.x
`
`Delayed-Release Oral Mesalamine at 4.8 g/day (800 mg
`tablet) for the Treatment of Moderately Active Ulcerative
`Colitis: The ASCEND II Trial
`
`Stephen B. Hanauer, M.D.,' William J. Sandborn, M.D.,2 Asher Kornbluth, M.D.,3 Seymour Katz, M.D.,4
`Michael Safdi, M.D.,5 Scott Woogen, M.D.,6 Gino Regalli, M.D., Ph.D.,7 Chyon Yeh, Ph.D.,7
`Nancy Smith-Hall, Pharm.D., M.D.,7 and Funmilay Ajayi, M.D.7
`'Division of Gastroenterology University of Chicago Medical Center, Chicago, Illinois; 2Division of
`Gastroenterology and Hepatology, Mayo Clinic, Rochester Minnesota; 3Mount Sinai School of Medicine, New
`York, New York; 4Long Island Clinical Research Associates, Long Island, New York; 5 Greater Cincinnati
`Gastroenterology Associates, Cincinnati, Ohio; 6 Richmond Gastroenterology Associates, Richmond, Virginia;
`and 7 Procter & Gamble Pharmaceuticals, Mason, Ohio
`
`BACKGROUND Preliminary data have shown that delayed release oral mesalamine (Asacol') dosed at
`AND AIMS: (cid:9)
`4.8 g/day provided additional efficacy benefit compared to 1.6 g/day in patients with mildly to
`moderately active ulcerative colitis. Additionally, Asacol dosed at 2.4 g/day has been proved to be
`more effective than 1.6 g/day. Whether 4.8 g/day of mesalamine (dosed with an investigational
`800 mg tablet) is more effective than Asacol 2.4 g/day (dosed with a 400 mg tablet) in patients
`with moderately active ulcerative colitis is unknown.
`
`METHODS: (cid:9)
`
`A randomized, double-blind, controlled trial (ASCEND II) was conducted to evaluate the efficacy of
`4.8 g/day of mesalamine in adults with active ulcerative colitis. Three hundred eighty-six patients
`with mild to moderate ulcerative colitis were randomized for treatment with mesalamine 2.4 g/day
`(400 mg tablet) or 4.8 g/day (800 mg tablet) for 6 wk, The primary efficacy population was 268
`patients with moderately active ulcerative colitis treated with 2.4 g/day (n = 139) or 4.8 g/day (n =
`129). The primary endpoint was the proportion of patients in each treatment group that achieved
`overall improvement ("treatment success," defined as either complete remission or a clinical
`response to therapy) from baseline at week 6.
`
`RESULTS: (cid:9)
`
`Seventy-two percent of patients receiving 4.8 g/day of mesalamine for moderate ulcerative colitis
`(89/124 patients) achieved treatment success at week 6, compared with 59% of those who
`received 2.4 g/day (77/130 patients) (p = 0.036). Both regimens were well tolerated. Adverse
`events and clinically significant changes in laboratory results were similar in both treatment groups.
`
`CONCLUSIONS: Patients with moderately active ulcerative colitis treated with 4.8 g/day of mesalamine (800 mg
`tablet) are significantly more likely to achieve overall improvement at 6 wk compared to patients
`treated with 2.4 g,/day.
`
`(Am .1 Gastroenterol 2005;100:2478-2485)
`
`INTRODUCTION
`
`Ulcerative colitis is a chronic inflammatory disorder of the
`colon of unknown etiology with clinical features of rectal
`bleeding and diarrhea (1). The first-line therapy for treat-
`ment of active ulcerative colitis is the use of compounds con-
`taining 5-aminosalicylate (5-ASA), including sulfasalazine,
`mesalamine, olsalazine, and balsalazide (2). Delayed-release
`oral mesalamine (Asacol', Procter & Gamble Pharmaceuti-
`cals, Mason, OH) is effective for the treatment of mildly to
`moderately active ulcerative colitis and for maintenance of
`remission (3-5). Preliminary data from dose response studies
`in patients with mildly to moderately active ulcerative coli-
`
`tis demonstrated that Asacol at a dose of 4.8 g/day provided
`additional benefit over 1.6 g/day (3). In addition, Asacol at a
`dose of 2.4 g/day was more effective than Asacol 1.6 g/day
`(4). Meta-analyses assessing all 5-ASA compounds have sug-
`gested a possible dose response at 5-ASA doses >3 g/day
`in the treatment of patients with active ulcerative colitis (6,
`7). Many clinicians initiate Asacol at a dose of 2.4 g/day in
`patients with mildly to moderately active ulcerative colitis,
`increasing the dose up to a maximum of 4.8 g/day for those
`patients who fail to respond to lower doses. Whether initial
`therapy with mesalamine at a dose of 4.8 g/day would be more
`effective than 2.4 g/day in patients with mildly to moderately
`active ulcerative colitis is unknown.
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`To answer this question, two randomized, double-blind,
`placebo-controlled trials were initiated to compare 4.8 g/day
`of mesalamine (dosed with an investigational 800 mg tablet)
`and Asacol 2.4 g/day (dosed with a 400 mg tablet) in patients
`with mildly to moderately ulcerative colitis. In the first trial
`(ASCEND I-Assessing the Safety & Clinical Efficacy of a
`New Dose of 5-ASA [4.8 g/day, 800 mg tablet]), 301 pa-
`tients with mildly to moderately active ulcerative colitis were
`randomized, and 286 patients were eligible for inclusion in
`the intention-to-treat primary efficacy population of mildly
`to moderately active ulcerative colitis patients. The primary
`endpoint was the proportion of patients in each treatment
`group, which achieved overall improvement from baseline
`at week 6. Overall improvement ("treatment success") was
`defined as either complete remission (complete resolution of
`signs and symptoms) or a clinical response to therapy (im-
`provement from baseline in physician's global assessment
`(PGA) accompanied by improvement in at least one other sign
`or symptom and no worsening of all remaining signs or symp-
`toms). Signs and symptoms assessed included rectal bleed-
`ing, stool frequency, PGA, patient functional assessment
`(PFA), and sigmoidoscopy. Overall improvement occurred
`in 51.3% of patients (77/150) treated with Asacol 2.4 g/day
`and 55.9% of patients (76/136) treated with 4.8 g/day (p =
`0.4411) (data on file, Procter & Gamble Pharmaceuticals). A
`prespecified subgroup analysis restricted to 169 patients with
`moderately active ulcerative colitis demonstrated overall im-
`provement in 57% of patients (53/93) treated with Asacol
`2.4 g/day and 72.4% (55/76) treated with 4.8 g/day of
`mesalamine (p = 0.0384). Based on the results of the first
`study, the protocol of the second study (still blinded and en-
`rolling patients at the time) was amended to restrict the entry
`criteria to patients with moderately active ulcerative colitis,
`the primary efficacy population was restricted to patients with
`moderate disease, and the sample size of moderate patients
`was increased accordingly. Here we present the results of the
`second study (ASCEND II: Assessing the Safety & Clini-
`cal Efficacy of a New-Dose of 5-ASA [4.8 g/day, 800 mg
`tablet])* , a 6-wk trial in which patients with moderately active
`ulcerative colitis received treatment with Asacol 2.4 g/day
`(dosed with a 400 mg tablet) or 4.8 g/day of mesalamine
`(dosed with an investigational 800 mg tablet). The primary
`analysis was performed in patients with moderately active
`disease only.
`
`METHODS
`
`Patients
`This multicenter, randomized, double-blind, controlled trial
`was conducted at 55 sites in the United States and Canada be-
`tween February 2001 and April 2004. The institutional review
`board or ethics committee at each site approved the protocol.
`All patients gave written informed consent.
`The criteria for eligibility included patients aged 18-75 yr
`with a diagnosis of ulcerative colitis confirmed within the
`past 24 months by endoscopy or radiography. Initially, pa-
`tients with both mildly active ulcerative colitis (PGA of 1)
`
`Delayed Release Oral Mesalamine (cid:9)
`
`2479
`
`and moderately active disease (PGA of 2) were eligible (3,
`4). Based on the results of the previous ASCEND I study
`described above, the protocol was amended while the cur-
`rent study was still blinded and enrolling patients to restrict
`the inclusion criteria to individuals with moderately active
`disease. Patients were excluded from the study if they had
`short bowel syndrome, intolerance or allergy to salicylates
`or 5-aminosalicylates, renal or hepatic disease, had a posi-
`tive stool examination for bacterial pathogens, ova and para-
`sites, or Clostridium difficik, or a history of alcohol or drug
`abuse. Patients were also excluded if they had used oral 5-
`aminosalicylate-containing products at a dose >1.6 g/day of
`5-ASA or topical rectal therapies within the last 7 days, had
`taken any corticosteroids (oral, intravenous, intramuscular,
`or rectal) within the last month, had taken immunomodula-
`tory drugs within the past 3 months, had received antidiar-
`rheal medications and/or antispasmodic medications after the
`screening visit, had been treated with a nicotine patch or any
`product containing fish oils within the last 7 days, had re-
`ceived antibiotics within the last 7 days, or had been treated
`with any investigational drug within the past month. Pregnant
`and lactating women were excluded flow study participation.
`During study participation, patients were prohibited from
`taking aspirin (other than for cardioprotective reasons—
`maximum dose of 325 mg/day) or other nonsteroidat anti-
`inflammatory drugs (NSAIDs), other mesalamine-containing
`products, corticosteroids, sulfasalazine, 6-mercaptopurine,
`azathioprine, cyclosporine, metronidazole, antibiotics (other
`than topical antibiotics) for more than 10 days throughout the
`study, topical rectal therapies, antidiarrheals and antispas-
`modics, immunomodulatory agents, nicotine patches, any
`products containing fish oils, or any investigational or mar-
`keted dnig that may have interfered with the evaluation of the
`study medication.
`
`PROTOCOL
`
`Assignment
`Eligible patients were randomly assigned at each site in a 1:1
`ratio to receive either Asacol 2.4 g/day (400 mg tablet, Proc-
`ter & Gamble Pharmaceuticals, Mason, OH) or 4.8 g/day of
`mesalamine (investigational 800 mg tablet, Procter & Gamble
`Pharmaceuticals, Mason, OH) and followed through week 6.
`Permutated blocks of four were used to randomly assign
`treatments to patients. The randomization scheme was gen-
`erated for each study center. No demographic or baseline dis-
`ease characteristics were used as stratification variables for
`randomization.
`
`Masking
`Both treatment regimens were administered as two tablets
`orally, three times daily. In addition, patients randomized
`to Asacol 2.4 g/day also received two placebo tablets three
`times daily that were identical in appearance to the 800 mg
`mesalamine tablets, and patients randomized to 4.8 g/day of
`mesalamine also received two placebo tablets three time daily
`that were identical in appearance to the Asacol 400 mg tablets
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`2480 (cid:9)
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`Hanauer et al.
`
`(a double-masked study design). Both patients and investiga-
`tive staff were blinded to treatment assignment.
`
`Participant Flow and Follow-Up
`Patients were assessed at weeks 0, 3, and 6. The PGA
`score was utilized for the assessment of disease severity
`and efficacy. The components of the PGA scoring system
`included stool frequency. rectal bleeding, endoscopic find-
`ings, and the patient's functional assessment (PFA). Stool fre-
`quency, rectal bleeding, and endoscopic findings were rated
`on a scale from 0 to 3, indicating normal to severe activity.
`In addition, the PFA was rated on a scale of 0 to 3, indicat-
`ing normal function to severe impairment. The patients used
`electronic diaries to collect daily data for stool frequency, rec-
`tal bleeding, and the PFA through a daily telephone call to an
`integrated voice response system. The investigator reviewed
`these data and assigned scores for each of these measures
`at the patient's visits at weeks 0, 3, and 6. The PGA score
`was then determined based on the above clinical assessment
`scores and the investigator's clinical judgment at weeks 0, 3,
`and 6. Overall improvement ("treatment success") was de-
`fined as either complete remission or a clinical response to
`therapy. Complete remission was defined as complete reso-
`lution of: (i) stool frequency (normal stool frequency); (ii)
`rectal bleeding (no rectal bleeding); (iii) PFA score (gener-
`ally well); (iv) endoscopy findings (normal), and a PGA score
`of 0. A clinical response to therapy was defined as improve-
`ment in the baseline PGA score and improvement in at least
`one other clinical assessment (stool frequency, rectal bleed-
`ing, PFA, endoscopy findings) and no worsening in any other
`clinical assessment.
`Data for all 268 randomized patients with moderate dis-
`ease activity were included in the safety analysis. At each
`visit, adverse events and concomitant medications were doc-
`umented and samples were collected for laboratory evalua-
`tions. Safety evaluations included vital signs, physical exam-
`inations, hematology, serum biochemistry, and urinalysis. In
`addition, blood samples were obtained from each patient at
`weeks 0, 3, and 6 for estimating plasma 5-ASA and N-Ac-5-
`A SA.
`
`Analysis
`The primary efficacy endpoint was overall improvement
`("treatment success") at week 6 in patients with moderately
`active ulcerative colitis (moderately active disease was de-
`fined as a baseline PGA score of 2). The primary efficacy
`intention-to-treat analysis included all randomized patients
`with moderately active disease who ingested at least one
`dose of drug and whose treatment outcome could be de-
`termined. Two sensitivity analyses including patients with
`moderately active disease not analyzable in the primary ef-
`ficacy intention-to-treat analysis were conducted: (i) week
`6 outcome set to failure; and (ii) week 6 outcome set to last
`known outcome. The secondary efficacy endpoints in patients
`with moderately active disease were overall improvement at
`week 3, improvement from baseline in each of the clinical
`assessment subscores at weeks 3 and 6, overall improvement
`
`at week 6 in the subgroup of patients with ulcerative colitis
`limited to the left side of the colon (proctitis, proctosigmoidi-
`tis, or left-sided colitis), time to normalization of stool fre-
`quency (based on the patient's daily diary), time to resolution
`of rectal bleeding (based on the patient's daily diary), and
`change from baseline in the Ulcerative Colitis Disease Ac-
`tivity Index (UCDAI). To compare the proportion of patients
`between treatment groups who achieved a specified endpoint
`(i.e., overall improvement and improvement from baseline),
`a two-sided x 2 test was used; the Cochran-Mantel-Haenszel
`x 2 test (with subgroup variables as the stratum) was used to
`assess the homogeneity of treatment effect among subgroups
`and a log-rank test was applied to the time-to-event analyses.
`A planned sample size of 224 patients with moderately ac-
`tive ulcerative colitis randomized in a 1:1 ratio to Asacol
`2.4 g/day administered as 400 mg tablets (n = 112) or
`4.8 g/day of mesalamine administered as 800 mg tablets (n =
`112) had a power of 80% at 5% significance to detect a differ-
`ence of 20% between the 4.8 g/day treatment group and the
`Asacol 2.4 g/day treatment group for overall improvement
`rates after 6 wk of treatment (primary analysis). This was
`based on the assumption of a 60% overall improvement rate
`for 4.8 g/day of mesalamine and a 40% overall improvement
`rate for Asacol 2.4 g/day.
`Subgroup analyses were conducted for the primary efficacy
`endpoint of overall improvement using the intent-to-treat pa-
`tients with moderate disease to evaluate the consistency of
`treatment effect across various patient populations. The dif-
`ference in the percentage of overall improvement between
`the two treatment groups was calculated for demographic
`parameters (age, sex, race, smoking status), disease history
`(extent of disease, length of disease history, H-2 blocker, and
`proton pump inhibitor use, prior ulcerative colitis medica-
`tion use, sulfasalazine intolerance, and relapse frequency),
`and baseline disease activity measures (stool frequency. rec-
`tal bleeding. PFA score, and sigmoidoscopy score) using the
`Cochran-Mantel-Haenszel x 2 test.
`
`RESULTS
`
`Patient Characteristics
`Three hundred eight-six (386) patients were randomized, of
`whom 268 had moderate disease at baseline. A summary of
`patient disposition is provided in Figure 1. The baseline char-
`acteristics were similar in the two treatment groups (Table 1).
`The majority of patients designated by the investigators as
`having moderately active ulcerative colitis (PGA score of
`2) reported increased stool frequency (60% with 3 or more
`stools above normal per day), rectal bleeding (56% with ob-
`vious blood most of the time), and had moderate or severe
`endoscopic findings (87% of the population).
`The primary efficacy intention-to-treat analysis included
`all randomized patients with moderately active disease who
`ingested at least one dose of drug and whose treatment out-
`come could be determined. This analysis included 130 pa-
`tients who had taken Asacol 2.4 g/day and 124 patients who
`had taken Asacol 4.8 g/day.
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`Delayed Release Oral Mesalamine (cid:9)
`
`2481
`
`386 Patients
`randomized at week 0
`
`56 Patient had
`mild disease
`
`139 Patients with
`moderate disease
`randomized to
`mesalamine 2.4 g
`
`129 Patients with moderate
`disease randomized to
`mesalamine 4.8 g
`
`62 Patients had
`mild disease
`
`26 Withdrawals:
`Protocol violation -2
`Adverse events - 4
`Voluntary withdrawal - 6
`Investigator recommendation -3
`Lack of treatment effect - 11
`
`113 Completed
`the trial
`
`113 Completed
`the trial
`
`16 Withdrawals:
`Protocol violation - 1
`Adverse events - 4
`Voluntary withdrawal - 5
`Investigator recommendation - 1
`Lack of treatment effect - 5
`
`9 Not analyzed
`for treatment
`success
`
`130
`Analyzed for
`treatment
`success
`
`_J
`
`124 Analyzed
`for treatment
`success
`
`5 Not analyzed
`for treatment
`success
`
`(cid:9) \ (cid:9)
`
`254 Patients in the primary
`efficacy population
`
`Figure 1. Patient disposition.
`
`Efficacy Among Patients With Moderate Disease
`Overall, 26 patients (18.7%) in the Asacol 2.4 g/day group
`withdrew from the study prematurely versus 16 patients
`(12.4%) in the 4.8 g/day group, primarily due to lack of treat-
`ment effect (Fig. 1).
`At week 6, 59.2% of patients in the Asacol 2.4 g/day
`group (77/130) were classified as having overall improve-
`ment, compared to 71.8% of patients (89/124) in the 4.8
`g/day group (Fig. 2). The difference in overall improve-
`ment rates was 12.5% (95% confidence interval [CI] =
`0.96-24.12%; p = 0.036). The "missing outcomes set to
`treatment failure" sensitivity analysis showed a difference
`of 13.6% between the two treatment groups at week 6,
`with a p value of 0.022 and a 95% CI of 2.11-25.09%
`and the "last-observation-carried-forward" sensitivity analy-
`sis showed a difference of 12.9% at week 6, with a p value of
`0.030 and a 95% Cl of 1.40-24.36%. In the Asacol 2.4
`g/day group in which 59.2% of patients (77/130) were
`classified as having overall improvement, 41.5% (54/77)
`experienced a clinical response to therapy and improved
`while 17.7% (23/77) achieved complete remission. In the
`4.8 g/day treatment group in which 71.8% of patients
`were classified as having overall improvement (89/124),
`51.6% experienced a clinical response to therapy (64/89)
`and improved while 20.2% achieved complete remission
`(25/89).
`At week 3, 51.5% of patients in the Asacol 2.4 g/day group
`(67/130) were classified as having overall improvement, com-
`pared to 61.3% (76/124) of patients in the 4.8 g/day group
`
`(p = 0.117) (Fig. 2). The rates of improvement for individual
`clinical assessments (including stool frequency, rectal bleed-
`ing, PGA, and endoscopy scores) were greater at weeks 3
`and 6 in the 4.8 g/day group, but these differences were not
`significant (Fig. 3).
`The rates of overall improvement in patients with ulcera-
`tive colitis disease extent limited to the left colon (including
`proctitis, proctosigmoiditis, and left-sided colitis) and those
`with pan-colonic involvement were greater at week 6 in the
`4.8 g/day group, but these differences were not significant
`(Fig. 4).
`The median times to symptom resolution (stool frequency,
`rectal bleeding, and both) are shown in Table 2. The me-
`dian time for rectal bleeding to resolve in patients with
`moderate disease was significantly shorter in the 4.8 g/day
`group (9 days) as compared with the Asacol 2.4 g/day group
`(16 days), p = 0.035.
`A numerical trend favoring the 4.8 g/day group was ob-
`served at week 6 in change fi (cid:9)uni baseline in UCDA I. The UC-
`DAI was defined as the sum of the clinical assessment scores
`and the sigmoidoscopy score. Although the mean change
`from baseline was significant for both the 4.8 g/day group
`and the 2.4 g/day group, the difference between the two treat-
`ment groups was not statistically significant (p = 0.1594).
`The treatment group receiving Asacol 2.4 g/day showed a
`43% improvement over baseline (mean change from baseline
`= -3.2), while the 4.8 g/day treatment group showed a 51%
`improvement over baseline (mean change from baseline =
`-3.7).
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`Table 1. Baseline Demographics and Ulcerative Colitis Treatment
`History
`
`Parameter
`Mean age (yr)
`18-64 yr
`>64 yr
`Sex
`Male
`Female
`Race
`Caucasian
`Black
`Hispanic
`Other
`Smoking history
`Never smoked
`Used to smoke
`Currently smokes
`Disease extent
`Proctitis
`Proctosigmoiditis
`Left-sided colitis
`Pancolitis
`Length of disease history
`< 1 yr
`1-5 yr
`>5-10 yr
`>10 yr
`Unknown
`Prior treatment
`Steroids (oral or IV)
`Immunomodulators
`Su lfasa lazi ne
`Sulfa-free oral 5-ASAs
`Any oral 5-ASAs
`Rectal therapies
`Known intolerance
`to sulfasalazine
`Yes
`No
`Relapse frequency
`Newly diagnosed
`More than once/month
`Once every• 6 months
`Once every 6-12 months
`Less than once/yr
`
`2.4 g/day
`(N = 139)
`n (%)
`42.3
`126 (90.6)
`13 (9.4)
`
`4.8 g/day
`(N = 129)
`n (%)
`42.0
`118 (91.5)
`11 (8.5)
`
`62 (44.6)
`77 (55.4)
`
`54 (41.9)
`75 (58.1)
`
`p Value*
`0.8760
`
`0.6506
`
`0.6979
`
`108 (77.7)
`11 (7.9)
`16 (11.5)
`4 (2.9)
`
`89 (64.0)
`40 (28.8)
`10 (7.2)
`
`20 (14.4)
`49 (35.3)
`42 (30.2)
`28 (20.1)
`
`54 (38.8)
`32 (23.0)
`22 (15.8)
`28 (20.1)
`3 (2.2)
`
`47 (33.8)
`3 (2.2)
`53 (38.1)
`57 (41.0)
`83 (59.7)
`50 (36.0)
`
`96 (74.4)
`14 (10.9)
`11 (8.5)
`8 (6.2)
`
`80 (62.0)
`38 (29.5)
`11 (8.5)
`
`21 (16.3)
`32 (24.8)
`49 (38.0)
`27 (20.9)
`
`49 (38.0)
`29 (22.5)
`25 (19.4)
`25 (19.4)
`1 (0.8)
`
`38 (29.5)
`5 (3.9)
`40 (31.0)
`53 (41.1)
`73 (56.6)
`48 (37.2)
`
`12 (22.6)
`41 (77.4)
`
`8 (20.0)
`32 (80.0)
`
`46 (33.1)
`21 (15.1)
`25 (18.0)
`18 (12.9)
`29 (20.9)
`
`45 (34.9)
`13 (10.1)
`27 (20.9)
`25 (19.4)
`19 (14.7)
`
`0.9024
`
`0.2861
`
`0.9168
`
`0.4439
`0.4090
`0.2210
`0.9896
`0.6045
`0.8335
`
`0.7589
`
`0.3055
`
`'p value determined using the y 2 test or t-test. where significance was defined asp
`0.05.
`
`Homogenous treatment effects were observed for all sub-
`group variables. Previous steroid use was found to be the
`only subgroup analysis variable predictive of treatment out-
`come; patients who had used steroids previously had a higher
`response rate than those who had not. In all subgroup vari-
`ables analyzed, the Asacol 4.8 g/day treatment group showed
`a trend toward greater overall improvement than that of the
`Asacol 2.4 g/day treatment group.
`
`Efficacy Among Patients With Mild Disease
`Among the patients with mild disease, 40.4% of patients
`(21/52) in the Asacol 2.4 g/day group experienced overall
`improvement at week 6, compared with 32.8% of patients
`(19/58) in the 4.8 g/day group (p = 0.410).
`
`_51
`
`80% •
`70%
`60%
`
`gt 50%
`40%
`a 30%
`O 20%
`10%
`0%
`
`r1.8%
`
`0,174 (cid:9)
`3 (cid:9)
`Wears Or Treatment
`
`fot 1 30 (cid:9)
`Week
`
`0.171
`
`Figure 2. Overall improvement at weeks 3 and 6; p < 0.05
`between 2.4 g/day and 4.8 g/day at week 6.
`
`Safety Among Patients With Moderate Disease
`The incidence of adverse events in patients with moderate
`disease was similar in the 2.4 g/day and 4.8 g/day groups
`(Table 3). Four patients in each treatment group discontin-
`ued treatment because of an adverse event. The most fre-
`quently reported adverse events in the two groups were simi-
`lar (Table 3). Serious adverse events occurred in two patients
`(1.4%) in the Asacol 2.4 g/day group (cholecystitis and pan-
`creatitis), and one patient (0.8%) in the 4.8 g/day group (peri-
`carditis). No deaths occurred during the study. There were no
`clinically significant changes in laboratory values in either
`treatment group.
`In the patient population with mild disease, the safety pro-
`file was similar to that seen with the moderate patient popu-
`lation.
`
`5-Aminosalicylate Phannacokinetics
`The mean (arithmetic) plasma 5-aminosalicylate concentra-
`tion at week 6 for the 2.4 g/day group was 1,021 ng/mL,
`and for the 4.8 g/day group it was 2,179 ng/mL. The mean
`plasma N-acetyl-5-aminosalicylate concentration at week 6
`for the 2.4 g/day group was 1,856 ng/mL, and for the 4.8 g/day
`group it was 2,916 ng/mL. The mean 5-aminosalicylate and
`N-acetyl-5-aminosalicylate concentrations at week 3 were
`very similar to those seen at week 6 for both treatment groups.
`Plasma concentration ratios of the arithmetic mean of the 4.8
`g/day dose to the 2.4 g/day dose were 1.93 at week 3 and 2.13
`at week 6 for 5-aminosalicylate and 1.48 at week 3 and 1.57
`at week 6 for N-acetyl-5-aminosalicylate.
`
`DISCUSSION
`
`The optimal dosing of delayed release oral mesalamine
`(Asacol) and other 5-aminosalicylate-containing compounds
`according to disease severity and extent in patients with ac-
`tive ulcerative colitis has been a matter of debate. Our re-
`sults show that 4.8 g/day of mesalamine (800 mg tablet) is
`superior to Asacol 2.4 g/day (400 mg tablet) at 6 wk in the
`treatment of patients with moderately active ulcerative colitis.
`Patients who received 4.8 g/day ofmesalamine to treat moder-
`ate disease were 1.2 times more likely to experience overall
`
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`

`
`Delayed Release Oral Mesalamine (cid:9)
`
`2483
`
`I of patients improved
`
`Stool frequency
`
`Rectal bleeding
`
`PGA
`
`Sig moidoscopy score
`
`Clinical Assessment
`
`Figure 3. Clinical assessment findings at week 6;
`p = not significant for any treatment group comparisons.
`
`improvement (complete remission or clinical response) to
`treatment than those who received Asacol 2.4 g/day, with an
`absolute treatment difference of 13%. The time to resolution
`of rectal bleeding was also significantly shorter in patients
`who received 4.8 g/day of mesalamine. In contrast, patients
`with mildly active ulcerative colitis did not experience addi-
`tional benefit from receiving the higher 4.8 g/day dose. These
`data confirm the exploratory findings from a previous study
`(ASCEND I) in which the additive benefit of the 4.8 g/day
`of mesalamine was limited to the subgroup of patients with
`moderately active disease (data on file, Procter & Gamble
`Pharmaceuticals).
`The results of our study have implications for clinical prac-
`tice in patients treated with mesalamine. In the past, patients
`with mildly to moderately active ulcerative colitis were ini-
`tially treated with Asacol 2.4 g/day, and in many cases the
`dose was subsequently escalated up to a maximum of 4.8
`
`g/day if patients failed to respond after 4-6 wk of treatment.
`Based on the results of our study, we believe that clinical prac-
`tice should be altered such that patients with mildly active ul-
`cerative colitis are treated initially with Asacol 2.4 g/day and
`patients with moderately active ulcerative colitis are treated
`initially with 4.8 gidayofmesalamine using the 800 mg tablet.
`The American College of Gastroenterology practice guide-
`lines for the treatment of ulcerative colitis in adults define
`mildly active ulcerative colitis as less than four stools per
`day (with or without blood) and moderately active ulcerative
`colitis as greater than four stools per day and no evidence
`of systemic toxicity (2). This working definition of moder-
`ate disease activity tracks well to the disease activity of the
`patients in our study whom the investigators designated as
`having moderately active disease (PGA of 2), and should
`aid clinicians in applying the results of our study to clinical
`practice.
`
`Lan-sided. nelkin
`PICA,;i?'yng7i'aiti§; (cid:9)
`Extent .of Dteetie
`Figure 4. Overall improvement by extent of disease;
`p = not significant for any treatment group comparisons.
`
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`
`2484 (cid:9)
`
`Hanauer et al.
`
`Table 2. Median Time to Symptom Relief (Days)
`2.4 g/day
`4.8 g/day
`(N = 130)
`(N = 124)
`Median (n) Median (n)
`13.0 (111)
`10.0 (96)
`16.0 (103)
`9.0 (102)
`32.0 (95)
`21.0 (83)
`
`Symptom
`Stool frequency
`Rectal bleeding
`Stool frequency
`and rectal bleeding
`
`Log-Rank
`p Value
`0.2883
`0.0352
`0.1397
`
`Symptom relief was defined as a total resolution of the symptom t symptom score 0).
`Time to symptom relief was defined as the number of days between the first day of
`dosing and the first day of symptom relief.
`
`In our study, 79.5% of patients had disease limited to the
`left colon (proctitis, proctosigmoiditis, or left-sided colitis).
`The treatment response rates among patients with disease
`limited to the left colon in our study were high (60% for
`Asacol 2.4 g/day and 70-75% for 4.8 g/day of mesalamine),
`and were similar to the treatment response rates observed in
`patients with pan-colonic disease. These data support that
`Asacol is an effective therapy for patients with moderately
`ulcerative colitis limited to the left colon.
`A recent study reported that nonadherence to maintenance
`therapy with oral mesalamine occurs frequently in patients
`with ulcerative colitis in remission; taking multiple medica-
`tions and male gender were considered risk factors, whereas
`endoscopy within 24 months and being married were pro-
`tective factors (8). Another recent study demonstrated that
`patients with ulcerative colitis who were nonadherent to
`mesalamine therapy were at increased risk for treatment fail-
`ure (9). Finally, the same investigators demonstrated that
`once-daily dosing with oral mesalamine resulted in greater
`
`Table 3. Summary• of Adverse Events
`2.4 g/day
`(N = 139)
`n (%)
`49 (35.3)
`9 (6.5)
`7 (5.0)
`4 (2.9)
`3 (2.2)
`4 (2.9)
`5 (3.6)
`4 (2.9)
`7 (5.0)
`5 (3.6)
`5 (3.6)
`4 (2.9)
`1 (0.7)
`1 (0.7)
`3 (2.2)
`3 (2.2)
`3 (2.2)
`0 (0.0)
`
`COSTART Term
`Overall
`Headache
`Abdominal pain
`Diarrhea
`Infection
`Dyspepsia
`Flu syndrome
`Rectal disorder*
`Rhinitis
`Cough increased
`Flatulence
`Rash
`Colitis ulcer*
`Bronchitis
`Dizziness
`lever
`Nausea
`Proctitis*
`
`4.8 g/day
`(N = 129)
`n (%)
`57 (44.2)
`11 (8.5)
`6 (4.7)
`6 (4.7)
`7 (5.4)
`4 (3.1)
`3 (2.3)
`4 (3.1)
`0 (0.0)
`1 (0.8)
`1 (0.8)
`2 (1.6)
`4 (3.1)
`3 (2.3)
`1 (0.8)
`1 (0.8)
`1 (0.8)
`3 (2.3)
`
`Total
`(N = 268)
`n (%)
`106 (39.6)
`20 (7.5)
`13 (4.9)
`10 (3.7)
`10 (3.7)
`8 (3.0)
`8 (3.0)
`8 (3.0)
`7 (2.6)
`6 (2.2)
`6 (2.2)
`6 (2.2)
`5 (1.9)
`4 (1.5)
`4 (1.5)
`4 (1.5)
`4 (1.5)
`3 (1.1)
`
`Patients who experienced more than one adverse event within an adverse event term
`are counted only once within that term.
`*Most frequent responses for each COSTART term: rectal disorder = hemorrhoids;
`colitis ulcer worsening of ulcerative colitis symptoms; moctitis rectal irritation.
`
`adherence to maintenance therapy (10). These studies sug-
`gest that optimization of adherence is important to patient
`outcome. The novel 800 mg mesalamine tablet used in the
`ASCEND studies, when marketed, will allow for 4.8 g/day
`of mesalamine to be given in only six tablets per day.
`Both the 2.4 and 4.8 g/day doses were well tolerated by
`patients in our study, and there were no significant differ-
`ences in the rates of adverse events or changes in labora-
`tory values between the two treatment groups. These results
`confirm the results of other studies, which have shown that
`adverse events attributable to 5-aminosalicylate occur infre-
`quently in patients with inflammatory bowel disease treated
`with mesalamine, olsalazine, and balsalazide (11), and that
`the frequency of renal insufficiency in a large safety data base
`for Asacol (400 mg tablet) did not show evidence of dose-
`dependent nephrotoxicity (12). Our study also d