ORIGINAL ARTICLE
`
`Delayed-release oral mesalamine 4.8 g/day (800 mg
`tablets) compared with 2.4 g/day (400 mg tablets) for
`the treatment of mildly to moderately active
`ulcerative colitis: The ASCEND I trial
`
`Stephen B Hanauer MD1, William J Sandborn MD2, Christian Dallaire MD3, Andre Archambault MD4,
`Bruce Yacyshyn MD5, Chyon Yeh PhDs, Nancy Smith-Hall PharmD5
`
`SB Hanauer, WJ Sandborn, C Dallaire, et al. Delayed-
`release oral mesalamine 4.8 g/day (800 mg tablets) compared
`with 2.4 g/day (400 mg tablets) for the treatment of mildly to
`moderately active ulcerative colitis: The ASCEND I trial. Can
`J Gastroenterol 2007;21(12):827-834.
`
`BACKGROUND: Delayed-release oral mesalamine 2.4 g/day to
`4.8 g/day has been shown to be effective in treating mildly to moder-
`ately active ulcerative colitis (UC), but it is unknown whether an
`initial dose of 4.8 g/day is more effective than 2.4 g/day in patients
`with mildly to moderately active UC and in the subgroup with mod-
`erate disease.
`PATIENTS AND METHODS: A six-week, multicentre, random-
`ized, double-blind, controlled trial assessing the safety and clinical
`efficacy of a new dose (ASCEND I) of medication randomly
`assigned 301 adults with mildly to moderately active UC to delayed-
`release oral mesalamine 2.4 g/day (400 mg tablet In=1541) or
`4.8 g/day (800 mg tablet [n=1471). The primary efficacy end point
`was overall improvement (ie, treatment success), defined as complete
`remission or response to therapy from baseline to week 6. Primary
`safety end points were adverse events and laboratory• evaluations.
`Data were also analyzed separately for the prespecified subgroup of
`patients with moderate 1.3C at baseline.
`RESULTS: Treatment success was not statistically different between
`the treatment groups at week 6; 51% of the group (77 of 150) who
`received delayed-release oral mesalamine 2.4 g/day and 56% of the
`group (76 of 136) who received 4.8 g/day reached the efficacy end
`point (P=0.441). Among the moderate disease subgroup, however,
`the higher initial dose was more effective; 57% of patients (53 of 93)
`given delayed-release oral mesalamine 2.4 g/day and 72% of patients
`(55 of 76) given 4.8 g/day achieved treatment success (P=0.0384).
`Both regimens were well tolerated.
`CONCLUSIONS: Delayed-release oral mesalamine is an effective
`and well-tolerated initial therapy in patients with mildly to moder-
`ately active UC, and a 4.8 g/day dose may enhance treatment success
`rates in patients with moderate disease compared with mesalamine
`2.4 g/day.
`
`Key Words: Delayed release; Inflammatory bowel disease;
`Mesalamine; Ulcerative colitis
`
`La prise de 4,8 g/jour (comprimes de 800 mg) de
`mesalamine orate a liberation retard& par rapport
`a 2,4 g/jour (comprimes de 400 mg) pour le
`traitement de la colite ukereuse dont Pactivite
`est Legere a moderee : L'essai ASCEND I
`
`HISTORIQUE : La prise de 2,4 g/jour a 4,8 g/jour de mesalamine orate
`a liberation retard& est efficace dans le traitement de la colire ulcereuse
`(CU) dont Pactivite est Legere a moderee, mais on ne sait pas si une dose
`initiate de 4,8 g/jour est plus efficace qu'une dose de 2,4 g/jour chez ces
`patients ainsi que chez ceux dont la maladie est moderee.
`PATIENTS ET METHODOLOGIE : Dans le cadre d'un essai multi-
`centre aleatoire et connote a double insu de six semaines (ASCEND 1),
`on a reparti de maniere aleanoire 301 adultes atteints d'une colite
`ulcereuse dont Pactivire emir legere a moderee entre 2,4 g/jour (corn-
`primes de 400 mg, [n=1541) et 4,8 g/jour (comprimes de 800 mg, In-1471)
`de mesalamine orate a liberation retardee. Le prametre ultime d'effica-
`cite primaire etait Parnetioration globale (c'est-a-dire le succes du traite-
`ment), defini comme une remission ou une reponse complete au
`traitement entre le debut du traitement et la semaine 6. Les parametres
`ultitnes d'efficacite primaire etaient les reactions indesirables et les evalu-
`ations de laboratoire. Les donnees etaient egatement analysees separe-
`ment dans le sous-groupe de patients precises d'avance, dont Pactivite de
`la CU emir moderee au debut du traitement.
`RESULTATS Le. succes du traitement n'etait pas statistiquemenr signi-
`ficatif entre les grouper de traitement a la semaine 6; 51 % du groupe
`(77 sur 150) qui avaient recu 2,4 g/jour de mesalamine orale a liberation
`retard& et 56% du groupe (76 sur 136) qui en avaient rect.' 4,8 g/jour ont
`atteint le pararnetre ultime d'efficacite (P=0,441). Au sein du sous-groupe
`de maladie moderee, cependant, la dose initiate plus elevee etait plus effi-
`cace : 57 % des patients (53 sur 93) qui avaient recu 2,4 g/jour de
`mesalamine orate a liberation retard& et 72 % du groupe (55 sur 76) qui
`en avaient recu 4,8 g/jour ont profile du succes du traitement (P=0,0384).
`Les deux posologies etaient bien tolerees.
`CONCLUSIONS : La mesalamine orate a liberation retard& esr un
`traitement initial bien totere chez les patients atteints d'une UC dont
`Pactivite est legere a moderee, et une dose de mesalamine de 4,8 g/jour
`peut ameliorer les taux de reussite du traitement chez les patients atteints
`dune maladie moderee par rapport a ceux qui en prennent 2,4 g/jour.
`
`'University of Chicago School of Medicine, Chicago, Illinois; 2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota,
`USA; 3Universite Laval, Quebec; 4L1niversiti de Montreal, Montreal, Quebec; 5Procter 6 Gamble Pharmaceuticals, Mason, Ohio, USA.
`Originating institution: University of Chicago Medical Center
`Correspondence and reprints: Dr Bruce Yacyshyn, Proctor & Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, Ohio 45040,
`USA.
`Received for publication April 13, 2007. Accepted May .31. 2007
`
`Can J Gastroenterol Vol 21 No 12 December 2007 (cid:9)
`
`©2007 Pulsus Group Inc. All rights reserved
`
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`
`Hanauer et al
`
`Ulcerative colitis (UC) is a chronic inflammatory disorder
`
`of the colon of unknown etiology. It affects men and
`women equally, with an initial peak during the third decade of
`life, followed by a plateau and, possibly, a second peak in later
`years (1,2). UC is characterized by a continuous pattern of
`inflammation that may either be isolated to the rectum or
`extend proximally to involve the entire colon (3). Although
`the condition is chronic and medically incurable, alternating
`sporadic flares and intermittent periods of drug-induced or
`spontaneous remission, or quiescent disease, typify the clinical
`course of UC. The severity of UC, is classified as mild, moder-
`ate, severe or fulminant, based primarily on clinical symptoms.
`It is estimated that approximately 71% of patients present with
`moderately active UC, whereas 20% present with mildly
`active disease (2).
`Initial therapy for patients with mildly to moderately active
`UC typically consists of a 5-aminosalicylic acid (5-ASA) com-
`pound (3). Depending on the location and extent of disease,
`oral or rectal therapies may be used individually or in combina-
`tion. The clinical benefit tends to be dose related. The content
`and the formulation delivering 5-ASA to specific areas of the
`gastrointestinal tract differentiate the marketed, orally adminis-
`tered 5-ASA products, which include sulfasalazine,
`mesalamine, balsalazide and olsalazine. Drug release profiles
`reflect differences in drug delivery systems, such as p11-
`dependent release associated with a resin coating, timed-release
`or release of 5-ASA after splitting by bacterial enzymes (4-6).
`Delayed-release mesalamine is formulated with a Eudragit-S
`(Asacol, Procter & Gamble Pharmaceuticals, USA) acrylic-
`based resin coating that disintegrates at a pH of at least 7,
`delivering 5-ASA beginning at the terminal ileum and contin-
`uing throughout the colon (5,6). Clinical trials have demon-
`strated that delayed-release or sustained-release mesalamine, at
`doses of 2.0 g/day to 4.8 g/day, can effectively treat mildly to
`moderately active UC (7-9). In addition to the 400 mg
`delayed-release oral mesalamine (Asacol) tablet, an 800 mg
`tablet has now been approved in Canada, with which the
`treatment of moderately active UC can be initiated with
`delayed-release oral mesalamine at 4.8 g/day (10). Because
`patient choice and convenience are important factors in deter-
`mining patient satisfaction with a medication (11), an 800 mg
`tablet may provide a desirable alternative treatment option for
`some patients who are prescribed these higher doses.
`The vast majority of patients presenting with active UC
`have either mildly or moderately active disease, suggesting the
`use of an initial delayed-release oral mesalamine dose of
`2.4 g/day to 4.8 g/day (3,4). Previously conducted studies indi-
`cate that a delayed-release oral mesalamine dose of 2.4 g/day or
`higher would be effective in patients with mildly to moderately
`active disease. However, it was unknown whether initial ther-
`apy with mesalamine at a dose of 4.8 g/day would be more
`effective than a dose of 2.4 g/day in patients with mildly to
`moderately active UC or in the subgroup of patients with
`moderately active UC.
`Two clinical trials assessing the safety and clinical efficacy
`of a new dose (ASCEND) of .5-ASA (ASCEND I and 11) were
`conducted to evaluate the efficacy and safety of the new
`800 mg Asacol tablet in the treatment of active UC.
`ASCEND I, the results of which are presented here, was a ran-
`domized, double-blind, controlled trial comparing the efficacy
`and safety of Asacol 4.8 g/day (800 mg tablet) with that of
`Asacol 2.4 g/day (400 mg tablet) in patients with mildly to
`
`moderately active UC. The parallel ASCEND II trial primarily
`enrolled patients with moderately active UC to receive either
`Asacol 4.8 g/day (800 mg tablets) or Asacol 2.4 g/day (12).
`
`PATIENTS AND METHODS
`The present six-week multicentre, randomized, double-blind,
`active-controlled trial was conducted at 41 centres across
`Canada and the United States between February 2001 and
`November 2002. The trial enrolled patients with mildly to
`moderately active UC, either newly diagnosed or with a flare
`of previously diagnosed disease. The institutional review board
`or ethics committee at each site approved the protocol, and all
`patients gave written informed consent.
`
`Inclusion and exclusion criteria
`Eligibility criteria included age of 18 to 75 years; confirmed
`UC.: with disease extent (proctitis to pancolitis) confirmed by
`endoscopy or radiography within 24 months before the base-
`line visit; and mildly to moderately active disease at entry, with
`a physician's global assessment (PGA) score of 1 or 2 at base-
`line (7,8,12). Exclusion criteria included short bowel syn-
`drome; intolerance of or allergy to salicylates or 5-ASA
`compounds; current renal or hepatic disease; current alcohol or
`drug abuse; medical contraindication to study participation;
`blood urea nitrogen or serum creatinine more than 1.5 times
`the upper limit of normal; hepatic enzymes more than
`2.0 times the upper limits of normal; positive stool examina-
`tion for bacterial pathogens, ova and parasites, or Clostridium
`difficile; use of 5-ASA-containing products by any route from
`which a total dose of more than 1.6 g/day was available within
`seven days before screening; use of corticosteroids (oral, intra-
`venous, intramuscular or rectal) within one month before the
`baseline visit; use of any topical rectal therapy within one week
`before screening; use of immunomodulatory drugs within
`three months before the baseline visit; use of antibiotics (other
`than topical), nicotine patches, any product containing fish oils,
`acetylsalicylic acid (except for a canlioprotective dose of no
`more than 32.5 mg, or nonsteroidal anti-inflammatory drugs
`within one week before screening; use of antidiarrheal and/or
`antispasmodic medications after the screening visit; treatment
`with any experimental or investigational medication within
`one month before the baseline visit; and pregnancy or lactation.
`Prohibited medications during the study were acetylsalycilic
`acid (other than a maximum dose of 325 mg/day for cardiopro-
`tective reasons), nonsteroidal anti-inflammatory drugs, other
`mesalamine-containing products, corticosteroids, immunomod-
`ulatory agents, metronidazole; antibiotics (other than topical
`antibiotics) for more than 10 days throughout the study, topical
`rectal therapies, antidiarrheal and antispasmodic medications,
`nicotine patches, products containing fish oils, and any investi-
`gational or marketed drug that could interfere with evaluation
`of the study medication.
`Patients were screened according to inclusion and exclu-
`sion criteria within seven days before the baseline visit.
`
`Random assignment and blinding
`Eligible patients were randomly assigned at the baseline visit in
`a I:1 ratio at each site to receive either delayed-release oral
`mesalamine 2.4 g/day (400 mg Asacol tablet) or delayed-release
`oral mesalamine 4.8 g/day (investigational 800 mg Asacol
`tablet), and were monitored for six weeks. Permutated blocks of
`four were used to randomly assign treatments to patients. The
`
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`
`random assignment scheme was generated for each study centre.
`No demographic or baseline disease characteristics were used as
`stratification variables for random assignment.
`A double-blind study design was used, with both patients
`and investigators blinded to treatment assignment. Patients
`randomly assigned to delayed-release oral mesalamine
`2.4 g/day received two 400 mg tablets and two placebo tablets
`identical to the 800 mg tablets three times per day (morning,
`midday and evening), and patients randomly assigned to
`delayed-release oral mesalamine 4.8 g/day received two 800 mg
`tablets and two placebo tablets identical to the 400 mg tablets
`three times per day (morning, midday and evening).
`
`Participant flow and follow-up examinations
`Patients were assessed at study visits at baseline (week 0),
`week 3 and study completion (week 6). Sigmoidoscopy was
`performed at screening, and at weeks 3 and 6. Study partici-
`pants recorded data for stool frequency and rectal bleeding,
`and patient's functional assessment (PFA) was done by daily
`telephone contact with an integrated voice-response system.
`The investigator reviewed these data; assigned scores for each
`measurement determined during patient visits at weeks 0, 3
`and 6, and determined a PGA score based on those clinical
`scores, the sigmoidoscopy score, and the investigator's clinical
`judgment.
`Patients completed the 32-question Inflammatory Bowel
`Disease Questionnaire (IBDQ) at each visit, and total quality
`of life (QOL) scores and the four subcategory scores (bowel,
`systemic, social and emotional) were calculated at each visit.
`Medication compliance was assessed at weeks 3 and 6. Blood
`samples were obtained from each patient at weeks 0, 3 and 6 to
`estimate plasma 5-ASA and N-acetyl 5-ASA (N-Ac-5-ASA),
`its major metabolite.
`Adverse events and concomitant medications were also doc-
`umented, and samples were collected for laboratory evaluation
`at each visit. Safety evaluations included vital signs, physical
`examination, hematology, serum biochemistry and urinalysis.
`
`Analysis and statistical methods
`The primary efficacy end point was overall improvement at
`week 6 in patients with mildly to moderately active U(.1
`Secondary efficacy end points included the proportion of
`patients who improved from baseline at week 3 and the per-
`centage of patients whose clinical assessment scores (stool fre-
`quency, rectal bleeding, sigmoidoscopy scores, PFA scores and
`PGA scores) improved from baseline scores at weeks 3 and 6.
`Tertiary end points analyzed included improvement in QOL
`from baseline to weeks 3 and 6, and time to symptom relief
`(stool frequency, rectal bleeding or both). Primary safety end
`points included reported adverse events and clinical laboratory
`evaluations. The safety analysis included data for all randomly
`assigned patients. Efficacy and safety data were also analyzed
`separately for the prespecified subgroup of patients with mod-
`erately active UC (PGA=2) at baseline.
`Overall improvement or treatment success was defined as
`either complete remission or a clinical response to therapy.
`Complete remission was defined as normal stool frequency, no
`rectal bleeding, a PFA score of 0 (generally healthy), normal
`endoscopy findings and a PGA score of 0 (quiescent disease
`activity). A clinical response to therapy was defined as a
`decrease in the PGA score of at least one point from baseline,
`plus improvement in at least one other clinical assessment
`
`Can J Gastroenterol Vol 21 No 12 December 2007
`
`Asacol 4.8 g/day in ulcerative colitis
`
`parameter (stool frequency, rectal bleeding, PFA or
`endoscopy findings) and no worsening in any of the other
`clinical assessments.
`The PGA score was used to assess disease severity and effi-
`cacy. The PGA, a four-point score, was a composite of the
`scores used to assess stool frequency, rectal bleeding, PFA,
`endoscopic findings and the investigator's clinical judgment.
`The PGA score corresponded to quiescent (score 0),
`mild (score=l), moderate (score=2) or severe (score=3) dis-
`ease activity. The PGA score was used to classify the disease
`activity for all randomly assigned patients at baseline, week 3
`and week 6 to permit comparison of PGA scores between the
`two treatment groups. At baseline (ie, random assignment),
`there were no significant differences in PGA scores between
`the two treatment groups (P=0.3582) for all randomly assigned
`patients. A comparison of PGA scores was not possible for the
`moderately active disease subgroup, because all patients had a
`PGA score of 2; a statistical comparison would have been irrel-
`evant. The PFA was also rated on a four-point scale, indicating
`generally well (score=0) to terrible (score=3).
`Subgroup analyses were conducted for the primary efficacy
`end point of overall improvement using the intention-to-treat
`(ITT) population to evaluate the consistency of the effect of
`treatment across various patient populations. The association
`between treatment and outcome was examined for treatment
`effect and consistency of effect for demographic characteristics
`such as age, sex, ethnic background and smoking status; disease
`history, including extent of disease, length of disease history,
`hydrogen blocker and proton pump inhibitor use, prior UC
`medication use, sulfasalazine intolerance and relapse frequency;
`and baseline disease activity measures, including PGA, stool
`frequency, rectal bleeding, PFA and sigmoidoscopy scores.
`The primary efficacy ITT analysis was the primary analysis,
`and included all randomly assigned patients with mildly to
`moderately active disease who ingested at least one dose of drug
`and whose treatment outcome could be determined. The sensi-
`tivity analysis (week 6 outcome set to treatment failure or to
`last known outcome) included patients whose outcome at
`week 6 could not be determined and therefore were not
`included in the primary efficacy ITT analysis. Per-protocol
`analyses were also performed. Randomly assigned patients who
`completed the study were classified as either treatment suc-
`cesses (complete or partial improvement) or failures. Randomly
`assigned patients who withdrew due to adverse events or lack of
`treatment effect were classified as treatment failures. The x2
`test was used to determine the overall treatment effect, and
`95% CIs for treatment differences between the two groups were
`provided. Subgroup analyses of demographic characteristics,
`disease history and disease activity measures to assess the con-
`sistency of treatment effect were performed using the Cochran-
`Mantel-Haenszel x2 test. Changes from baseline in total and
`subcategory IBDQ scores for both treatment groups were ana-
`lyzed using the paired t test to examine the within-group treat-
`ment effect, and Wilcoxon's signed rank test was used to
`compare the between-group treatment effect.
`The sample size calculation was based on the assumption
`that the true rate of improvement was 40% for the group
`receiving delayed-release oral mesalamine 2.4 g/day and 60%
`for the group receiving delayed-release oral mesalamine
`4.8 g/day. To detect a 20% difference between these groups
`with 90% power, 280 patients with mildly to moderately active
`UC were required to complete the study.
`
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`
`Hanauer et al
`
`TABLE 1
`Baseline demographics and ulcerative colitis treatment
`history of all randomly assigned patients
`
`Delayed-release oral mesalamine dose
`
`Patients given
`2.4 glday (n-154)
`
`Patients given
`4.8 g/day (m147)
`
`Parameter
`
`P*
`
`43.5
`141
`13
`
`75
`79
`
`122
`18
`10
`4
`
`78
`66
`10
`
`51
`7
`57
`61
`67
`
`8
`49
`
`-
`91.6
`8.4
`
`48.7
`51.3
`
`79.2
`11.7
`6.5
`2.6
`
`50.6
`42.9
`6.5
`
`16.2
`29.2
`29.2
`25.3
`
`40.3
`16.2
`18.2
`24.7
`0.6
`
`33.1
`4.5
`37.0
`39.6
`43.5
`
`14.0
`86.0
`
`45.9
`133
`14
`
`80
`67
`
`116
`18
`9
`4
`
`69
`63
`15
`
`29
`38
`46
`34
`
`50
`40
`23
`33
`1
`
`43
`7
`43
`70
`60
`
`8
`35
`
`-
`90.5
`9.5
`
`54.4
`45 6
`
`78.9
`122
`6.1
`2.7
`
`46.9
`42.9
`10.2
`
`19.7
`25 9
`31.3
`23.1
`
`34.0
`27.2
`15 6
`22.4
`0.7
`
`29.3
`4.8
`29.3
`47.6
`40.8
`
`18.6
`81.4
`
`0.1237
`
`0.3209
`
`0 9873
`
`0.4822
`
`0.7824
`
`0.1430
`
`0.4695
`0.9290
`0.1530
`0.1612
`0.6366
`0.5372
`
`0.3979
`
`Mean age, years
`18-64
`65
`Sex
`Male
`Female
`Ethnic background
`Caucasian
`Black
`Hispanic
`Other
`Smoking history
`Never smoked
`Used to smoke
`Currently smoke
`Disease extent
`25
`Proctitis
`45
`Proctosigmoiditis
`45
`Left-sided colitis
`39
`Pancolitis
`Length of disease history, years
`<1
`62
`1-5
`25
`28
`>5-10
`>10
`38
`Unknown
`1
`Prior treatment
`Steroids (oral or IV)
`Immunomodulators
`Sulfasalazine
`Sulfa-free oral 5-ASAs
`Rectal therapy
`Intolerant to sulfasalazine
`Yes
`No
`Relapse frequency
`35.7
`29.3
`43
`55
`Newly diagnosed
`9.1
`More than once per month 14
`13.6
`20
`9.5
`13.0
`14
`Once every 6 months
`20
`21.8
`32
`16.9
`Once every 6-12 months 26
`25.9
`38
`25.3
`Less than once per year
`39
`*P value determined using X 2 test or t test, with significance defined as
`Ps-0.05. 5-ASA 5-aminosalicylic acid; IV Intravenous
`
`301 petlerde
`mndomked et week 0
`
`completed
`
`129 mmpl
`
`14; patiot, with hold 16
`m0001460 0150358 Milc0ro4.
`dolfii"O-rOleifiSO anti
`nuisnbarnme 4 8 Wow
`
`24 rotid,awalS
`Pr0100ol ohholpn. hoe
`MvileSei Owehlo. o-6
`Vokrce,y mIndrewak n.13
`inveallelor ..e.xpinmenoEdmn, n-2
`ach 01014,10. nr.7
`
`154 peewits wen 011164o-
`moderate deeeee rerelamked
`to delewel-releeee oral
`meseirmine 2.4 pnley
`
`21 wIlhdrewels.
`Protocol NoletIon. n.1
`&Wenn went% 0=8
`Vountery (cid:9)
`r02
`i.woeftetor recommendation, 0-2
`Lack of el st n-6
`
`4 pedants not
`enelyzeble et
`week 6
`
`150 patients
`welyzeble ot
`week 6
`
`136p Pelts
`enew.aole 01
`week 6
`
`11 hatient,
`anolyzateo
`Male 6
`
`286 pet•ents
`Iwailahle for
`onalySiS (ITT!
`
`Figure 1) Patient disposition. Patients who could not be analyzed at
`week 6 included those who completed week 6 but were missing at least
`one symptom score (one patient in each treatment group), and patients
`who did not complete the study due to voluntary withdrawal
`(two patients in the 2.4 g/day delayed-release oral mesalamine group
`and six patients in the 4.8 g/day group) or to protocol deviations
`(one patient in the 2.4 g/day delayed-release oral mesalamine group
`and four patients in the 4.8 g/day group). ITT Intention-to-treat
`
`in Figure 1. The primary efficacy ITT analysis included
`150 patients assigned to delayed-release oral mesalamine
`2.4 g/day and 136 patients assigned to delayed-release oral
`mesalamine 4.8 g/day. Patients who were not analyzed at week 6
`included those who completed the study but were missing at
`least one symptom score, as well as those who did not complete
`the study due to voluntary withdrawal or protocol deviation.
`
`Efficacy outcomes: All patients
`The ITT analysis for the primary end point indicated that the
`percentage of patients with mildly to moderately active UC
`and treatment success at six weeks was not statistically differ-
`ent between the two treatment groups (Figure 2). At week 6,
`51% of the group (77 of 150) receiving delayed-release oral
`mesalamine 2.4 g/day and 56% of the group (76 of 136) receiv-
`ing delayed-release oral mesalamine 4.8 g/day experienced
`overall improvement (P=0.441), and at week 3, 42%
`(63 of 150) and 39% (53 of 137) of these groups, respectively,
`experienced overall improvement (P=0.5677). Sensitivity
`analyses using missing outcomes set to treatment failure and
`last observation carried forward found no statistical differences
`in treatment outcomes between the groups receiving delayed-
`release oral mesalamine 2.4 g/day and 4.8 g/day.
`Among patients who were considered to have treatment
`success, a greater number of patients in the delayed-release oral
`mesalamine 4.8 g/day group (35 of 76, 46%) had a complete
`response than in the delayed-release oral mesalamine 2.4 g/day
`group (30 of 77, 38%). However, the differences in the sec-
`ondary end points of PGA, stool frequency, rectal bleeding,
`PFA and sigmoidoscopy scores were not significantly different
`between the groups at weeks 3 or 6.
`The median time for patients to return to normal stool fre-
`quency and for rectal bleeding to resolve was not statistically
`different between the treatment groups. However, the median
`time for both clinical assessments (ie, rectal bleeding and stool
`frequency) to resolve and return to normal was shorter in the
`
`RESULTS
`
`Patient characteristics
`A total of 301 patients were studied, with 154 randomly assigned
`to delayed-release oral mesalamine 2.4 g/day and 147 randomly
`assigned to delayed-release oral mesalamine 4.8 g/day. Baseline
`patient characteristics were similar between the two treatment
`groups (Table 1). An overview of patient disposition is provided
`
`830
`
`Can J Gastroenterol Vol 21 No 12 December 2007
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`Asacol 4.8 g/day in ulcerative colitis
`
`Figure 2) Asacol (Proctor & Gamble Pharmaceuticals, USA) treat-
`ment outcomes at weeks 3 and 6 in all patients with mildly to moder-
`ately active ulcerative colitis
`
`patients who received delayed-release oral mesalamine
`4.8 g/day (for 15 days) than in patients who received delayed-
`release oral mesalamine 2.4 g/day (for 24 days) (P=0.0719).
`The total IBDQ scores and all subcategory scores for
`patients with mildly to moderately active UC improved signif-
`icantly from baseline to weeks 3 and 6 in both treatment
`groups. The total IBDQ score and all subcategory scores, with
`the exception of social score, showed a statistically greater
`improvement among patients who received delayed-release
`oral mesalamine 4.8 g/day than among those who received
`delayed-release oral mesalamine 2.4 g/day (Figure 3).
`An analysis of outcomes by demographic, disease history
`and disease extent variables identified homogenous treatment
`effects for all subgroup variables except baseline disease sever-
`ity, prior use of corticosteroids, extent of disease, stool fre-
`quency score and PFA score. For these subgroup parameters,
`the treatment effects suggested that patients with more severe
`disease may have responded better than patients with less
`severe disease. Patients who had used steroids previously had a
`higher response rate than those who had not. The rates of
`overall improvement in patients with disease extent limited to
`the left colon (including proctitis, proctosigmoiditis and left-
`sided colitis) and those with pancolonic involvement were
`greater at week 6 in those who received delayed-release oral
`mesalamine 4.8 g/day than in those who received delayed-
`release oral mesalamine 2.4 g/day, but these differences were
`not significant. In all subgroup variables analyzed, patients who
`received delayed-release oral mesalamine 4.8 g/day showed a
`trend toward greater overall improvement than patients who
`received delayed-release oral mesalamine 2.4 g/day. The per-
`protocol primary efficacy analysis was not statistically signifi-
`cant, although the per-protocol rectal bleeding score, a
`secondary efficacy outcome, was statistically significant.
`
`Efficacy outcomes: Moderate disease subgroup
`Across the study population at baseline, 121 patients had mildly
`active (PGA=1) and 180 patients had moderately active
`(PGA=2) disease. The primary efficacy analysis for the moder-
`ately active subgroup included 96 patients who received
`delayed-release oral mesalamine 2.4 g/day and 84 patients who
`received delayed-release oral mesalamine 4.8 g/day. Baseline
`patient characteristics in the moderately active disease subgroup
`were similar in both treatment groups (Table 2). Premature
`withdrawals in the moderate disease subgroup were primarily
`due to a lack of treatment effect or to adverse events; those
`included 18 patients (19%) who received delayed-release oral
`mesalamine 2.4 g/day and 17 patients (20%) who received
`delayed-release oral mesalamine 4.8 g/day.
`
`Can J Gastroenterol Vol 21 No 12 December 2007
`
`Figure 3) The total Inflammatory Bowel Disease Questionnaire
`(IBDQ) scores and all subcategory scores for patients with mildly to
`moderately active ulcerative colitis improved significantly from baseline
`to weeks 3 and 6 in both treatment groups (Asacol, Proctor & Gamble
`Pharmaceuticals, USA). *Significant difference in the between-
`treatment comparison using Wilcoxon's signed rank test (Psi) .05)
`
`At week 6, 57% of patients (53 of 93) who received
`delayed-release oral mesalamine 2.4 g/day and 72% of patients
`(55 of 76) who received delayed-release oral mesalamine
`4.8 g/day achieved overall improvement (Figure 4). The differ-
`ence in overall improvement was 15% (95% CI 1.16% to
`29.6%, P=0.0384). Improvement in individual clinical assess-
`ments was greater at weeks 3 and 6 in the group who received
`delayed-release oral mesalamine 4.8 g/day, but most differences
`were not significant. However, the PGA and sigmoidoscopy
`scores improved significantly at week 6 in the 4.8 g/day group
`compared with the 2.4 g/day group. Analysis of outcomes by
`extent of disease demonstrated comparable treatment effects
`regardless of the extent of disease.
`Although not statistically significant, the median time for
`rectal bleeding to resolve in patients with moderate disease was
`shorter in the group that received delayed-release oral
`mesalamine 4.8 g/day (for nine days) than in the group that
`received delayed-release oral mesalamine 2.4 g/day (for 13 days)
`(P=0.0930). The median times to symptom resolution (stool
`frequency, rectal bleeding and both) are shown in Table 3.
`The improvement in IBDQ scores was statistically signifi-
`cant (Figure 5). At week 3, the change in total IBDQ score was
`in favour of the delayed-release oral mesalamine 4.8 g/day
`group (P=0.0.519). A statistically significant improvement in
`bowel (P=0.0167) and systemic (P=0.0450) subscores was seen
`in the delayed-release oral mesalamine 4.8 g/day treatment
`group. At week 6, statistically significant improvements from
`baseline were seen in the total IBDQ score and in all subcate-
`gory scores in both treatment groups (P<0.0001), and signifi-
`cantly greater improvements in the total score (P=0.0336) and
`bowel subcategory score were seen at week 6 in the group that
`received delayed-release oral mesalamine 4.8 g/day than in the
`group that received delayed-release oral mesalamine 2.4 g/day.
`
`Safety outcomes: All patients
`The incidence of adverse events was similar in both treatment
`groups, as were the most frequently reported adverse events
`(Table 4). Eight patients (5%) in the 2.4 g/day treatment group
`and five patients (3%) in the 4.8 g/day treatment group discon-
`tinued treatment because of an adverse event. Serious adverse
`events occurred in three patients (2%) in the delayed-release
`oral mesalamine 2.4 g/day group and one patient ( I%) in the
`4.8 g/day group; all four patients had moderately active UC at
`
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`Hanauer et al
`
`TABLE 2
`Baseline demographics and ulcerative colitis treatment
`history of patients with moderately active ulcerative colitis
`Delayed-release oral mesalamine dose
`
`Patients given
`2.4 g/day (nm96)
`
`Patients given
`4.8 g/day (n=84)
`
`Parameter
`
`n
`
`%
`
`n
`
`%
`
`P*
`
`43.0
`88