`
`Exhibit 1004
`
`Stephen Hanauer et al., Mesalamine
`Capsules for Treatment of Active Ulcerative
`Colitis: results of A Controlled Trial, 88
`AMERICAN J. GASTROENTEROLOGY 1188
`(1993) (“Hanauer”)
`
`

`
`
`
`UU(l2-927i}/93/3308-I133303.00,/Cl
`Tm: A.‘-1l;'Rlf‘!\.\'
`.l0l.‘R.\’Al. or GA5TR(lEN"l‘ER(ll.0(.iY
`Copyright-tr I993 by Am. Coll. of Gastroenterology
`
`V I 3
`ofingigiihsiliglii
`" "\-
`
`Mesalamine Capsules for Treatment of Active Ulcerative
`Colitis: Results of a Controlled Trial
`
`Stephen Hanauer, M.D., Jerrold Schwartz, M.D., Malcolm Robinson, M.D., Walter Roufail, M.D.,
`Sanjeev Arora, M.D., John Cello, M.D., Michael Safdi. M.D., and the Pentasa“ Study Group
`Um'ver.riiy ofCliicago Sclrool ofMedicine, Chicago, Illinois: i\i'or'iliii'e.s'I Urixii-omrrfriilris:i.s'i.s'.
`:ll‘ll.'i‘t.'{lriil iii’i_r,rlri.r. llliiioir; Hfii
`Prcarbvierian Hospital, Oklahoma City, Oklahoma,‘ Forsyilr Meclicul S[J(’r'iali.\'i.s’_ H riixinir-.S'irlciii. Jorrlr ( rrrr_iliira; i\‘€’lt‘l;'.'1gl(1i1rl
`i
`Medical Center, Boston, Mas'.raclttt.relt.s.' San Frrrriciscv G(’li'£’l'(l'l llo.rpii(il_ Sim 1-'i‘rriii'i.s‘m. ('rilrloririu.'
`Greater Cincinnati Gasirowirei-oliig_ii .4.s'.s'r;ciirit'.r. ('inr'iimr.rii', ()liiu
`
`The efficacy of a capsule formulation of mesalamine
`was assessed in 374 patients with mild to moderately
`active ulcerative colitis. Patients, Stratified to pancolitis
`or |eft-§ided disease, received either placebo or mc5a—
`iamine at 1, 2, 01- 4 g daily fo; 3 wk_ Efficacy was
`assessed using clinical improvement—physician global
`assessment, sigmoidoscopic index, biopsy score, trips
`to the toilet, and clinical symptoms (abdominal pain,
`urgency, stool consistency, and rectal bleeding)—and
`intilletiell Of Femi55i0fl (mete stringent etitetia i0i' Pill"
`Sieititi gi0i33i assessments Sigm0iti0Se0Die index. anti
`biopsy 5°°i'°)- F91’ Piwsiciaii gioiiai 3ssessmei1t0iti'e3t'
`meilt benefit» 79% and 34% Oi Patients 011 tile 2'3 anti
`4'8 ti0SeS 0f mesfiiaminei l'eSl1eetiVei¥, l‘eeeiVed tFeflt-
`"lent benefits eemllateti With 54% 011 lJi3eei30 (P E
`0.0002). For the physician global assessment of treat-
`ment success, both the 2-g and 4-g doses of mesalamine
`were s“Del'i0T t0 Piaeeim (57% and 59% 0f patients,
`P = 0-0021 and 0-0012, respectively), compared with
`36% on placebo. Both the 2-g and 4-g doses produced
`statistically significant macroscopic (endoscopic) im-
`provement compared with placebo (p < 0.004). The 4-
`g dose also produced a statistically significant micro-
`scopic (histologic) improvement compared to placebo
`( p < 0.002). Significant improvement compared to pia-
`eebo “'35 sis“ °i35e"’ed at 2 E and 4 g for the four
`clinical symptoms and trips to the toilet (p 5 0.003),
`Oral mesalamine capsules were significantly Superior
`to placebo for inducing remission, with 29% of patients
`at 2 g and 29% at 4 g achieving remission by physician
`global assessment, compared with 12% on placebo.
`Forty-four percent and 48% of patients receiving 2 g
`and 4 g of mesalamine, respectively, achieved remission
`by sigmoidoscopic index (p < 0.05), compared with
`31% on placebo. Thirty-nine percent of patients at 4 g
`daily achieved microscopic remission, compared with
`23% on placebo (p < 0.03). Treatment response was
`not affected by extent of disease or prior steroid or
`Received Sept. 17, I992; accepted Feb. 15, I993.
`
`that CO"-
`Sflifflsaiillifle tilet3P3'- iii“-‘Se tiatii suggest
`trolled-release mesalamine capsules are a safe and el-
`fective monotlicrapr in doses of 2-4 g daily for treating
`I0 IIl0d(.‘l":llL‘l)' active ulcerative colitis, 35 well 25
`for inducing remission, regardless of prior oral steroid
`01' Slliiasiliiiliiie ti"-‘W133’ 01' extent 0t disease»
`
`-.
`,
`IN FRODUCHON
`Since its introduction over 40 vr ago, sulfasalazine
`has become the most widely prcsciibed medication for
`the treatment of inflammatory bowel disease. specifi-
`cally ulcerativc colitis (UC). Oral sulfasalazine has been
`demonstrated (using various criteria) to be effective for
`the treatment of mild-to-moderate UC and for the
`maintenance of‘ remission (1). When administered in
`oral doses of 4-6 g daily for up to 1 month. oral
`sulfasalazine has been reported to induce remission in
`35-80% of patients. depending on duration of therapy.
`dose. and the endpoints used to determine.efficae_v fi-
`5). This is twice the spontaneous remission rate ob-
`served in the placebo groups (I-3).
`Just as there is a dose-dependent response rate. there
`is also a dose-—dcpendent rate of adverse effects which
`limit the acute and chronic use of sulfasalazine. Com-
`mon adverse effects include nausea and headachefi-it
`7). Historically (in 20 UC trials) adverse effects hare
`been noted in 13-60% of patients (4). Sperm abnor-
`maiiiiesh in Particular, can be documented in 309? 0i
`miiies taking sulfasalazine (1. 8-15). Less common and
`more severe adverse effects include hemolytic anemia.
`“Ci-iti'0DeniE1. hepatitis. pancreatitis. and worsening of
`C0iitiS (1). Most of the serious comp1ications_.excePti°i
`mi‘? C3535 of P'=i“Cte3tititS- PeI'iC8FCiitiS- OT W°i5e“i“g (if
`C‘:-’hti5 (acme itit0ie1'anC€).
`are related to the 5ltii3Pi'”'
`d”_“3 iT10ieIy. All except for the last complication. WOTS‘
`enmg of C°iiii5- are Side effects that have been related
`to the Suifapyridins m0iet1v'-
`Sulfasalazine is composed of sulfapyridine and 11365‘
`aiamitie (5—aminosalicylic acid) linked by an azo bond-
`
`I E88
`
`
`
`MvcoNovo. Inc. Foxhill Oooortunitv Fund. L.P. Ex 1004
`
`

`
`f
`
`Augtlsf 1993
`
`MESALAMINE CAPSULES FOR TREATMENT OF ACUTE UC
`
`H89
`
`
`u—?-——-_-_—-_—..._:_....._._.__.
`—..._.j...j_.-.j..__
`
`This bond is metabolized by colonic bacteria. causing
`the release of the mesalamine and sulfapyridine mole-
`cules(l6-l8). In 1977'. Azad Khan 01 at’. (16) demon-
`strated definitively that mesalamine was a therapeuti-
`cally active moiety of sulfasalazine. This discovery led
`to the development of mesalamine formulations or
`delivery systems used for both UC and Crohn‘s disease_
`These delivery systems include an enema formula-
`tion that has been shown to be effective in the treatment
`of distal UC (19). Although effective in the treatment
`of active distal disease, the enema formulation of mes-
`alamine does not benefit most patients with disease
`proximal to the splenic llexure (20). Oral administra-
`tion of mesalamine is limited by absorption in the
`proximal small bowel. necessitating protected delivery
`systems for distribution to distal sites of enterocolonic
`inflammation (21 ).
`In general. two types of agents have evolved to give
`delayed. targeted delivery of mesalamine to the small
`bowel and/or colon: a2.o—bond prodrugs and nonlinked
`agents. Prodrugs. such as olsalazine (Dipcntum), join
`two mesalamine molecules with an azo bond and re-
`
`quire azo-reductase to release active drug in the colon.
`To date. two types of nonlinked agents have evolved:
`1) delayed-release formulations consist ofacrylic-based
`resin-coated mesalamine that dissolves at a pH greater
`than 7. releasing active drug in the distal ileum and
`colon (20. 21): and 2) a slow-release. capsule formula-
`tion encapsulates mesalamine in ethyleellulose-coated
`beads and delivers active drug continuously to the small
`and large bowel, independent of intestinal pH (22, 23).
`This trial was developed through the collaborative
`efforts of an international group of clinicians to provide
`clinically appropriate criteria for subjective and objec-
`tive assessment of mesalamine efficacy and safety in
`UC. This study assessed a controlled— release, capsule
`formulation of oral mesalamine (Pentasa. Marion Mer-
`rell Dow lnc.. Kansas City, M0) for the treatment of
`and induction of remission in patients with mildly to
`moderately active UC.
`
`MATERIALS AND METHODS
`
`Each study site received individual Institutional Re-
`view Board approval, and all patients gave Written
`informed consent.
`
`4-
`
`Patient selection
`Patients over the age of 18 yr. with mildly to mod-
`mteiy active UC. were selected for entry into this trial
`between March 6, 1987. and August 4. 1988. Patients
`were included if they had a diagnosis of UC and the
`presence of active disease confirmed by both clinical
`5)/Tiilltoms and colonoscopic evidence of active inflam-
`mation of 5 or more on a 15-point index scale. Patients
`were stratified based on extent of disease. Patients With
`
`disease distal to the splenic llexure were considered to
`have‘left—sided involvement, whereas those with disease
`proximal to the splenic flexure were classified as having
`pancolitis.
`
`Continuation of therapy with steroids, sulfasalazine,
`or other mesalamine formulations was not allowed
`during participation in this trial. Prior use of steroid,
`sulfasalazine, or other mesalamine formulations re-
`quired a 7-day “washout” prior to baseline evaluations.
`Prior use of an immunosuppressive agent required a
`90-day washout. Positive stool culture for enteric path-
`ogens. the presence of fecal ova and parasites, or Clos-
`tridirrm drflicile toxin were also exclusion criteria. In
`addition, medications known to have a therapeutic
`effect (sulfasalazinc, topical mesalamine, or any corti-
`costeroids), mask symptoms (antispasmodics, antidi-
`arrheals except loperamide), change absorption (choles-
`tyramine). or possibly worsen the disease (antibiotics,
`NSAIDS) were prohibited during the trial. Female pa-
`tients were required to be taking a medically prescribed
`form of birth control throughout the trial or to not be
`of child-bearing potential. Pregnant or lactating females
`were also excluded from participation.
`
`SIua'_t»' design
`This was a multicenter, double-blind, placebo-con-
`trolled. parallel, dose-response trial. At 20 study sites,
`patients were stratified by disease location, pancolitis
`or left-sided disease, and were randomized to receive
`either placebo or mesalamine at 1, 2, or 4 g daily for 8
`wk.
`
`Study drug administration
`Patients meeting the admission criteria were ran-
`domly assigned to one of four treatment regimens:
`placebo or 1 g, 2 g, or 4 g of oral mesalamine daily.
`Study drug was supplied in 250-mg capsules in identical
`blister cards to ensure blinding of both the investigator
`and the patient. Mesalarnine 1 g daily was administered
`as one active and three placebo capsules, qid; mesalam-
`ine 2 g daily as two active and two placebo capsules,
`qid; and mesalamine 4 g daily as four active capsules.
`qid. Placebo was administered as four placebo capsules,
`gin’. Dosing was continued for the entire 8-wl< study.
`Loperamide (2 mg) was dispensed to patients only
`when absolutely necessary for Control Of diarrhea-
`
`Evaluation methods and schedtifing
`Physician global assessment (PGA) is an arbitrarily
`designed, multicomponent measure of disease activity
`that uses the phvsician’s assessment of improvement or
`worsening in clinical status based on disease activity
`and symptom severity as compared to baseline. PGA
`was evaluated by the physician at weeks I. 4. and 8. 01'
`upon withdrawal using six categories, as shown in
`Table l.
`
`L...“
`
`

`
`
`
`1190
`
`HANAUER at at’.
`
`TABLE 1
`
`P}1_1‘.rlr'imr Global .~1s5es.mrem Scale
`
`1 = Complete relief of symptoms
`2 = Marked improvement of symptoms
`3 = Moderate improvement of symptoms
`4 2* Slight improvement of symptoms
`5 = No change in symptoms
`6 = Worsening of symptoms
`
`A baseline colonoscopy documented the linear extent
`and severity of proctocolonic inflammation. Sigmoid-
`oscopic or proctoseopic evaluations were also per-
`formed at weeks 1, 4, and 8, or upon withdrawal from
`the study. All endoscopic evaluations were documented
`in the most severe area of disease involvement located
`5-15 cm from the anal verge. The evaluations focused
`on the presence and severity of erythema, friability,
`granularity/ulceration. mucopus, and the appearance
`of mucosal vascular pattern. Each of these five cate-
`gories was assigned a value from 0 to 3 (0 = normal,
`1
`= mild, 2 = moderate, and 3 = severe), and the five
`scores were totaled to produce an index score of 0-15
`(with a maximum severity score of 15). Changes in
`sigmoidoscopic index were computed as the last avail-
`able sigmoidoscopic score minus baseline.
`A treatment failure assessment was an additional
`
`efficacy parameter used not only to allow patients to
`withdraw from the trial if they were not receiving
`therapeutic benefit. but also to compare the percent of
`patients in each treatment group that were not receiving
`therapeutic benefit. This assessment was made to iden-
`tify a worsening of disease at 7 days or greater. post
`baseline. A patient with an increase of 5 points in the
`sigmoidoscopic index, a worsening or no improvement
`in daily trips to the toilet. and a worsening or no
`improvement in any symptoms would be classified as
`a "treatment failure” and could be removed from the
`
`In addition, patients could leave the study as
`trial.
`treatment failures at or after 14 days if there was no
`improvement in the sigmoidoscopic index and patient
`symptoms. Although treatment failure was utilized dur.
`ing the trial to allow patients to withdraw if they were
`not receiving therapeutic benefit. categorization as a
`treatment failure was independent from withdrawal or
`reasons for withdrawal from the trial.
`
`Biopsies, taken at the area representative of disease
`activity from 5 cm to 15 cm from the anal verge, were
`collected at baseline and at week 8 or upon withdrawal
`(endpoint). Histological changes were identified by a
`central reference pathologist, using a 4-point categorical
`scale (0 = normal colonic mucosa through 3 = high
`grade, active inflammatory bowel disease).
`A baseline assessment of four clinical Symptoms and
`daily trips to the toilet (any attempt at a bowel move-
`ment) was collected at the baseline visit through conab-
`oration between the investigator and the patient_
`
`Vol. 88, No. 8, 1993
`
`Patients then recorded their impressions of symptom
`severity weekly throughout the trial. Symptoms. includ.
`ing stool consistency. rectal bleeding. abdominal/rectal
`pain. and urgency. were recorded using a horizontal
`visual analog scale with a possible rating of0 (absence
`of symptoms) to 10 (symptoms as severe as possible).
`Daily trips to the toilet were recorded by patients in a
`diary at baseline and throughout the trial. Mean daily
`trips were computed for the patient at endpoint. using
`a weekly mean of the patient‘s daily trips to the toilet.
`Physical examinations and evaluation of adverse ef-
`fect rcports were also conducted at each visit. Clinical
`laboratory assessments were collected at baseline and
`at endpoint.
`
`l;_'_[l'.?t'Lrt'_t' ]J£H'£lHi't’l(’l".$'
`
`To establish ellicacy. two broad criteria were used:
`clinical improvement and induction of remission. Clin-
`ical improvement was asscsscd using PGA. assessment
`of treatment
`failure.
`sigmoidoscopic index. biopsy
`score. patient perceptions of severity of the four clinical
`symptoms, and trips to the toilet. Induction of remis-
`sion was assessed by more stringent criteria for PGA.
`sigmoidoscopic index. and biopsy score.
`C‘i’r'r1.r'cai’
`r'r27,r)r‘r)vrwrerrI. For PGA.
`two assessments
`(treatment success and treatment benefit) were used.
`Treatment success was defined by an assessment at
`endpoint of those patients who had complete relief of
`symptoms (category 1) or marked improvement of
`symptoms (category 2) only. Treatment benefit was
`defined as any improvement at endpoint over baseline.
`including patients in categories 1 and 2. as well as those
`with moderate improvement (category 3) and slight
`improvement (category 4). Efficacy for treatment fail-
`ure was the opposite of therapeutic success. and was
`determined by assessing the percentage of patienls
`meeting the treatment failure criteria. Efficacy for sig-
`moidoscopic index was determined using mean change
`from baseline to endpoint on a 15-point scale. For
`biopsy score analysis. patients were classified as either
`improved (decrease of at least one category from base-
`line to last available record) or not improved (no change
`or an increase in category). Efficacy for the four clinical
`symptoms and trips to the toilet was assessed usins
`mean change from baseline to endpoint.
`Indrrctiorr of reim'ssr'on. Induction of remission W35
`assessed individually for PGA. sigmoidoscopic index-
`and biopsy score at final visit using stringent criteria: 3
`rating Of Category 1 (complete relief of symptoms) 01113’
`for PGA~ 3 grade of 0 to 4 points (out of a maximum
`Of 15) On the sigmoidoscopic index, or a grade of0 E0
`1 0“ bi0DSY Sf-‘Ore (thought to indicate clinically normal
`mucosa or inactive UC) with a minimum of?! We‘
`grade decrease from baseline to final visit.
`
`
`
`_. «s «:5
`
`

`
`<—7
`
`.i£t'R1(.S'i’ 1993
`
`MESALAMINE C“
`
`APSULES FOR TREATMENT or ACUTE UC
`
`1191
`
`.Si'titi'.i‘!i‘t'.:il nit'!iiou'i
`
`Trial size was specilied before the trial began as 70
`patients per treatment group. which was approximately
`the mean of sample sizes calculated for four of the
`response variables. The estimated sample sizes for the
`fourt-aiiables ranged from 23 to 100 patients per group
`for st)“; power to detect dilTerences between mcgalam-
`me and placebo using two-sided statistical tests at (Y =
`(1.03.
`
`-\l| randomized patients Va ho ingested study medi-
`cation were included in the analysis. I-Indpoints were
`assigned according to the intention-to-treat principle.
`using the last obsersation carried forward. lmputation
`was emp|o_\ed for data missing at baseline or endpoint.
`Baseline C0t‘l'It‘I;Ir1ll‘Iill1) across treatment groups was
`tested by the l\'ruslsal—\\'allis test (continuous factors)
`and the if test (categorical tiictors).
`Continuous response \;u'iables were anal_\i7_ed using
`analysis ttiiL‘t)\;1Fl;lllL‘L‘. ('liange from baseline was ana-
`lired. adjusting tor baseline and center. The rank trans-
`formation was employ ed when there was evidence that
`the data were not normall_v distributed (24).
`Diehotomous
`response sariablcs (two categories)
`were analyzed using logistic regression. adjusting for
`baseline (when a baseline existed) and center.
`All statistical
`tests were two-sided.
`In addition to
`
`testing dillcrenccs between placebo and each treatment
`group. a three-dose linear trend test using orthogonal
`contrasts was emplo_\ed to determine whether there was
`an increasing response with increasing dose for the 1hF€€
`mesalamine treatment groups (35)-
`Scven of the 20 sites enrolled l() or fewer I33ti5‘1“5-
`Before the study was unblinded. five sites were I300l€d
`into one group and two sites were combined into an-
`other group for purposes of statistical analysis. The
`other 13 sites enrolled between 15 and 44 I33tlf—‘m5-
`
`RESULTS
`
`B£i‘.\'£’l'l‘i‘t(’ dmttigrupfritw
`Baseline demographic characteristics for the 374 pa-
`tients who were randomized and received drug are
`shown in Table 2 and did not ditTer significantly among
`
`treatment groups.
`
`Earl)’ di.§('(HIIl}IIl{l!f()Il of AI}l(’i“£!}'1'_1'
`the trial
`__
`The number of patients withdrawing from
`Drematurely was significantly smaller in the 2-g (P T
`0-008) and the 4-g treatment groups (iv = 0.002) tharlic
`in the placebo treatment group (Fig l)- The number 0
`from the trial
`patients from the 1-g group withdrawing
`t number 111
`Drematurely (23/92) was smaller than tha
`11
`ll‘? Placebo group (30/90):
`the difference across 3
`treatments was statistically significanl (P = 0005)’
`
`Ci’i'm'::'al improvement
`Ph_vsic'ian glribal assessment. For the PGA assess-
`ment
`that measured treatment benefit, 71% (p =
`0.0191), 79% (p = 0.0002), and 84% (p < 0.0001) of
`patients, respectively, on the 1-g, 2-g, and 4-g doses
`were assessed by the physician to have received treat-
`ment benefit, compared to 54% on placebo. A three-
`dose trend across the three active mesalamine doses
`was also significant [p = 0.0267 (Fig. 2)].
`For the PGA assessment that measured treatment
`success, both the 2- and 4-g doses of mesalamine were
`significantly superior to placebo. with 57% ( p = 0.0021)
`and 59% (p = 0.0012) of patients, respectively, achiev-
`ing complete relief or marked improvement of symp-
`toms, in contrast to 36% on placebo. Treatment success
`was achieved in 45% of patients receiving the 1-g dose.
`which was not significantly different from placebo
`( 1) = 0.1681). However, a three-dose trend across the
`three mesalamine doses was marginally significant [p =
`0.0610 (Fig. 2)].
`Sigmriidoscopic index. Mean change in sigmoido-
`scopic index was statistically significant for the 2-g and
`4-g closes with mean respective decreases (improve-
`ment) of 4.3 and 5.0, in contrast to a 25-point decrease
`with placebo [17 = 0.0033 and 0.0001.
`respectively
`(Table 3)]. For the 1-g treatment group.
`the mean
`change in the sigmoidoscopic index (3.4) was not sig-
`nificantly different than placebo (p = 0.1600). Regard-
`less. a significant dose-response relationship was de-
`tected across the three active mesalamine doses (,0 =
`0.0108), indicating a trend for improvement with an
`increase in mesalamine dose.
`_
`_
`Treatment_f21ilure. Nine percent of patients in the 4-
`g treatment group were classified as treatment failures
`in contrast to 18%, 17%, and 22% in the 2—g, 1-2‘ _and
`placebo groups, respectively. A dose-response relation-
`ship was not detected across the three active mesalam—
`ine doses.
`Biopsy score. A statistically significant decrease (im-
`provement) in biopsy score compared to placebo was
`observed in 58% of patients at the 4-_g dose. C0mD31'€d
`to 37% on placebo (p = 0.0015). Neither the 1- or 2-g
`dose was statistically significantly different from pla-
`cgbo, with 42% and 41 %_. respectively. improving over
`baseline. A significant dose-response relationship was
`detected across the three active doses ( p = 0.0366).
`indicating a trend for improvement as the mesalamine
`dose increased.
`I
`_
`Cgmjcaf ,t'mpr()t’(’m€r1! by disease i'ot'riii0n. For the
`PGA assessment that measured treatment success. there
`were no significant differences in response for Elillel:
`the 2- or 4-g dose of mesalarnine between patients \hl’:lI
`pancolitis and those withdtstal UC ( I7 > 0-6915)
`01’
`pancolitis patients receiving the. 2-3 and 4-3 d0$~‘3- re}
`spectively. 61% and 52% experienced complete re re
`
`g¥
`
`

`
`l192
`
`HANAUER er al.
`
`T4311: 2
`Baseline C'l1arac1'eri.1'rir.r*
`
`
`
`V01’. ("18, !\"u. 8, I993
`
`Sex
`Mar:
`Femaie
`Smoking
`yes
`N0
`Location
`Distat
`Pancol
`Recent oral steroid use
`Yes
`No
`Recentr SASP;t use
`Yes
`No
`Age (yr) (mean 1 SD)
`
`Years of UC disease (mean 1 SD)
`
`Placebo
`(n = 90)
`
`549:, (49/90)
`46% (41/90)
`
`(5/90)
`(,9;
`94% (85/90)
`
`69% (62/90)
`31% (23/90)
`
`28% (25/89}
`72% (64/39)
`
`42% (38/90)
`58% (52/90)
`39.6 1 13.4
`(n=90)
`7.1 1 7.0
`(n=90)
`
`I g
`(n = 92)
`
`5392 (49/92)
`47% (43/92)
`
`(5/92)
`79.3
`93% (86/92)
`
`65% (60/92)
`3592132/92)
`
`30% (27/91)
`'.'t1%(64/91)
`
`35% (32/92)
`65% (60/92)
`39.9 1 13.2
`(11:92)
`7.1 t 7.9
`(n=92)
`
`2 s
`(n = 97)
`
`51% (49/97)
`4991.. (43/97)
`
`7% (7/90)
`939;. (89/96)
`
`08% ((36/97)
`3291131/971
`
`21% (30/97)
`799;. (77/97)
`
`41% (40/97)
`59% (57/97)
`40.1 1 14.6
`(I1 = 971
`5.9 i It-l
`(I1 = 97}
`
`4 3
`in = 951
`_
`_
`4497 142/951
`569} (53/951
`_
`_
`(15/95)
`rut“;
`949.‘ 019/951
`
`72¢; ms/951
`28".‘ (27/951
`
`29'?’ (27/92)
`711‘; 165/931
`
`40"} (38/94)
`00')‘ (56/94)
`40.91 13.0
`(11:95!
`7-9 i 3-”
`(I1=‘?51
`
`* No statistical differences detected across treatment groups for any baseline characteristics.
`1‘ Recent = use of SASP or oral steroids within 30 days of starting study medication.
`It Sulfasalazine.
`35
`
`I00
`
`'10
`
`- lnsufficlcnl Ti'10f:|pE1lllL Erect
`Adverse Event‘
`lr\IEtI:lmElI!CDnd111r)fi
`Vnlmttnry Withdrawal.‘
`1541 :0 Follow-up
`
`
`
`4:43
`
`:10
`
`25
`
`
`
`”..UfFalIim15
`
`_\:mC:
`
`7 gram
`Placebo
`n=92
`rI=9O
`‘Statistically Siqflillcanl compared In placebo. p<.D5
`
`Tmazmem
`
`2 gram
`n-J37
`
`-1 gram
`n:95
`
`F1(;. 1. Summary of early tenninations [percent (11) of patients].
`
`or marked improvement of symptoms in contrast to
`32% on placebo. In comparison, 55% and 62% of
`patients with distal disease receiving the 2—g and 4-g
`doses, respectively, experienced treatment success as
`measured by PGA, compared with 37% on placebo.
`Differences in mean change in sigmoidoscopic index
`between patients with pancolitis and distal disease were
`not statistically significant for the 2-g and 4-g closes
`[p > 0.7963 (Table 4)]. Also, no statistically significant
`differences were noted in the number of treatment
`failures between patients with pancolitis and those with
`distal UC (p > 0.7325). In the 2-g and 4-g groups,
`respectively, 16% and 15% of pancolitis patients were
`classified as treatment failures, compared with 29%
`receiving placebo; in the group of patients with distal
`
`[:3 flmir-1-1
`
`
`Finrlii--.1t:r1
`
`E‘ S‘‘" """
`
`54639)
`
`7116514-
`
`
`
`
`
`
`NU
`
`70
`
`M!
`
`511)
`
`-ID
`
`20
`
`10
`
`
`
`‘:.Lr'F‘.'_1|1DfiI!.
`
`
`
` __ I
`
`o 1.1r.oI)o
`1 am"
`2 gram
`4 ya
`""90
`" 92
`rm..r=m¢
`”'="
`“:95
`*51.1hs1u..11Iy mm-Iucarniu-u.-aredtu :11-WUIK; p. ns
`
`Physician global assessment (PG.!\}: Percent (11) ofpatients
`FIG.
`who achieved remission. treatment success. or treatment benefit by
`PGA.
`
`T711511: 3
`1:_]_f)‘ic‘aL[1’ Rt*.\‘1t.1'!.\' y/{Ur .S'igrr1m'do5cnp1c lnr1'e.\‘
`
`Sigmoidoscopic Index
`
`Tremmcnvk
`__ __ ___ g__ __
`Placebo (n = 90)
`1 g in = 92)
`2 g in = 97)
`4 g (n = 95)
`
`Baseline
`(mean 1 SE)
`10.3 1 0.30
`9.9 1 0.29
`10.2 1 0.26
`10.3 1 0.27
`
`Endpoint
`(mean 1 SE)
`7.8 1 0.54
`6.6 1 0.49
`5.9 1 0.47
`5.3 1 0.45
`
`Change
`(mean 1 SE)
`-2.5 1 0.45
`-3.4 1 0.45
`-4.31 043+
`-5.0 1 044+
`
`"‘ A three-dose trend across the three active mesalamine doses was
`statistically significant, p < 0_05_
`I Smtislicilliy Significant. compared with placebo, p < 0.05.
`
`-Ln.-1
`
`

`
`
`
`Aiigiist 1993
`
`Tniiiii 4
`
`MESALAMINE CAPSULES FOR TREATMENT OF ACUTE UC
`
`I193
`
`Ei'flt'6!€‘.l‘ Hi’-"ll-73.73’? 5'1i£’-"?0l6l'w‘t-‘villi!’ 1'!Idt‘.\' 1'11: Di'.\‘cci.i‘c l'.r)c'm'."¢m
`(ii = 374,”
`
`Trenlmenfi
`
`Endpoint
`Baseline
`(mean t SE)_ _(mean :_sE)
`Sig;rir)icl'rJ.i'm)'ift' Itidc_\' (.l').i'.s‘.'m' UC)
`—2_4 i ()_54
`Placebo [ii = 62)
`10.2 1 0.36
`7.9 : 0,65
`lg(n=6U)
`l0.0i0.35
`7.1 :0.fi4 —3.| i0.5(i
`2gln=66)
`9910.32
`5.7 : 0.58
`-4.4: 0.53
`-1gtn=68)
`l0.2:0.3l
`5.2 10.51
`~5.l $0.52
`
`Change
`(mean 4; SE)
`
`Signitiirt'm;mpli' hidtit’ {Piiiiti-i."i'i'i'.i")
`-18 1 0,8]
`Placebo (it = 28)
`10.8 t 0.57
`7.7 i 1.02
`-4.0 i 0.76
`l gin = 32}
`9.7 t 0.50
`5.6 i 0.70
`2gtn=3ll
`ll.0:0.40
`fi.4:0.H4 —4.3i0.77
`-lgln=27l
`[0.7:0.54
`5.8 :0.92 —4.7:0.83
`
`‘The test for dilterenccs in treatment effect on sigmoidoscopic
`index between patients with distal UC and patients with pancolitis
`was not statistically significant (p = 0.7963).
`
`disease. 18% and 7% receiving 2 g and 4 g of mesalam—
`iiie were categorized as treatment failures. in contrast
`to 19% receiving placebo. Finally. there were no signif-
`icant differences in decreases in biopsy score for either
`the 2-g or 4-g doses between patients with pancolitis
`and those with distal UC (p > 0.4061). For pancolitis
`patients receiving the 2-g and 4-g dose, respectively.
`35% and 59% experienced a decrease in biopsy score
`in contrast to 29% on placebo. In comparison, 44%
`and 57% of patients with distal disease receiving the 2-
`g and 4-g doses experienced a decrease in biopsy score.
`compared with 40% on placebo.
`Trips to the mile! and ci'mi'ccii' .i'_vmpI0m.r. Compared
`with placebo, the 2- and 4-g doses of mesalamine pro-
`duced statistically significant improvement in trips to
`the toilet and in all four clinical symptoms (p = 0.0040
`and p = 0.0010, respectively). Mean decreases of 23%
`at 2 g and 30% at 4 g for trips to the toilet were reported.
`compared to a l2% decrease on placebo. Mean de-
`creases of 35% and 39% at 2 g and 4 g. respectively.
`were noted for abdominal/rectal pain, compared with
`a 5% decrease with placebo. Similar significant de-
`creases were also recorded for the other clinical symp-
`toms. compared with placebo (Table 5). For the 1-g
`
`treatment group. only stool consistency was signifi-
`cantly improved. compared with placebo ( p = 0.0148).
`lmprovenient in trips to the toilet (p = 0.1606). rectal
`bleeding (p = 0.2002). abdominal/rectal pain (,0 =
`0.2249). and urgency (p = 0.1214) did not reach statis-
`tical significance for this dose. compared with placebo.
`A statistically significant dose-response relationship was
`detected across the three active mesalamine doses for
`
`trips to the toilet. rectal bleeding. and abdominal/rectal
`pain (p < 0.05) and was borderline for stool consistency
`(p = 0.0552) and urgency (in = 0.0825).
`
`Induction of remi'ssi'on
`
`PGA (Table 6. Fig. 2). Both the 2~g ([1 = 0.0024) and
`4-8 (13 = 0.0019) doses of mesalaminc were statistically
`significant for inducing remission by PGA. compared
`with placebo. Twenty-nine percent of patients in the 2-
`g group and 29% of patients in the 4—g group achieved
`remission as assessed by the physician. compared to
`12% on placebo. Twenty—one percent of patients in the
`1-g group achieved remission by the PGA parameter:
`however. this did not reach statistical significance when
`compared to placebo (p = 0.0925).
`Sigmoidoscopfc i'ndex (Table 6). The 2-g ( p = 0.0469)
`and 4-g ( p = 0.0140) doses of mesalamine were statis-
`tically significant for inducing remission by sigmoido-
`scopic index, compared with placebo. Forty-four per-
`cent and 48% of patients in the 2—g and 4-g groups.
`
`respectively, achieved endoscopic remission, compared
`to 3 l % on placebo. Forty percent of patients in the 1-
`g group reached endoscopically defined remission
`which was not significantly different than placebo (p =
`0.1637‘).
`Biopsy score (Table 6). The 4-g dose of mesalaniine
`was statistically significant (p = 0.0213) for inducing
`remission by biopsy score. compared with placebo.
`Thirty—nine percent of patients achieved histologic rc-
`mission. compared with 23% on placebo. Treatment
`with either the 2-g or 1-g doses of mesalaiiiinc did not
`produce remission by this parameter that was statisti-
`cally significant compared to placebo.
`
`.
`‘
`
`TABLE 5
`l,[eg,tp mm‘ (%)* Cilimigc in Cfiriicril S_i'iii_r).'orm‘ and TrIp.\' In 'l"r:i'i't'i'
`
`‘
`_
`_
`Clinical Symptom
`W
`Trips to roiletl
`Stool consistency
`Rectal bleedingt
`Abdominal/rectal paint‘
`Urgency
`
`Placebo
`(n 1 90)
`‘
`*0-7 (12%)
`- l .4 (260/E)
`-1.7 (35%)
`-0.2 (5%;
`_1_2 (31 Q}
`
`_
`
`_
`
`3 E
`(U = 9;)
`--
`‘
`-1.1 (13%)
`~2.6i (42%)
`-2-3 (47?)
`41).; Egg;
`— .
`._
`a
`
`_
`
`_
`
`2 3
`»(n =/97') _
`1.51 (334)
`_‘l"3: (“,',',)
`7-7* ‘-ggj}
`—...-
`_
`1.
`
`< 0 0‘
`. -.
`
`£39‘
`tn - .)
`—i7it3u%i
`-1‘
`65'?
`lb-J,-:32‘;
`_‘l'_'1t(w,,(.)
`-7-51(s()‘,'g)
`-.
`.
`
`.
`_
`in 5lr'mI31f3m 5‘3""31'l_W_-
`* "/E reflects the percentage decrease (imPF0V€m€f10
`’r Three—dose trend across three active mesalamine doses achieved statistical significance. p
`:l Statistically significant compared with placebo. P < 0-05-
`
`I I
`
`I l
`
`

`
`
`
`II94
`
`(11.
`HANAUER at
`TABLE 6
`
`j~_',',l.Fm¢-i- Ry,mi'!.\' .fhr l'n(.’m'Ir'rm ol'Rc'r1ii5.\'ir)rr [Perwnr {Ii} ofPr1n'r-nr.t'
`in Rcmi'.\'.vr'on,’
`
`Treatment
`
`TD
`
`in
`
`
`
`VH1’. 88. N0. 8, 1993
`
`_
`
`Parameter
`
`4 g
`2 g
`1 g
`H placebo
`(n=97}_ (n=9S)
`(n=92)
`(_r_i=90)
`21% (19) 29% (28)* 29% Q8)‘
`12% (1 l)
`PGA
`40% (37) 44% (43}* 43% (46)*
`31% {Z8}
`Sigmoidoscopy
`28% (26)
`29% (28)
`39% (3".')*
`23% (ll)
`Biopsy
`"' Statistically significant. compared with placebo. p < 0.05.
`
`V
`
`Subgroup anal'_t.'.te.s
`The demographic subgroups (years since UC diag-
`nosis, age, gender, smoking status, disease location.
`recent oral steroid use, or recent sulfasalazine use) were
`examined for the consistency of treatment effect (inter-
`action) with each of the nine efficacy parameters. None
`of the subgroups were found to be consistent predictors
`of treatment response. In addition, the treatment-by-
`site interaction was not statistically significant for any
`of the efficacy parameters for clinical
`improvement
`and/or induction of remission, indicating that the mag-
`nitude of treatment effects was not significantly differ-
`ent between investigative sites.
`
`Complicmce
`Of the 374 patients who ingested study medication,
`338 (90%) were considered to be medication compliant,
`using the following criteria: compliance was 2 70% for
`the duration of the study, patients had not been off
`medication for more than 2 days prior to final visit,
`and patients consumed study medication for at least 4
`days prior to terminating study participation.
`
`Adverse reactions to u'ierapy
`A total of 32 patients discontinued participation in
`the trial due to an adverse reaction (treatment- or
`nontreatment-related): ll receiving placebo and live.
`nine, and seven. respectively. receiving the 1—g. 2—g. and
`4—g doses of mesalamine. The most common events
`that led to discontinuation of therapy were diarrhea,
`which occurred in 3% (8/284) of patients receiving
`mesalamine and 9% (8/90) of patients receiving pla-
`cebo: abdominal pain. which occurred in 0.4% ( 1/284)
`of patients receiving mesalamine and 8% (7/90) of
`patients receiving placebo; fever, which occurred in 2%
`(5/284) of patients receiving mesalamine and 2% (2/
`90) of patients receiving placebo; and melena, which
`occurred in 0.4% (1/284) of patients receiving mesa-
`lamine and 7% (6/90) patients receiving placebo,
`Sixteen percent (45/284) of patients