Budesonide Multimatrix Is Efficacious for Mesalamine-refractory, Mild to Moderate Ulcerative Colitis: A Randomised, Placebo-controlled Trial

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1 Journl of Crohn's nd Colitis, 2017, doi: /ecco-jcc/jjx032 Advnce Access publiction Mrch 4, 2017 Originl Article Originl Article Budesonide Multimtrix Is Efficcious for Meslmine-refrctory, Mild to Moderte Ulcertive Colitis: A Rndomised, Plcebo-controlled Tril Dvid T. Rubin, Russell D. Cohen, Willim J. Sndborn, b Gry R. Lichtenstein, c Jeffrey Axler, d Robert H. Riddell, e Cindy Zhu, f Andrew C. Brrett, f Enoch Bortey, f Willim P. Forbes f Inflmmtory Bowel Disese Center, University of Chicgo Medicine, Chicgo, IL, USA b Division of Gstroenterology, University of Cliforni [UC] Sn Diego nd UC Sn Diego Helth System, Sn Diego, CA, USA c Division of Gstroenterology, Perelmn School of Medicine of the University of Pennsylvni, Phildelphi, PA, USA d Toronto Digestive Disese Assocites, Toronto, ON, Cnd e Deprtment of Pthology nd Lbortory Medicine, Mt Sini Hospitl, Toronto, ON, Cnd f Slix Phrmceuticls, Rleigh, NC, USA Corresponding uthor: Dvid T. Rubin, MD, The University of Chicgo Medicine, 5841 S. Mrylnd Avenue, MC 4076, Chicgo, IL 60637, USA. Tel: ; fx: ; emil: drubin@medicine.bsd.uchicgo.edu Conference presenttions: these dt were presented in prt t the Crohn s nd Colitis Foundtion s Clinicl & Reserch Conference [December 4 6, 2014; Orlndo, FL, USA]. Abstrct Bckground nd Aims: Sfety nd efficcy of budesonide multimtrix, n orl extended-relese second-genertion corticosteroid designed for trgeted delivery throughout the colon, were exmined for induction of remission in ptients with mild to moderte ulcertive colitis refrctory to bseline meslmine therpy. Methods: A rndomised, double-blind, plcebo-controlled, multicentre tril evluted efficcy nd sfety of budesonide multimtrix for induction of remission [ulcertive colitis disese ctivity index score 4 nd 10] in 510 dults rndomised to once-dily orl budesonide multimtrix 9 mg or plcebo for 8 weeks. Ptients continued bseline tretment with orl meslmine 2.4 g/dy. Results: Combined clinicl nd endoscopic remission t Week 8 ws chieved by 13.0% nd 7.5% of ptients receiving budesonide multimtrix [n = 230] or plcebo [n = 228], respectively, in the modified intention-to-tret popultion [p = 0.049]. Clinicl remission [ulcertive colitis disese ctivity index rectl bleeding nd stool frequency subscle scores of 0] ws similr in both groups [p = 0.70]. More ptients receiving budesonide multimtrix vs plcebo chieved endoscopic remission [ulcertive colitis disese ctivity index mucosl ppernce subscle score of 0; 20.0% vs 12.3%; p = 0.02] nd histologicl heling [27.0% vs 17.5%; p = 0.02]. Adverse event rtes were similr [budesonide multimtrix, 31.8%; plcebo, 27.1%]. Men morning cortisol concentrtions decresed t Weeks 2, 4, nd 8 with budesonide multimtrix but remined within the norml rnge. Conclusion: Budesonide multimtrix ws sfe nd efficcious for inducing clinicl nd endoscopic remission for mild to moderte ulcertive colitis refrctory to orl meslmine therpy. Key Words: Ulcertive colitis; inflmmtory bowel disese; inflmmtion; clinicl trils The Author Published by Oxford University Press on behlf of Europen Crohn s nd Colitis Orgnistion. This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution License ( which permits unrestricted reuse, distribution, nd reproduction in ny medium, provided the originl work is properly cited. 785

2 786 D. T. Rubin et l. 1. Introduction Ulcertive colitis [UC] is chronic inflmmtory bowel disese tht ffects the colonic mucos, extending proximlly from the rectum. 1 Clinicl symptoms of UC include rectl bleeding, dirrhoe, urgency, tenesmus, nd bdominl pin. 1 Current tretment guidelines recommend tht ptients with ctive, mild to moderte UC receive either rectl meslmine for more distl forms of UC, or orl meslmine for more extensive forms of the disese. 2,3 Systemic corticosteroids re usully prescribed fter ptients fil to respond to meslmine therpy, 2,3 but re ssocited with potentilly serious dverse events [AEs] including infections, ophthlmologicl complictions, nd cushingoid fetures. 2 Budesonide is second-genertion corticosteroid tht undergoes extensive first-pss heptic metbolism due to its low systemic biovilbility [~ 10%]. 4,5 Budesonide multimtrix [MMX] extended-relese tblets were developed to pss through the stomch intct nd relese ctive drug throughout the length of the colon. 6,7 Results of two phse 3, rndomised, double-blind, plcebo-controlled studies [colonic relese budesonide (CORE) I 8 nd CORE II 9 ] of ptients with ctive, mild to moderte UC demonstrted tht budesonide MMX 9 mg induced combined clinicl nd endoscopic remission in significntly greter percentge of ptients compred with plcebo [CORE I, 17.9% vs 7.4%, respectively, p = ; CORE II, 17.4% vs 4.5%, respectively, p = 0.005] nd hd fvourble sfety profile comprble with plcebo. Concomitnt use of other UC therpies ws not permitted in these studies. 8,9 Potentil glucocorticoid-relted dverse effects [eg, moon fce, fluid retention, sleep chnges] occurred infrequently in both groups, nd men morning plsm cortisol concentrtions decresed with budesonide MMX but remined within norml levels during both studies. A smll phse 2 study consisting of 4-week rndomised, double-blind, plcebo-controlled phse followed by 4-week open-lbel extension phse, demonstrted tht clinicl improvement or remission ws chieved by 47.1% nd 33.3% of ptients who received budesonide MMX 9 mg or plcebo, respectively, for tretment of UC, despite concomitnt orl meslmine use. 10 Budesonide MMX 9 mg hd fvourble sfety profile; men cortisol concentrtions decresed fter 4 weeks with budesonide MMX 9 mg, but remined within norml rnge for the durtion of the study. These findings suggest tht budesonide MMX my be included in tretment lgorithms fter meslmine hs filed, but before systemic corticosteroid use. 11 The current study evluted budesonide MMX 9 mg dministered once dily for 8 weeks for the induction of remission of mild to moderte UC not dequtely controlled by stble, orl meslmine therpy. 2. Mterils nd Methods 2.1. Ptients Ptients ged 18 to 75 yers with ctive UC [ulcertive colitis disese ctivity index [UCDAI] mucosl ppernce subscle score 1] by flexible sigmoidoscopy t screening, s well s mild to moderte UC [bseline UCDAI score 4 nd 10, mucosl ppernce subscore 1, nd physicin s rting of disese ctivity score of 1 or 2, despite receiving orl meslmine 2.4 g/dy (or equivlent) for 6 weeks before rndomistion] were included. Previously rndomised ptients without histologicl evidence of ctive UC [s determined by centrl histopthologicl reding] continued the study but were not included in the primry efficcy nlysis popultion. Exclusion criteri included: evidence of limited distl proctitis [extending from the nl verge up to 15 cm bove the pectinel line]; Crohn s disese or indeterminte colitis; microbiologiclly confirmed infectious colitis or history of infectious colitis within 30 dys of screening; history of pncolitis [disese extending to the heptic flexure or beyond] for 8 yers or left-sided colitis [disese distl to the splenic flexure] for 15 yers without surveillnce colonoscopy for dysplsi/colorectl cncer screening within the pst yer; or liver cirrhosis, heptic or renl disese or insufficiency, or 2.5 times the upper limit of norml [ULN] for lnine minotrnsferse, sprtte minotrnsferse, gmm glutmyl trnsferse, or 2 times ULN for cretinine. Ptients could not hve received previous tretment with: budesonide MMX; orl corticosteroids, including other formultions of budesonide, during the previous 4 weeks; ny rectl meslmine or corticosteroid formultion during the previous 2 weeks; immunosuppressive gents during the previous 8 weeks; or biologic therpies during the previous 3 months. Systemic or rectl steroids, ny meslmine other thn the existing orl meslmine t the sme dose ptient ws receiving t study initition, nti-tumour necrosis fctor-α gents nd other biologics, nd immunosuppressnts were prohibited. The protocol ws pproved by institutionl review bords nd ethics committees. All ptients provided written informed consent. All uthors hd full ccess to the study dt nd reviewed nd pproved the finl mnuscript Study design This phse 3, multicentre, rndomised, double-blind, plcebo-controlled study [NCT ] ws conducted in the USA, Cnd, nd Europe between December 2011 nd December Ptients were rndomised 1:1 to receive budesonide MMX 9 mg or plcebo once dily fter brekfst for 8 weeks in n outptient setting. Ptients were ssigned to tretment groups vi n interctive voice response system [IVRS] using computer-generted rndomistion nd strtifiction by study centre. Ptients continued tretment with the sme preprtion nd dosge of orl meslmine [or equivlent] reported t study entry. Minimum required doses were 2.4 g/dy for meslmine, 4.0 g/dy for sulphslzine, 2.0 g/ dy for olslzine, or 6.75 g/dy for blslzide. The study consisted of 2-week screening phse, n 8-week tretment phse, nd 4-week posttretment phse [Supplementry Figure 1, vilble s Supplementry dt t ECCO-JCC online] Assessments The primry efficcy endpoint ws the percentge of ptients chieving combined clinicl nd endoscopic remission [totl UCDAI score, ccording to Sutherlnd, 12 of 1, with subscle scores of 0 for rectl bleeding, stool frequency, nd mucosl ppernce] t Week 8. Secondry efficcy outcomes included the percentge of ptients chieving clinicl remission [UCDAI subscle scores of 0 for rectl bleeding nd stool frequency] nd the percentge of ptients chieving endoscopic remission [UCDAI subscle score of 0 for mucosl ppernce] t Week 8. An explortory endpoint included the percentge of ptients chieving histologicl heling [histologicl ctivity grde of 0] t Week 8. For this endpoint, three mucosl biopsies were tken from the most severely ffected colonic region[s] during endoscopy procedures performed t screening nd Week 8; biopsies were nlysed nd scored by blinded, independent histopthologist t centrl lbortory using the Geboes system. 13 Additionl explortory endpoints included the percentge of ptients with clinicl improvement [ 3-point improvement from bseline in UCDAI score nd rectl bleeding score 1] t Week 8, nd serum C-rective protein [CRP] nd fecl clprotectin concentrtions t Week 8. Qulity

3 Budesonide MMX for Meslmine-refrctory UC 787 of life [QOL] ws evluted t Weeks 2, 4, nd 8 using the inflmmtory bowel disese qulity of life [IBD-QOL] instrument, 32-item questionnire comprising bowel function, emotionl function, systemic symptoms, nd socil function dimensions, with higher scores indicting improved QOL. Sfety ssessments included AE monitoring, potentil predefined glucocorticoid-relted dverse effects [ie, moon fce, strie rubre, flushing, fluid retention, mood chnges, sleep chnges, insomni, cne, hirsutism], clinicl lbortory tests [including morning cortisol concentrtions nd drenocorticotrophic hormone (ACTH) chllenge tests], physicl exmintions, nd vitl sign mesurements. A norml response to the ACTH chllenge test ws defined s n increse from bseline in plsm cortisol concentrtion > 7 µg/dl, or plsm cortisol concentrtion > 18 µg/ dl 30 min post-acth chllenge Sttisticl nlyses The intention-to-tret [ITT] popultion included ll rndomised ptients who received 1 dose of study drug nd hd ctive UC t study entry s cuse of symptoms [bsed on photogrphic mucosl evidence]; the sfety popultion included ll ptients who received 1 dose of study drug. The modified ITT [mitt] popultion included ll ptients in the ITT popultion with histologicl evidence of ctive UC nd no evidence of enteric infection. Bsed on n ssumption of remission rtes of 15% for plcebo nd 27% for budesonide MMX, totl of 250 ptients per group would be expected to provide 90% power to detect significnt difference between the two groups with twosided α = Complince with budesonide MMX ws determined by dily self-report of study drug dministrtion through the IVRS, s well s by subtrcting the mount of drug returned t Weeks 4 nd 8 from the mount of drug dispensed. The Wilcoxon rnk sum test ws used for tests of continuous vribles, nd the chi-squre method ws used for tests of binomil proportions, unless the expected cell frequency ws less thn five for more thn one cell in two x two tble; in tht cse, Fisher s exct test ws used. Missing dt for ptients in the mitt popultion were hndled using worst-cse imputtion scheme, where ptients with missing dt were considered nonresponders; clinicl improvement, IBD-QOL, nd serum CRP dt were nlysed using the lst observtion crried forwrd method. 3. Results 3.1. Ptient disposition nd demogrphics Of the 510 rndomised ptients who received 1 dose of study drug [ITT popultion], 52 were excluded from efficcy nlyses due to norml histology bsed on centrl lbortory reding [n = 51] or infectious colitis [n = 1]; the mitt popultion included 230 nd 228 ptients receiving budesonide MMX or plcebo, respectively. For the mitt popultion, 85.2% nd 93.0% of ptients receiving budesonide MMX or plcebo, respectively, completed the study [Figure 1]. Demogrphic nd bseline disese chrcteristics were generlly comprble between tretment groups [Tble 1]. The mjority of ptients received concomitnt tretment with meslmine t doses 2.4 g/dy but < 4.8 g/dy Efficcy A significntly greter percentge of ptients receiving budesonide MMX 9 mg chieved combined clinicl nd endoscopic remission fter 8 weeks [primry efficcy endpoint] compred with plcebo [13% vs 7.5%, respectively; p = 0.049; worst-cse nlysis; Figure 2]. The UCDAI mucosl ppernce score ws the primry driver for this effect, with 20.0% nd 12.3% of ptients in the budesonide MMX or plcebo groups, respectively, chieving mucosl ppernce subscore of 0 [p = 0.02]. A comprble percentge of ptients receiving budesonide MMX 9 mg nd plcebo chieved clinicl remission [ie, UCDAI rectl bleeding nd stool frequency subscle scores of 0; 24.3% vs 22.8%, respectively; p = 0.70]. A greter percentge of ptients receiving budesonide MMX 9 mg chieved endoscopic remission compred with plcebo fter 8 weeks [20.0% vs 12.3%, respectively; p = 0.025; Figure 2]. The percentge of ptients with UCDAI rectl bleeding subscore of 0 ws comprble between groups [budesonide MMX, 48.7%, vs plcebo, 47.8%]; similr percentge of ptients in ech group chieved UCDAI stool frequency score of 0 [budesonide MMX, 34.3%, vs plcebo, 31.1%]. Histologicl heling ws chieved by significntly greter percentge of ptients receiving budesonide MMX 9 mg compred with plcebo [27% vs 17.5%, respectively; p = 0.016]. No significnt differences were noted between budesonide MMX [47.0%] nd plcebo [39.0%; p = 0.09] for the explortory endpoint of percentge of ptients with clinicl improvement t Week 8. Serum CRP concentrtions decresed from bseline to Week 8 with only plcebo, wheres fecl clprotectin concentrtions decresed from bseline in both groups; for both biomrkers, the chnge from bseline ws comprble between groups [Supplementry Tble 1, vilble s Supplementry dt t ECCO- JCC online]. Totl nd subscle scores of the IBD-QOL instrument were improved from bseline with both budesonide MMX nd plcebo by Week 2, nd mintined through Week 8 [Supplementry Tble 2, vilble s Supplementry dt t ECCO-JCC online]. Rndomised to tretment [n = 510] Budesonide MMX 9 mg [] Plcebo [] Sfety popultion [n = 510] Norml histology [n = 24] Infectious colitis [n = 1] Norml histology [n = 27] Budesonide MMX 9 mg [n = 230] Plcebo [n = 228] mitt popultion [n = 458] Study discontinutions [n = 34; 14.8%] Ptient withdrew from study [n = 14; 6.1%] Adverse event [n = 12; 5.2%] Worsening UC [n = 11; 4.8%] Lck of efficcy [n = 4; 1.7%] Lost to follow-up [n = 3; 1.3%] Protocol violtion [n = 1; 0.4%] Study discontinutions [n = 16; 7.0%] Adverse event [n = 8; 3.5%] Worsening UC [n = 8; 3.5%] Lost to follow-up [n = 4; 1.8%] Ptient withdrew from study [n = 2; 0.9%] Lck of efficcy [n = 1; 0.4%] Protocol violtion [n = 1; 0.4%] Budesonide MMX 9 mg [n = 196] Plcebo [n = 212] Study completion Figure 1. Ptient disposition. mitt, modified intention-to-tret; MMX, multimtrix; UC, ulcertive colitis.

4 788 D. T. Rubin et l. Tble 1. Demogrphic nd bseline chrcteristics, modified intention-to-tret popultion. Chrcteristic 3.3. Sfety Budesonide MMX 9 mg n = 230 Plcebo n = 228 Age, yers, men [SD] 44.5 [14.1] 44.6 [13.7] Sex, mle, n [%] 121 [52.6] 127 [55.7] Rce, White, n [%] 219 [95.2] 210 [92.1] BMI, kg/m 2, men [SD] 25.7 [5.2] 25.6 [5.0] Durtion of disese, 80.4 [91.0] 78.9 [90.5] months, men [SD] Durtion of current flre, n [%] 4 weeks 43 [18.7] 36 [15.8] 5 12 weeks 87 [37.8] 94 [41.2] > 12 weeks 90 [39.1] 94 [41.2] Missing 10 [4.3] 4 [1.8] Extent of disese, n [%] Proctosigmoiditis 94 [40.9] 85 [37.3] Left-sided UC 84 [36.5] 94 [41.2] Extensive colitis 13 [5.7] 16 [7.0] Pncolitis 39 [17.0] 33 [14.5] Severity of current flre, n [%] Mild 42 [18.3] 47 [20.6] Moderte 188 [81.7] 181 [79.4] Bseline UCDAI totl score, men [SD] 6.5 [1.5] 6.6 [1.6] Bseline UCDAI rectl bleeding subscore, n [%] 0 29 [12.6] 34 [14.9] [55.7] 111 [48.7] 2 69 [30.0] 77 [33.8] 3 3 [1.3] 6 [2.6] Bseline UCDAI stool frequency subscore, n [%] 0 28 [12.2] 25 [11.0] 1 85 [37.0] 85 [37.3] 2 69 [30.0] 75 [32.9] 3 47 [20.4] 43 [18.9] Bseline UCDAI mucosl ppernce subscore, n [%] [17.4] 43 [18.9] [70.0] 155 [68.0] 3 29 [12.6] 30 [13.2] Bseline UCDAI physicin s rting of disese ctivity subscore, n [%] [19.6] 49 [21.5] [80.4] 179 [78.5] Totl dily dose of bckground meslmine equivlent, n [%] < 2.4 g 33 [14.3] 42 [18.4] 2.4 g to < 4.8 g 170 [73.9] 158 [69.3] 4.8 g 27 [11.7] 28 [12.3] Men dose, g [SD] 3.1 [1.4] 3.0 [1.2] Prior biologic therpy use, n [%] b Adlimumb 2 [0.8] 1 [0.4] Golimumb 0 1 [0.4] Infliximb 10 [3.9] 9 [3.5] BMI, body mss index; MMX, multimtrix; SD, stndrd devition; UC, ulcertive colitis; UCDAI, ulcertive colitis disese ctivity index. Dt missing for 1 ptient. b Dt presented for sfety popultion; budesonide MMX [] nd plcebo []. Budesonide MMX 9 mg ws well tolerted when dministered in combintion with orl meslmine, s the mjority of AEs [28.7%] with budesonide MMX were mild to moderte in intensity. Overll, 31.8% nd 27.1% of ptients receiving budesonide MMX or plcebo, respectively, reported AEs, with the most common AE in both groups being UC [Tble 2]. Serious AEs occurred in smll percentge of ptients receiving budesonide MMX [UC (2.4%), pncretitis (0.4%), bronchitis (0.4%), nemi (0.4%), hypoklemi (0.4%)] or receiving plcebo [UC (0.4%), type 2 dibetes mellitus (0.4%)]. Study discontinution due to AEs occurred in 4.7% nd 3.5% of ptients receiving budesonide MMX or plcebo, respectively. Potentil glucocorticoid-relted AEs occurred in 9.0% nd 5.9% of ptients receiving budesonide MMX or plcebo, respectively, with moon fce [3.1% vs 2.0%, respectively], sleep chnges [2.0% vs 1.6%], fluid retention [1.6% vs 2.0%], nd mood chnges [0.4% vs 2.0%] reported by t lest 2% of ptients in either tretment group. Men morning plsm cortisol concentrtions were within norml levels in both tretment groups t bseline, Week 2, Week 4, nd Week 8 [Figure 3; Supplementry Tble 3, vilble s Supplementry dt t ECCO-JCC online]. Men cortisol concentrtions fter ACTH stimultion were comprble t bseline in ptients receiving budesonide MMX nd plcebo [22.3 µg/dl nd 21.7 µg/dl, respectively]. However, men cortisol concentrtions fter ACTH stimultion were below norml with budesonide MMX fter 8 weeks [15.6 µg/dl]; ptients receiving plcebo hd cortisol concentrtions comprble with bseline fter 8 weeks [22.3 µg/dl]. The mjority of ptients mintined norml totl concentrtions nd hd norml response to ACTH chllenge during the study [Tble 3]. 4. Discussion The results of this rndomised, double-blind, plcebo-controlled study demonstrted the efficcy, sfety, nd tolerbility of oncedily, orl budesonide MMX 9 mg for the induction of remission of ptients with mild to moderte UC unresponsive to orl meslmine monotherpy. All ptients in this study continued tretment with stble dose of orl meslmine in ddition to the study drug, in contrst with the CORE I nd CORE II studies, which prohibited concomitnt orl meslmine. 8,9 However, more thn 50% of ptients in the CORE I nd CORE II studies reported previous use of meslmine, with 54.5% of ptients in CORE I reporting mesl mine exposure within 14 dys of rndomistion. The percentge of ptients receiving budesonide MMX or plcebo who chieved combined clinicl nd endoscopic remission ws comprble between this study nd the CORE I nd CORE II studies. 8,9 The results of the primry endpoint of the current study were primrily driven by the UCDAI mucosl ppernce score, with significntly greter percentge of ptients chieving endoscopic remission with budesonide MMX fter 8 weeks compred with plcebo. The percentge of ptients chieving stool frequency score of 0 ws comprble between groups; however, budesonide MMX my not hve lrge effect on this component of the UCDAI, s 20% to 43% of ptients with ctive UC my hve formed stools. 15 Clinicl remission [ie, rectl bleeding nd stool frequency subscle scores of 0], subjective secondry outcome mesure bsed on ptient-reported outcomes, ws not sttisticlly significnt for budesonide MMX compred with plcebo. However, the objective secondry endpoints of endoscopic remission nd histologicl heling were significnt for budesonide MMX vs plcebo in this study. Histologicl nd endoscopic scores hve been shown to be positively correlted, 16 but it is uncler why the percentge of ptients with histologicl heling ws greter thn the percentge of ptients with combined clinicl nd endoscopic remission, s mny ptients with UC in clinicl remission

5 Budesonide MMX for Meslmine-refrctory UC Budesonide MMX 9 mg [n = 230] Plcebo [n = 228] 30 p = p = Ptients [%] p = p = Clinicl nd endoscopic remission Primry efficcy endpoint Clinicl remission Endoscopic remission b Secondry efficcy endpoints Histologicl heling c Figure 2. Ptients chieving primry nd secondry efficcy outcome mesures t Week 8. MMX, multimtrix. Clinicl remission defined s rectl bleeding nd stool frequency subscores = 0. b Endoscopic remission defined s mucosl ppernce subscore = 0. c Histologicl heling defined s histologicl ctivity grde = 0 [norml mucos], by centrl reding. Tble 2. Summry of dverse events, sfety popultion. Adverse event, n [%] Budesonide MMX Plcebo Any AEs 81 [31.8] 69 [27.1] Drug-relted AEs 31 [12.2] 15 [5.9] Discontinutions due to AE 12 [4.7] 9 [3.5] Serious AEs 10 [3.9] 2 [0.8] Drug-relted serious AEs b 2 [0.8] 0 AE intensity Mild 44 [17.3] 41 [16.1] Moderte 29 [11.4] 26 [10.2] Severe 8 [3.1] 2 [0.8] Most common AEs c UC 15 [5.9] 10 [3.9] Decresed blood cortisol levels 10 [3.9] 0 Acne 3 [1.2] 5 [2.0] Serious AEs UC 6 [2.4] 1 [0.4] Acute pncretitis 1 [0.4] 0 Bronchitis 1 [0.4] 0 Anemi 1 [0.4] 0 Hypoklemi 1 [0.4] 0 Type 2 dibetes mellitus 0 1 [0.4] AE, dverse event; MMX, multimtrix; UC, ulcertive colitis. Serious AEs reported in the budesonide MMX group: UC [n = 6], nemi [n = 1], cute pncretitis [n = 1], bronchitis [n = 1], hypoklemi [n = 1]. Serious AEs reported in the plcebo group: UC [n = 1], type 2 dibetes mellitus [n = 1]. b Drug-relted serious AEs included UC nd cute pncretitis. c Common AEs included those reported in 2% of ptients in either group. lso hve histologicl evidence of inflmmtion. 16 Rectl bleeding nd stool frequency re components of the definition of clinicl remission tht my not be cused by inflmmtion, which my ccount for the finding of histologicl heling in this study. Serum CRP concentrtions, biomrker of inflmmtion, were unchnged from bseline with budesonide MMX nd decresed with plcebo t Week 8; it is uncler why decresed serum CRP concentrtions were only observed in ptients receiving plcebo, but it my be due to poor ssy sensitivity. 17 The decrese from bseline in fecl clprotectin concentrtions ws comprble between groups t Week 8. Of note, these biomrkers re currently not recommended for ssessing therpeutic response. 17 A limittion of this study ws the stringent definition of remission, which my hve limited the number of ptients who chieved the primry nd secondry efficcy outcomes. However, more stringent definitions of remission help decrese the incidence of flsepositives in study. 18 Combined clinicl nd endoscopic remission is considered n pproprite therpeutic endpoint in clinicl studies of UC. 19 Clinicl remission is n importnt endpoint for ptients, s the rectl bleeding nd stool frequency components of the Myo score hve performed well s indictors of ptient perception of clinicl response to therpy. 18 However, lthough sigmoidoscopy nd colonoscopy re invsive procedures not viewed fvourbly by most ptients, 18 mucosl heling, shown by the bsence of mucosl ulcertion nd erosions, hs been suggested s the ultimte gol of tretment in ptients with UC. 20 Tretment with corticosteroids or orl meslmine hs been ssocited with n incresed likelihood for mucosl heling within 1 yer in ptients with UC. 21 Histologicl heling hs not been historiclly evluted s therpeutic endpoint in clinicl studies of ptients with UC nd, when evluted, hs been limited by lck of vlidtion nd stndrdistion of how histologicl endpoints re scored, reported, nd defined. 19,22 Thus, the percentge of ptients who chieved the primry nd secondry efficcy outcomes in the current study ws most likely limited by the rigorous definition of remission, so direct comprisons with previously published studies of mild to moderte UC my not pply. This study did not confirm endoscopic scoring using independent, centrl reders, which my hve ffected endoscopic outcomes. Fegn et l. 23 previously noted tht site reders overestimted outcomes only with plcebo tretment in study of meslmine, resulting in greter tretment differences vs ctive drug; however, the sttisticl significnce between tretments remined unchnged. Further, use of flexible sigmoidoscopy, rther thn colonoscopy, my

6 790 D. T. Rubin et l. 30 Budesonide MMX 9 mg Plcebo Men morning cortisol [µg/dl] Upper limit of norml [25 µg/dl] Lower limit of norml [5 µg/dl] 0 Bseline Week 2 Week 4 Week 8 Figure 3. Men morning plsm cortisol concentrtions. MMX, multimtrix. Tble 3. Totl cortisol concentrtions nd norml response to ACTH chllenge Prmeter, n/n [%] Budesonide MMX 9 mg Plcebo Totl cortisol > 5 µg/dl b Bseline 249/255 [97.6] 241/255 [94.5] Week 2 146/244 [59.8] 237/249 [95.2] Week 4 144/241 [59.8] 233/242 [96.3] Week 8 150/225 [66.7] 231/236 [97.9] Norml response to ACTH chllenge c Bseline 222/248 [89.5] 223/254 [87.8] Week 8 119/224 [53.1] 202/236 [85.6] ACTH, drenocorticotrophic hormone; MMX, multimtrix. Denomintor N is the number of ptients with vlue t ech given week during the study. b Lower limit of norml. c Defined s increse from bseline in plsm cortisol concentrtion > 7 µg/ dl, or plsm cortisol concentrtion > 18 µg/dl 30 min fter ACTH chllenge. not be s informtive in ptients with more extensive UC. Another limittion of this study ws the bsence of sfety nd efficcy dt beyond 8 weeks. To dte, dt regrding the sfety nd efficcy of budesonide MMX for mintennce of remission hve not been published. Long-term follow-up dt regrding durtion of remission nd relief of clinicl symptoms in ptients who chieved clinicl nd/or endoscopic remission in this study re not vilble. Additionl clinicl studies re wrrnted to exmine these unnswered questions. The sfety profile of budesonide MMX ws fvourble nd comprble with tht of other studies exmining similr doses of budesonide MMX in ptients with ctive, mild to moderte UC. 8,9 Thus, concomitnt tretment with orl meslmine hd no pprent effect on the incidence of AEs with budesonide MMX, lthough some serious AEs occurred in ptients receiving budesonide MMX nd not in those receiving plcebo [ie, pncretitis, bronchitis, nemi, hypoklemi: ll 0.4% ech]. The incidence of potentil glucocorticoid-relted effects ws low nd comprble with reports from previous clinicl studies of budesonide MMX. 8,9 Importntly, men morning plsm cortisol concentrtions remined within norml rnge during the 8-week study. In conclusion, once-dily orl budesonide MMX is well-tolerted, efficcious therpeutic option for induction of combined endoscopic nd clinicl remission in mild to moderte UC, including in ptients with UC not dequtely controlled with orl meslmine therpy lone. Funding This work ws supported by Sntrus, Inc., previously wholly owned subsidiry of Slix Phrmceuticls [Rleigh, NC]. The tril ws designed nd mnged by Sntrus, Inc. [Sn Diego, CA]. The dt were housed nd nlysed by Sntrus, Inc., nd Slix, in collbortion with study investigtors. The uthors hd full ccess to the dt. Conflict of Interest DTR hs received reserch grnts nd served s consultnt for Slix Phrmceuticls nd Sntrus, Inc. [previously wholly owned subsidiry of Slix]. RDC hs served s consultnt nd dvisory bord prticipnt for Slix nd Sntrus, Inc. WJS hs received consulting fees from Slix nd Sntrus, Inc. GRL hs received reserch grnts nd/or served s consultnt for Slix nd Sntrus, Inc. JA hs nothing to disclose. RHR hs served s consultnt for Slix for this project. CZ, ACB, EB, nd WPF were employees of Slix t the time the nlyses were conducted. Acknowledgments The study ws supported by Slix Phrmceuticls, Rleigh, NC, USA. Technicl editoril ssistnce ws provided, under the direction of the uthors, by Mry Beth Moncrief, PhD, nd Sophie Bolick, PhD, for Synchrony Medicl Communictions, LLC, West Chester, PA. Funding for this support ws provided by Slix. Author Contributions All uthors prticipted in drfting of the mnuscript or criticl revision of the mnuscript for importnt intellectul content, nd provided pprovl of the finl submitted version. DTR ws involved with: conception nd design of the study; genertion, collection, ssembly, nlysis, nd/or interprettion of dt; drfting nd revision of the mnuscript; nd pprovl of the finl mnuscript for submission. RDC ws involved with: conception nd design of the study; genertion, collection, ssembly, nlysis, nd/or interprettion of dt; drfting nd revision of the mnuscript; nd pprovl of

7 Budesonide MMX for Meslmine-refrctory UC 791 the finl mnuscript for submission. WJS ws involved with: conception nd design of the study; nlysis nd/or interprettion of dt; drfting nd revision of the mnuscript; nd pprovl of the finl mnuscript for submission. GRL ws involved with: conception nd design of the study; genertion, collection, ssembly, nlysis nd/or interprettion of dt; drfting nd revision of the mnuscript; nd pprovl of the finl mnuscript for submission. JA ws involved with: interprettion of dt nlyses; drfting nd criticl revision of the mnuscript; nd pprovl of the finl mnuscript for submission. RHR ws involved with: interprettion of dt nlyses; drfting nd criticl revision of the mnuscript; nd pprovl of the finl mnuscript for submission. CZ ws involved with: interprettion of dt nlyses; drfting nd criticl revision of the mnuscript; nd pprovl of the finl mnuscript for submission. ACB ws involved with: interprettion of dt nlyses; drfting nd criticl revision of the mnuscript; nd pprovl of the finl mnuscript for submission. EB ws involved with: interprettion of dt nlyses; drfting nd criticl revision of the mnuscript; nd pprovl of the finl mnuscript for submission. WPF ws involved with: interprettion of dt nlyses; drfting nd criticl revision of the mnuscript; nd pprovl of the finl mnuscript for submission. Supplementry Dt Supplementry dt re vilble t ECCO-JCC online. References 1. Ordás I, Eckmnn L, Tlmini M, Bumgrt DC, Sndborn WJ. Ulcertive colitis. Lncet 2012;380: Kornbluth A, Schr DB; Prctice Prmeters Committee of the Americn College of Gstroenterology. Ulcertive colitis prctice guidelines in dults: Americn College of Gstroenterology, Prctice Prmeters Committee. Am J Gstroenterol 2010;105:501 23; quiz Dignss A, Lindsy JO, Sturm A, et l. Second Europen evidence-bsed consensus on the dignosis nd mngement of ulcertive colitis prt 2: current mngement. J Crohns Colitis 2012;6: Ryrfeldt A, Andersson P, Edsbäcker S, Tönnesson M, Dvies D, Puwels R. Phrmcokinetics nd metbolism of budesonide, selective glucocorticoid. Eur J Respir Dis Suppl 1982;122: Brttsnd R. Overview of newer glucocorticosteroid preprtions for inflmmtory bowel disese. Cn J Gstroenterol 1990;4: Brunner M, Ziegler S, Di Stefno AF, et l. Gstrointestinl trnsit, relese nd plsm phrmcokinetics of new orl budesonide formultion. Br J Clin Phrmcol 2006;61: Fiorino G, Fries W, De L Rue SA, Mlesci AC, Repici A, Dnese S. New drug delivery systems in inflmmtory bowel disese: MMX nd tilored delivery to the gut. Curr Med Chem 2010;17: Sndborn WJ, Trvis S, Moro L, et l. Once-dily budesonide MMX extended-relese tblets induce remission in ptients with mild to moderte ulcertive colitis: results from the CORE I study. Gstroenterology 2012;143: e Trvis SP, Dnese S, Kupcinsks L, et l. Once-dily budesonide MMX in ctive, mild-to-moderte ulcertive colitis: results from the rndomised CORE II study. Gut 2014;63: D Hens GR, Kovács A, Verguwe P, et l. Clinicl tril: Preliminry efficcy nd sfety study of new budesonide-mmx 9 mg extended-relese tblets in ptients with ctive left-sided ulcertive colitis. J Crohns Colitis 2010;4: Dnese S, Siegel CA, Peyrin-Biroulet L. Review rticle: integrting budesonide-mmx into tretment lgorithms for mild-to-moderte ulcertive colitis. Aliment Phrmcol Ther 2014;39: Sutherlnd LR, Mrtin F, Greer S, et l. 5-Aminoslicylic cid enem in the tretment of distl ulcertive colitis, proctosigmoiditis, nd proctitis. Gstroenterology 1987;92: Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Löfberg R. A reproducible grding scle for histologicl ssessment of inflmmtion in ulcertive colitis. Gut 2000;47: Syncthen [tetrcosctrin]. North Ryde, NSW: Novrtis Phrmceuticls; Ro SS, Red NW, Brown C, Bruce C, Holdsworth CD. Studies on the mechnism of bowel disturbnce in ulcertive colitis. Gstroenterology 1987;93: Rosenberg L, Nnd KS, Zenle T, et l. Histologic mrkers of inflmmtion in ptients with ulcertive colitis in clinicl remission. Clin Gstroenterol Heptol 2013;11: Mosli MH, Zou G, Grg SK, et l. C-rective protein, fecl clprotectin, nd stool lctoferrin for detection of endoscopic ctivity in symptomtic inflmmtory bowel disese ptients: systemtic review nd met-nlysis. Am J Gstroenterol 2015;110:802 19; quiz Lewis JD, Chui S, Nessel L, Lichtenstein GR, Aberr FN, Ellenberg JH. Use of the noninvsive components of the Myo score to ssess clinicl response in ulcertive colitis. Inflmm Bowel Dis 2008;14: Levesque BG, Sndborn WJ, Ruel J, Fegn BG, Snds BE, Colombel JF. Converging gols of tretment of inflmmtory bowel disese from clinicl trils nd prctice. Gstroenterology 2015;148:37 51.e Wlsh A, Plmer R, Trvis S. Mucosl heling s trget of therpy for colonic inflmmtory bowel disese nd methods to score disese ctivity. Gstrointest Endosc Clin N Am 2014;24: Frøslie KF, Jhnsen J, Moum BA, Vtn MH; IBSEN Group. Mucosl heling in inflmmtory bowel disese: results from Norwegin popultionbsed cohort. Gstroenterology 2007;133: Brynt RV, Winer S, Trvis SP, Riddell RH. Systemtic review: histologicl remission in inflmmtory bowel disese. Is complete remission the new tretment prdigm? An IOIBD inititive. J Crohns Colitis 2014;8: Fegn BG, Sndborn WJ, D Hens G, et l. The role of centrlized reding of endoscopy in rndomized controlled tril of meslmine for ulcertive colitis. Gstroenterology 2013;145: e2.