Postgraduate Medicine

ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20

Once-daily mesalamine granules for maintaining remission of ulcerative colitis: pooled analysis of efficacy, safety, and prognostic factors Salam F. Zakko, Glenn L. Gordon, Uma Murthy, Shahriar Sedghi, Ronald Pruitt, Andrew C. Barrett, Enoch Bortey, Craig Paterson, William P. Forbes & Gary R. Lichtenstein To cite this article: Salam F. Zakko, Glenn L. Gordon, Uma Murthy, Shahriar Sedghi, Ronald Pruitt, Andrew C. Barrett, Enoch Bortey, Craig Paterson, William P. Forbes & Gary R. Lichtenstein (2016): Once-daily mesalamine granules for maintaining remission of ulcerative colitis: pooled analysis of efficacy, safety, and prognostic factors, Postgraduate Medicine, DOI: 10.1080/00325481.2016.1152876 To link to this article: http://dx.doi.org/10.1080/00325481.2016.1152876

Accepted author version posted online: 10 Feb 2016.

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Date: 14 February 2016, At: 12:06

Publisher: Taylor & Francis Journal: Postgraduate Medicine DOI: 10.1080/00325481.2016.1152876 Article Type: Original Research Once-daily mesalamine granules for maintaining remission of ulcerative colitis: pooled analysis of efficacy, safety, and prognostic factors

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Salam F. Zakko,1 Glenn L. Gordon,2 Uma Murthy,3 Shahriar Sedghi,4 Ronald Pruitt,5 Andrew C. Barrett,6 Enoch Bortey,6 Craig Paterson,6 William P. Forbes,6 and Gary R. Lichtenstein7

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Connecticut Gastroenterology Institute, Bristol Hospital, Bristol, Connecticut, USA, 2Center

for Digestive and Liver Diseases, Inc., Mexico, Missouri, USA, 3Syracuse VA Medical Center, Syracuse, New York, USA, 4Gastroenterology Associates of Central Georgia, LLC, Macon, Georgia, USA, 5Nashville Medical Research Institute and The Maria Nathanson Center at Saint Thomas Hospital, Nashville, Tennessee, USA, 6Salix, a Division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ, USA, and 7University of Pennsylvania School of Medicine, Department of Medicine, Philadelphia, Pennsylvania, USA

Correspondence: Salam F. Zakko, MD, Connecticut Gastroenterology Institute, Bristol Hospital, 39 Brewster Road, Bristol, CT 060l0, USA. Tel.: +1 860 585-3838; Fax: +1 860 585-3248. E-mail: [email protected]

Running title: Mesalamine granules for ulcerative colitis remission

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Abstract Objectives: Mesalamine granules (MG) was developed for once-daily dosing and better compliance. The study aim was to evaluate MG efficacy and tolerability in maintaining ulcerative colitis (UC) remission. Methods: Pooled analysis of 2 identical phase 3, randomized, double-blind trials of once-daily MG 1.5 g or placebo for up to 6 months. The primary endpoint was percentage of patients remaining relapse-free at month 6 versus placebo. Relapse was defined as revised Sutherland

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Disease Activity Index (SDAI) rectal bleeding score ≥1 and mucosal appearance score ≥2, UC flare, or UC–related adverse event (AE). Results: Data were pooled for patients receiving MG (n = 373) and placebo (n = 189). Significantly more patients were relapse-free at 6 months with MG (79.4%) than placebo (62.4%; P < 0.001) and across subgroups based on select demographic and baseline characteristics (P < 0.05). Secondary outcome measures including rectal bleeding, physician rating of disease activity, stool frequency, total SDAI score, and relapse-free duration favored MG (P < 0.01). Common AEs with MG and placebo, respectively, were headache (10.9% and 7.6%), diarrhea (7.9% and 7.0%), and abdominal pain (6.3% and 6.5%) Conclusion: Once-daily MG was more efficacious than and as well tolerated as placebo in maintaining UC remission. ClinicalTrials.gov identifiers: NCT00744016 and NCT00767728.

Keywords: Inflammatory bowel disease, ulcerative colitis, mesalamine, remission

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Introduction Ulcerative colitis (UC), a chronic, idiopathic, inflammatory bowel disease involving the colon and rectum, is characterized by periods of exacerbations and remission [1-3]. When active, the disease is characterized by bloody diarrhea, abdominal pain, fecal urgency, and tenesmus. Overall treatment goals in the management of UC are to induce and maintain remission [3,4]. Effective maintenance of remission of UC has been shown to improve quality of life and reduce the need for long-term corticosteroid use [3]. The first-line of therapy for management of UC is

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the use of compounds containing 5-aminosalicylate (5-ASA), or mesalamine, which act topically on the colonic mucosa to reduce inflammation [3,4]. Because free 5-ASA is readily absorbed by the upper gastrointestinal tract, oral formulations have been developed to delay drug release until the 5-ASA agent reaches the colon [5]. These formulations include enteric coatings to facilitate pH-dependent delayed release, semipermeable membranes that allow for controlled time-dependent release, and chemically bonded prodrugs that release 5-ASA in the colon once exposed to colonic bacteria. Most currently available 5-ASA formulations require multiple daily dosing, which is a significant contributor to poor medication adherence and potential disease relapse [6]. The effectiveness of oral 5-ASA therapy relies on medication adherence, which has been shown to be inversely related to the frequency of dosing [7,8]. To improve adherence to therapy, once-daily formulations of mesalamine have been developed [9,10]. Mesalamine granules (MG), a unique capsule formulation (Apriso®; Salix Pharmaceuticals, Inc., Raleigh, NC, USA) approved for the maintenance of remission in patients with UC, comprises both delayed-release and extended-release delivery mechanisms that allow for once-daily mesalamine dosing [11]. The outer coating of each granule of MG dissolves at pH ≥6, and the polymer matrix facilitates slow, sustained mesalamine release throughout the colon. In each of two identically designed, randomized, double-blind, placebo-controlled, phase 3 clinical

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studies, MG was demonstrated to be efficacious and well tolerated for the maintenance of remission of UC for the 6-month duration of the studies [12,13]. In this analysis, data from these two studies were pooled to more accurately assess the efficacy and safety of MG in the maintenance of UC remission. The strength of this study is the pooling of data, which provides a larger patient population and greater power to perform analysis of efficacy by subgroup, identification of prognostic factors independently associated with maintenance of remission, and the potential to identify uncommon adverse events (for example, mesalamine-

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related renal dysfunction) that may not be detected in smaller population studies.

Materials and methods Study design This was a pooled analysis of data from two multicenter, identically designed, randomized, double-blind, placebo-controlled, phase 3 studies (studies MPUC3003 and MPUC3004 registered under ClinicalTrials.gov identifiers NCT00744016 and NCT00767728, respectively) conducted to evaluate the use of MG 1.5 g once daily for maintaining remission for 6 months in patients with UC. The protocols and any amendments for both studies were approved by an Institutional Review Board or Independent Ethics Committee at each study site. Both studies were conducted in accordance with International Conference on Harmonisation Guidelines for Good Clinical Practice, which are based on the Declaration of Helsinki, and other applicable laws and regulations. Written informed consent was obtained from all patients prior to beginning study procedures. The detailed design of these trials has been previously described [12,13], and the study designs were identical. Briefly, the studies consisted of a screening phase, a treatment phase (up to 6 months), and a follow-up visit (2 weeks after the end-of-treatment [EOT] visit). Patients who were in remission from UC were randomly assigned 2:1 to receive MG 1.5 g once daily

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(dosed as four capsules, 0.375 g mesalamine each) or placebo for 6 months. Key prohibited concomitant medications included immunosuppressants, chronic nonsteroidal anti-inflammatory drugs, corticosteroids, oral antibiotics (except as 7- to 10-day courses for conditions unrelated to UC), psyllium-containing compounds, and other 5-ASA formulations. The treatment phase consisted of four scheduled clinic visits to assess disease activity and monitor adverse events—baseline/randomization (day 1), month 1, month 3, and month 6 or EOT. Flexible sigmoidoscopy was performed at screening and the end of month 6 (or at

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the time of withdrawal from the study). UC disease activity was assessed using a revised Sutherland Disease Activity Index (SDAI), which evaluates rectal bleeding, mucosal appearance, stool frequency, and physician rating of disease activity, each on a scale of 0 to 3 (3 being the highest rating for disease activity), with a maximum total score of 12 [14]. The revision to the SDAI was the deletion of “friability” from a mucosal appearance score equal to 1 to clarify the definition of remission. All four components of the SDAI were evaluated at screening and at month 6. An abbreviated SDAI, which excluded mucosal appearance, was evaluated on day 1 and at the end of months 1 and 3. Adverse events were monitored throughout the treatment period, and clinical laboratory evaluations and vital signs were assessed at each visit and at follow-up. Compliance was assessed by pill counts at months 1, 3, and 6 during the scheduled visits.

Patients Both studies enrolled patients ≥18 years of age with a confirmed diagnosis of mild to moderate UC in remission (rectal bleeding score of 0 and mucosal appearance score of ≤1) for ≥1 month and ≤12 months, with a history of ≥1 flare with symptoms within the past 1 to 12 months before screening that required intervention, and who had not received corticosteroids or immunosuppressive agents within 30 days before screening. Exclusion

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criteria included evidence of impaired immune function; prior bowel surgery except appendectomy; positive serology results for human immunodeficiency virus or hepatitis (B or C); renal disease manifested by serum creatinine or blood urea nitrogen 1.5 times the upper limit of normal (ULN); calculated creatinine clearance (Cockcroft-Gault calculation) level of ≥60 mL/min; liver disease manifested by 2 times the ULN for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, or total bilirubin.

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Efficacy and safety assessments The pooled intent-to-treat (ITT) population was defined as patients who enrolled in either of the double-blind trials and who received ≥1 dose of study medication. The primary outcome measure was the percentage of patients who remained relapse-free after 6 months of treatment or at the EOT visit with MG versus placebo treatment. Relapse was defined as a rectal bleeding score of ≥1 and mucosal appearance score of ≥2 on the SDAI. In addition, a UC flare or initiation of medication previously used to treat a UC flare, or early study termination if the reason for termination was lack of efficacy or the occurrence of an adverse event related to UC (abdominal pain, abdominal tenderness, UC, diarrhea, frequent bowel movements, hematochezia, loose stools, proctitis, rectal hemorrhage, rectal tenesmus, stomach discomfort, or watery stools) was considered a treatment failure (a relapse). Subgroup analyses for the primary outcome measure were performed across subgroups based on the following demographic and baseline characteristics: age (≤45 years versus >45 years); sex (male versus female); country (US versus Russia); body mass index (≤27 kg/m2 versus >27 kg/m2); disease duration (