Clinical trial: once-daily mesalamine granules for maintenance of remission of ulcerative colitis – a 6-month placebo-controlled trial

Authors


Dr W. P. Forbes, Salix Pharmaceuticals, Inc., 1700 Perimeter Park Drive, Morrisville, NC 27560, USA.
E-mail: Bill.Forbes@salix.com

Abstract

Aliment Pharmacol Ther 2010; 32: 990–999

Summary

Background  Ulcerative colitis (UC) is a chronic relapsing and remitting idiopathic inflammatory bowel disorder.

Aim  To evaluate once-daily mesalamine (mesalazine) granules (MG) for maintenance of remission of UC.

Methods  Randomized, double-blind, placebo-controlled trial of patients (n = 209 MG, n = 96 placebo) with UC in remission [revised Sutherland Disease Activity Index (SDAI) rectal bleeding = 0, mucosal appearance <2] who took MG 1.5 g or placebo once-daily for up to 6 months. Primary efficacy endpoint: the percentage of patients who remained relapse-free at month 6/end of treatment. Relapse was defined as SDAI rectal bleeding score ≥1 and a mucosal appearance score ≥2, a UC flare, or initiation of medication to treat a UC flare.

Results  The percentage of relapse-free patients at month 6/end of treatment was higher with MG than placebo (78.9% vs. 58.3%, < 0.001) in the intent-to-treat analysis. Significant differences (P ≤ 0.025) favouring MG were observed for most secondary endpoints including improvement in rectal bleeding, physician’s disease activity rating, stool frequency, the SDAI at month 6/end of treatment, patients classified as a treatment success and relapse-free duration. The incidence of adverse events was similar between groups.

Conclusions  Once-daily mesalamine (mesalazine) was effective in maintaining remission of UC for 6 months.

Introduction

Ulcerative colitis (UC) is a chronic, relapsing and remitting idiopathic inflammatory bowel disorder that impairs quality of life, disrupts the patient’s ability to partake in daily activities, and is associated with an elevated risk of morbidity and mortality from associated digestive diseases including colorectal cancer.1–4 Long-term maintenance of symptomatic remission and maintenance of mucosal healing are main goals of therapy.5 Effective maintenance of remission of inflammatory bowel disease reduces the risk of complications and the need for surgery, and improves patients’ well-being and functional ability.6–9

Mesalamine (5-aminosalicylic acid; 5-ASA) and its derivatives are the mainstay of therapy for the induction and maintenance of remission in patients with UC.5 These agents act topically on the gastrointestinal mucosa and inhibit multiple inflammatory processes.10 Several oral 5-ASA agents differentiated by their delivery systems have been developed. Time- and pH-dependent delivery systems are available as are azo-bonded prodrugs that release 5-ASA in the colon upon exposure of the prodrug to colonic bacteria.10 When given for maintenance of remission of UC, 5-ASA agents are conventionally administered in multiple daily doses in various dosing schedules that may contribute to non-adherence to the therapeutic regimen,11–13 a major cause of UC relapse.14, 15

Mesalamine granules (MG), a unique formulation that was designed with the aim of maximizing drug delivery to the colon and minimizing systemic absorption, were approved for the maintenance of remission of UC in the United States in October 2008 [Apriso™ (mesalamine) extended-release capsules; Salix Pharmaceuticals, Inc., Morrisville, NC, USA]. MG is dosed once-daily with or without food as four capsules containing 0.375 g of mesalamine granules each. The delayed-release enteric coating on each granule begins to dissolve at pH 6 and above, and the extended-release polymer matrix core is designed for the targeted, gradual release of mesalamine to the terminal ileum and throughout the colon. The release of mesalamine beginning at pH 6 may be beneficial, because recent studies have shown that in some patients with UC, a luminal pH ≥6 is sustained, whereas a value ≥7 is reached transiently.16, 17

The study described herein is the first Phase III, randomized, double-blind, placebo-controlled trial conducted over 6 months to assess the efficacy and safety of once-daily MG for the maintenance of remission of UC.

Methods

Patients

Men and non-pregnant, nonlactating women ≥18 years of age were eligible for the study if they had a confirmed diagnosis of UC and were in remission for at least 1 month, but not more than 12 months, a history of at least one flare with symptoms that required intervention within 1–12 months before screening, and had not used steroids or immunosuppressive agents within 30 days before screening. Remission was defined as both a rectal bleeding score of 0 (no bleeding) and a mucosal appearance score of 0 or 1 on the revised Sutherland Disease Activity Index (SDAI)18, 19 as described below, at screening. Exclusion criteria included evidence of impaired immune function; receipt of immunosuppressive therapy or corticosteroids within 30 days before screening; prior bowel surgery except appendectomy; positive serology results for human immunodeficiency virus or hepatitis B or hepatitis C; presence of infectious, ischaemic, or immunological diseases involving the gastrointestinal tract; renal disease manifested by serum creatinine or blood urea nitrogen 1.5 times the upper limit of normal; liver disease manifested by values twice the upper limit of normal for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or total bilirubin. Patients were prohibited from using immunosuppressants, chronic nonsteroidal anti-inflammatory drugs, corticosteroids, oral antibiotics (except as 7- to 10-day courses for conditions unrelated to UC), psyllium-containing intestinal regulators and 5-ASAs.

Procedures

Salix Pharmaceuticals, Inc. sponsored this study (Salix protocol MPUC3003), which was registered under the ClinicalTrials.gov (http://clinicaltrials.gov/) identifier NCT00744016. A total of 48 centres participated in this study (42 in the United States and 6 in Russia). The study was started in December 2004 (first subject, first visit) and completed in April 2007 (last subject, last visit). The protocol was approved by institutional review boards or ethics committees and conducted in accordance with ICH guidelines and other applicable laws and regulations. All patients provided written informed consent.

The study included a screening phase completed within a week before randomization and a treatment phase that lasted up to 6 months. Eligible patients were uniquely identified by a consecutively assigned ID number, allocated in the order of enrolment within each study site. Patients who continued to meet eligibility criteria at Visit 1 [Baseline/Randomization (day 1)] were assigned a unique Treatment ID number via a randomization schedule. Treatments were randomly assigned to consecutive treatment numbers using an allocation ratio of 2:1 to receive MG 1.5 g once-daily (dosed as four capsules, 0.375 g mesalamine each) or matching placebo in a double-blinded fashion for up to 6 months during the treatment phase. The investigators, the subjects and the research staffs (including project biostatisticians) were blinded to study medication assignment until after database lock at the end of the study. Study drug was self-administered by patients on an out-patient basis; four capsules were taken together once-daily.

The treatment phase included four clinic visits [at randomization (baseline) on day 1 and at the end of months 1, 3, and 6] to assess disease activity and monitor patients for adverse events. Per protocol, if at any time during the study a patient experienced a UC flare, including rectal bleeding, an unscheduled visit occurred; patients meeting relapse criteria based on the physician’s assessment were withdrawn from the study, and treated per standard of care. In addition, a flexible sigmoidoscopy was performed at screening and at the end of month 6 (or upon premature withdrawal from the study). Disease activity was assessed with the SDAI, which evaluates stool frequency, rectal bleeding, mucosal appearance and physician’s rating of disease severity on scales of 0 to 3 with a maximum total score of 12.18–22 All four components of SDAI were evaluated at screening and month 6 (or upon premature withdrawal from the study); an abbreviated SDAI including all indices except mucosal appearance were evaluated on day 1 (baseline) and at the end of months 1 and 3. Treatment-emergent adverse events and serious adverse events were monitored throughout the treatment period. Clinical laboratory evaluations and vital signs were assessed at each visit during the study and at a follow-up visit 2 weeks after the end of study.

Endpoints and data analysis

Efficacy data were analysed for the intent-to-treat (ITT) population, defined as randomized patients who received at least one dose of study medication. The primary efficacy endpoint was the percentage of patients who remained relapse free after 6 months of treatment. Relapse or treatment failure was defined as a rectal bleeding score ≥1 and a mucosal appearance score ≥2 on the SDAI, a UC flare, or initiation of medication previously used to treat a UC flare. In the primary efficacy analysis, premature withdrawal from the study was not considered to be a relapse unless the reason for early termination was lack of efficacy or a UC-related adverse event. For patients prematurely withdrawing from the study for other reasons, the last SDAI assessment was used to determine relapse status. Safety endpoints included the incidence of treatment-emergent adverse events, and change from baseline in laboratory parameters; these were analysed for randomized patients who received at least one dose of study medication, with one post-baseline safety assessment (safety population).

Secondary efficacy endpoints were the percentages of patients with each level of change from baseline in rectal bleeding score, mucosal appearance score, physician’s rating of disease activity and stool frequency on the SDAI at months 1, 3, and 6/end of treatment; mean change from baseline in the SDAI at month 6/end of treatment; the percentage of patients classified as treatment successes, defined as maintaining the SDAI total score ≤2 with no individual component >1 and rectal bleeding score of 0 at month 6/end of treatment; and relapse-free duration, defined as the number of days between the start of study medication and the date of first relapse or premature withdrawal from the study plus 1 day. The last-observation-carried-forward (LOCF) methodology was used for imputing missing values for secondary efficacy endpoints for patients who prematurely withdrew from the study.

In sample-size calculations, it was estimated that 200 patients in the group receiving MG and 100 patients in the placebo group would provide ≥90% power (β = 0.10) to reject the null hypothesis of no difference between treatment groups with a 2-sided significance level of 5% (α = 0.05), a 2:1 allocation ratio, and the assumption of a relapse-free rate of 70% with MG and 50% with placebo.

The treatment groups were compared on the primary endpoint with a Cochran-Mantel-Haenszel test controlled for country. Statistical testing of the secondary endpoints was performed in a predefined hierarchical fashion until a nonsignificant P-value was identified (> 0.05), after which point significance tests were considered supportive. Differences between treatment groups were tested with a Cochran-Mantel-Haenszel test controlled for country for the categorical variables and with rank analysis of covariance adjusted for baseline value and country for mean change from baseline in the SDAI at month 6/end of treatment. For relapse-free duration, a Cox proportional hazards regression model adjusted for country was used to assess differences between treatment groups, and Kaplan–Meier methods were used to calculate cumulative relapse-free probability estimates for each treatment group at months 1, 3, and 6/end of treatment. Chi-squared tests were used to identify the week at which MG separated from placebo with respect to relapse-free probability. Safety data were summarized with descriptive statistics for the Safety population.

Demographics, baseline clinical characteristics and compliance were summarized with descriptive statistics. Compliance was calculated using pill counts (i.e. number of tablets dispensed and returned) and the following equation:

image

A patient was considered compliant per the protocol if he or she took at least 70% of the study drug.

Results

Patients

Of 356 patients screened for the study, 305 were randomized to treatment (n = 209 MG, n = 96 placebo). All 305 randomized patients received at least one dose of study medication and were included in the ITT population. Five (5) of these 305 patients did not return a post-baseline safety assessment; therefore, 300 patients were included in the safety population. Figure 1 shows patient disposition. As noted previously, UC relapse or treatment failure was defined as a rectal bleeding score ≥1 and a mucosal appearance score ≥2 on the SDAI, a UC flare, or initiation of medication previously used to treat a UC flare; 19.6% MG-treated patients and 39.6% placebo-treated patients were withdrawn from the study for UC relapse, and 4.3% MG and 2.1% placebo-treated patients were withdrawn due to other adverse events.

Figure 1.

 Patient disposition. The category ‘UC relapse’ above include patients who withdrew from the study with a reason of lack of efficacy and/or due to a UC-related adverse event, as mandated per protocol, to receive standard of care. Withdrawals due to non-UC related adverse events are listed under the category ‘adverse event’.

Demographics and baseline disease characteristics were similar between treatment groups (Table 1). The mean time since the most recent UC flare was 25.6 weeks in both groups, and the mean duration of remission was approximately 16 weeks. The mean baseline SDAI score was 0.8 (s.d. 0.8) in the group receiving MG and 1.0 (s.d. 1.3) in the placebo group.

Table 1.   Demographics and baseline disease characteristics
 Mesalamine granules (n = 209)Placebo (n = 96)
  1. * Patients could indicate more than one racial category and therefore could be represented in more than one category.

Demographics
 Age, years: mean (s.d.)47 (14)46 (14)
 Male gender: n (%)92 (44)53 (55)
 Race:*n (%)
  American Indian/Alaskan Native4 (2)0 (0)
  Asian1 (<1)0 (0)
  Black/African American19 (9)11 (12)
  White188 (90)85 (89)
 Body mass index, kg/mg2: mean (s.d.)27 (6)26 (5)
Disease characteristics
 Duration of disease, weeks: mean (s.d.)310 (322)313 (311)
 Time since last flare, weeks: mean (s.d.)26 (13)26 (13)
 Duration of current remission, weeks: mean (s.d.)17 (11)16 (11)
 Baseline SDAI scores: mean (s.d.)
  Total0.8 (0.8)1.0 (1.3)
  Stool frequency0.1 (0.2)0.1 (0.4)
  Rectal bleeding0.0 (0.0)0.0 (0.2)
  Mucosal appearance0.5 (0.5)0.7 (0.5)
  Physician’s rating of severity0.2 (0.4)0.2 (0.5)

The mean compliance for the duration of the treatment period was 96.2% (s.d. 11.6) and 96.7% (s.d. 6.4) for the MG and placebo groups, respectively.

Primary efficacy endpoint: proportion of relapse-free patients

In the primary efficacy analysis, the proportion of patients who were relapse free at month 6/end of treatment was significantly higher in the group receiving MG compared with the placebo group (78.9% vs. 58.3%, < 0.001) (Figure 2). In this analysis, patients who prematurely withdrew from the study were not counted as having relapsed unless they withdrew for lack of efficacy or a UC-related adverse event.

Figure 2.

 Primary efficacy analysis: the percentage of patients relapse free at month 6/end of treatment. Patients were counted as treatment failures if they withdrew for lack of efficacy or an ulcerative colitis-related adverse event.

Patients in the MG group had a higher probability of remaining relapse-free (Figure 3). The hazard ratio for the risk of relapse in the group receiving MG relative to that in the placebo group was 0.42 (95% CI 0.27, 0.65), a result reflecting a 58% reduction in the risk of relapse with MG compared with placebo over the 6-month treatment period. For the probability of remaining relapse-free, a number-needed-to-treat analysis revealed that one UC relapse was prevented for every five patients treated with MG.

Figure 3.

 Kaplan–Meier estimates of time to relapse during the treatment period in the ITT population.

Secondary efficacy endpoints

Statistically significant differences favouring MG over placebo were observed for most secondary efficacy endpoints, including the proportions of patients at each level of change from baseline in the SDAI scores for rectal bleeding (= 0.008), physician’s rating of disease activity (= 0.005), and stool frequency (= 0.005); the proportion of patients classified as treatment successes (= 0.003); mean change from baseline in the SDAI total score (= 0.025); and probability of remaining relapse-free over 6 months (< 0.001) (Table 2). For the remaining secondary efficacy endpoint (the proportion of patients at each level of change from baseline in the SDAI score for mucosal appearance), numerical results favoured MG, but were not significant at the  0.05 level (= 0.098) (Table 2). With the predefined hierarchical testing strategy employed for secondary endpoints, significance tests were considered supportive after a nonsignificant P-value was identified. Therefore, the significance tests for all secondary endpoints except change from baseline in rectal bleeding score and change from baseline in mucosal appearance were considered supportive (Table 2).

Table 2.   Summary of results for secondary efficacy endpoints*
 Mesalamine granules (n = 209)Placebo (n = 96)P-value
  1. * Statistical testing of the secondary endpoints was performed in a predefined hierarchical fashion in the order listed in this table until a nonsignificant P-value was identified (> 0.05), after which point significance tests were considered supportive.

Change from baseline in rectal bleeding score at month 6/end of treatment, n (%)
 −10 (0.0)1 (1.0)0.008
  0170 (81.3)64 (66.7) 
  122 (10.5)11 (11.5) 
  216 (7.7)19 (19.8) 
  31 (0.5)1 (1.0) 
Change from baseline in mucosal appearance at month 6/end of treatment, n (%)
 −132 (15.3)13 (13.5)0.098
  0129 (61.7)51 (53.1) 
  132 (15.3)20 (20.8) 
  214 (6.7)11 (11.5) 
  32 (1.0)1 (1.0) 
Change from baseline in physician’s rating of disease at month 6/end of treatment
 −21 (0.5)0 (0.0)0.005
 −116 (7.7)6 (6.3) 
  0146 (69.9)55 (57.3) 
  135 (16.7)17 (17.7) 
  210 (4.8)18 (18.8) 
  31 (0.5)0 (0.0) 
Maintenance of SDAI ≤2 with no individual component >1 and rectal bleeding = 0 at month 6, n (%)147 (70.3)51 (53.1)0.003
Mean (s.d.) change from baseline in the SDAI at month 6/end of treatment0.9 (2.4)2.0 (3.3)0.025
Month 6 cumulative relapse-free probability (SE)0.77 (0.03)0.56 (0.05)<0.001
Change from baseline in stool frequency at month 6/end of treatment
 −14 (1.9)1 (1.0)0.005
  0167 (79.9)64 (66.7) 
  120 (9.6)11 (11.5) 
  28 (3.8)11 (11.5) 
  310 (4.8)9 (9.4) 

Safety and tolerability

The percentage of patients with ≥1 treatment-emergent adverse event was 64% in each treatment group. Other than worsening UC, the only treatment-emergent adverse events reported in ≥10% of patients in either treatment group was headache. Headache was reported in a higher percentage of patients treated with MG (11% MG, 7% placebo). Table 3 lists treatment-emergent adverse events reported in ≥3% of patients in a treatment group and reported more frequently with MG than placebo.

Table 3.   Treatment-emergent adverse events reported in ≥3% of patients in a treatment group and reported more frequently with mesalamine granules than placebo
 Mesalamine granules n = 206
n (%)
Placebo n = 94
n (%)
Headache23 (11)7 (7)
Diarrhoea18 (9)7 (7)
Abdominal pain15 (7)6 (6)
Nasopharyngitis10 (5)3 (3)
Upper abdominal pain8 (4)3 (3)
Abnormal faeces (mucous in stool)7 (3)2 (2)
Back pain6 (3)2 (2)
Nausea7 (3)1 (1)

Treatment-emergent adverse events affecting the renal or hepatic systems were rare in both treatment groups. One patient in the MG group had mild creatinine clearance decrease that was considered related to study drug, and was withdrawn from the study. Elevations in liver-associated laboratory chemistry results reported as treatment-emergent adverse events were less frequent in patients receiving MG than in patients receiving placebo: <1% of patients vs. 4% of patients for elevated AST; 0% vs. 4% for elevated ALT; and <1% vs. 2% for elevated ALP.

No deaths were reported in the study. Serious adverse events were reported in four patients: two in the group receiving MG and two in the placebo group. In the group receiving MG, one patient experienced moderate distal esophagitis after 21 weeks of treatment; another patient experienced a moderate UC flare after 11 weeks of treatment and was hospitalized 6 days after discontinuing study drug and initiating rescue therapy for UC. The investigators did not consider either of these events to be caused by study medication. In the placebo group, one patient experienced a serious adverse event of UC flare after 17 weeks and 4 days of treatment. The investigator considered this event possibly related to study medication. Another placebo-treated patient developed a severe opportunistic infection secondary to a pre-existing lymphedema after 22 weeks of treatment. The investigator did not consider this event to be caused by study medication.

In addition to UC-related events, the percentage of patients with treatment-emergent adverse events (other than UC) that led to premature withdrawal from the study was 4.3% in the MG group and 2.1% in the placebo group (Figure 1).

Mean changes from baseline in clinical laboratory test results showed no meaningful differences between the MG and placebo groups. Likewise, no meaningful differences were observed in shifts to high or low clinical laboratory values, including those for total bilirubin, AST, ALT, serum creatinine and calculated creatinine clearance.

Discussion

In this study, MG administered once-daily for up to 6 months provided significant protection against UC relapse. A higher percentage of patients treated with MG (78.9%) were relapse-free for the duration of the 6-month treatment period compared with placebo-treated patients (58.3%). Over the 6-month treatment period, MG reduced the risk of relapse by 58% compared with placebo, demonstrating a substantial protective effect of MG in the primary efficacy analysis. Secondary efficacy measures support the primary analysis in demonstrating significantly greater probability of remaining relapse-free over 6 months, as well as significantly better scores for rectal bleeding, physician’s rating of disease activity and stool frequency. These results in conjunction with data from other research, including another Phase III trial of the same design,19 supported the October 2008 licensing of MG in the United States for once-daily dosing for the maintenance of remission of UC in patients 18 years of age and older. In the replicate Phase III trial,19 as in the current study, MG was statistically superior to placebo for the primary endpoint, the percentage of patients remaining relapse-free after 6 months of treatment.

In the current study, the only adverse event occurring in >2% and more frequently with MG than placebo patients was headache, a known side effect of 5-ASA agents.23, 24 Patient withdrawals due to UC relapse were twofold lower in the group receiving MG vs. placebo. The incidences of adverse events affecting the hepatic and renal systems – which have been reported, albeit rarely, with other mesalamine formulations23–25– were low and similar in both groups.

Two large Phase III, double-blind, placebo-controlled pivotal trials demonstrated efficacy of a once-daily mesalamine formulation [Lialda™ (USA), Mezavant™ (EU); also known as MMX mesalamine and SPD476; Shire Pharmaceuticals Inc., Wayne, PA, USA, under license from Giuliani SpA, Milan, Italy] for induction of remission of active, mild-to-moderate UC.26, 27 However, to date, only four studies have been published that evaluated once-daily mesalamine vs. conventional dosing for maintenance of remission of UC, none of which included a placebo arm.28–31 The first was a 6-month pilot study that showed similar relapse rates between dosing regimens,28 and the second was a 12-month randomized open-label trial, which showed that both dosing regimens were equally effective in maintaining UC remission.29 The third study, a single-blind non-inferiority trial of 362 patients with quiescent UC, showed better remission rates and self-reported adherence to therapy with once-daily dosing.30 The fourth study, a large single-blind non-inferiority trial of 1023 patients with mild-to-moderate UC, reported that once-daily and twice-daily dosing regimens were equally effective in maintaining UC remission.31

The study described herein is the first report of a 6-month, Phase III, randomized, double-blind, placebo-controlled trial that clearly established the efficacy of a novel once-daily delayed and extended release mesalamine formulation vs. placebo for the maintenance of remission of UC. The delayed-release enteric coating on the 5-ASA-containing granules within the capsules dissolves at a lower pH (≥6) compared with other delayed-release formulations and may be particularly advantageous as it has been recently reported that a luminal pH ≥6 was sustained, but a value ≥7 was only transiently reached after consumption of a standardized breakfast in patients with mildly to moderately active UC.17In addition, a majority of healthy volunteers reach a pH ≥6 at the small bowel; however, a substantial minority do not reach pH ≥7.16 A formulation comparable to MG with similar pH release characteristics was shown to result in mesalamine distribution at target regions in the gastrointestinal tract, the terminal ileum and ascending colon.32

The once-daily 1.5-g dose of MG taken with or without food provides simple and effective long-term protection from UC flares. The compliance rate for this once-daily administration, on average, exceeded 95% over the 6-month treatment period. To date, the dosing regimens of all other mesalamine products licensed in the US for the maintenance of remission of UC require multiple doses per day, which might reduce compliance in some patients.11–15

In conclusion, this study demonstrated that MG, a unique once-daily formulation of mesalamine in a delayed and extended release dosage form, was effective in the long-term maintenance of remission of UC. Approximately eight of 10 patients on active treatment maintained remission for the 6-month treatment period compared with approximately 6 of 10 placebo-treated patients. MG treatment resulted in clinically favourable and statistically significant scores for rectal bleeding, physician’s rating of disease activity and stool frequency, when compared with placebo.

Acknowledgements

Declaration of personal interests: Dr Lichtenstein, Dr Gordon and Dr Zakko have received honoraria for consulting with Salix Pharmaceuticals. Dr Zakko has received an unrestricted grant from Salix Pharmaceuticals and holds stock in the company. Dr Gordon, Dr Zakko, Dr Murthy, Dr Sedghi, and Dr Pruitt were investigators for the clinical trial described in this manuscript. Dr Merchant, Dr Shaw and Dr Bortey are employees of Salix Pharmaceuticals and hold stock in the company. Dr Forbes is an officer and employee of Salix Pharmaceuticals and holds stock in the company. Declaration of funding interests: This study was funded by Salix Pharmaceuticals, who performed the data analyses. The authors thank Jane Saiers, PhD, of The WriteMedicine, Inc., who provided writing support and Andrew Grigston, David Sorscher and Kristofer Klein (employees of Salix Pharmaceuticals), who assisted with critical review and editing of the manuscript. Dr Saiers’ work was funded by Salix Pharmaceuticals.

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