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Enteric-Coated Mycophenolate Sodium Versus Mycophenolate Mofetil in Renal Transplant Recipients Experiencing Gastrointestinal Intolerance: A Multicenter, Double-Blind, Randomized Study

Langone, Anthony J.1,5; Chan, Laurence2; Bolin, Paul3; Cooper, Matthew4

doi: 10.1097/TP.0b013e318205568c
Clinical and Translational Research
Free
SDC

Background. Two open-label studies demonstrated that conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) significantly reduces gastrointestinal (GI) symptom burden and improves GI-specific health-related quality of life. Using a randomized design, this study evaluated changes in GI symptoms and health-related quality of life in patients converted from MMF to EC-MPS versus patients who continued with MMF-based treatment.

Methods. In this 4-week, multicenter, randomized, prospective, double-blind, parallel-group trial, renal transplant recipients with GI symptoms receiving MMF plus a calcineurin inhibitor±corticosteroids were randomized to an equimolar dose of EC-MPS+MMF placebo or continue on their MMF-based regimen+EC-MPS placebo. The primary efficacy outcome was a change from baseline in total Gastrointestinal Symptom Rating Scale score of a minimally important difference of more than or equal to 0.3.

Results. Three hundred ninety-six patients (EC-MPS group: n=199; MMF group: n=197) were included. A greater proportion of EC-MPS patients (62%) reached the primary efficacy outcome compared with MMF patients (55%); however, the difference was not statistically significant (P=0.15). EC-MPS patients had a significantly greater decrease in the Gastrointestinal Symptom Rating Scale indigestion syndrome dimension versus MMF patients. Within the subgroups of patients with diabetes, patients transplanted 6 to 12 months of study enrollment, and patients on steroids, a statistically significant greater proportion of EC-MPS versus MMF patients reached the primary efficacy outcome.

Conclusions. Conversion from MMF to EC-MPS may be associated with improvements in presence and severity of GI symptoms, particularly in patients with indigestion, diabetes, on steroids, and in patients converted between 6 and 12 months posttransplantation.

1 Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN.

2 Division of Nephrology, University Colorado Health Sciences Center, Denver, CO.

3 Division of Nephrology and Hypertension, Brody School of Medicine at East Carolina University, Greenville, NC.

4 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.

This work was supported by Novartis Pharmaceuticals Corporation.

5 Address correspondence to: Anthony Langone, M.D., S-3223 MCN, Vanderbilt University Medical School, Nashville, TN 37232.

E-mail: anthony.langone@vanderbilt.edu

A.J.L. participated in the study design and execution, direct participation with patient recruitment, data analysis, and writing of the manuscript; and L.C., P.B., and M.C. participated in the study design and execution, direct participation with patient recruitment, and writing of the manuscript.

Received 12 May 2010. Revision requested 1 June 2010.

Accepted 3 November 2010.

Mycophenolate mofetil (MMF, CellCept, Nutley, NJ) is an esterified prodrug of mycophenolic acid (MPA), which inhibits inosine monophosphate dehydrogenase and consequently the pathway of de novo guanosine nucleotide synthesis. T and B lymphocytes are critically dependent on de novo synthesis of purines for their proliferation, whereas other cell types can use salvage pathways. As a consequence, the cytostatic effects of MPA are more selective for lymphocytes than on other cell types (1).

MMF is associated with excellent short- and long-term efficacy after renal transplantation (2–5). However, dose reductions, omissions, and impaired compliance subsequent to MMF-related gastrointestinal (GI) toxicity are associated with an increased risk of rejection (6–8) and graft loss (8–10). MMF dose adjustments are also associated with increased short-term treatment costs (7).

Enteric-coated mycophenolate sodium (EC-MPS [Myfortic, Novartis, East Hanover, NJ]) is an advanced formulation of MPS that delays the release of the MPA until it reaches the duodenum where the enteric pH rises above 5. EC-MPS was developed with the aim to improve GI tolerability of MPA therapy. EC-MPS is not bioequivalent to MMF (11), although the area under the curve is similar, and EC-MPS is equal in efficacy and safety to MMF (12–14). Compared with MMF, the use of EC-MPS is associated with fewer dose changes, interruptions, and discontinuations (15).

Two published open-label trials concluded that GI improvements occurred after a conversion from MMF to EC-MPS. Patient Reported Outcomes in Renal Transplant Patients with or without Gastrointestinal Symptoms (PROGIS) was a 1-month, longitudinal, international, multicenter trial where GI outcomes were evaluated for patients with MMF-associated GI complaints converted to EC-MPS. Conversion to EC-MPS was associated with significantly reduced GI-related symptom burden and improved patient functioning and well being (16). The study also incorporated a cohort where patients without GI complaints who remained on MMF were followed up.

MyTime was a 3-month, longitudinal, US multicenter, prospective trial in adult renal transplant patients with self-reported GI symptoms considered by their physician to be related to MMF who were converted to an equimolar dose of EC-MPS. Significantly reduced GI symptom scores, improved GI-specific quality of life, and improved overall well being were observed after conversion from MMF to EC-MPS (17).

This study was conducted to further evaluate the potential for GI tolerability improvements in an MMF to EC-MPS conversion protocol. The aim of this study was to investigate, in a blinded, randomized fashion, the safety and tolerability of converting kidney transplant recipients with MMF-associated GI symptoms to an equimolar dose of EC-MPS. The comparator arm was composed of patients who continued on their MMF-based regimen.

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RESULTS

Patient Disposition and Baseline Characteristics

Details on patient disposition are included in Table 1. Four hundred patients from 67 centers (56 United States, 6 Canada, and 5 Mexico) were enrolled in the study (200 in EC-MPS group and 200 in MMF group). The ITT and safety population included 199 (99.5%) of enrolled patients in the EC-MPS group and 197 (98.5%) of enrolled patients in the MMF group. The per-protocol population included 170 (85.0%) of enrolled patients in the EC-MPS group and 171 (85.5%) of enrolled patients in the MMF group.

TABLE 1

TABLE 1

Patients in the EC-MPS and MMF groups were similar in demographic characteristics with no statistically significant differences between the groups in age, gender, race, time since most recent transplant, or types of end-stage renal disease leading to transplantation (Table 2). Mean GSRS total scores at baseline were the same for EC-MPS and MMF (2.6±0.9) patients. There was no difference in the use of proton pump inhibitors (EC-MPS 105 [52.8%] and MMF 106 [53.8%]). Demographic and background characteristics in the per-protocol population were similar to those in the ITT population.

TABLE 2

TABLE 2

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MPA Exposure

The average daily dose of MMF at baseline was similar in both groups (1410 vs. 1389 mg MMF) as was the mean and median duration of exposure to study medication. Most (>95%) of the patients received more than or equal to 2 weeks of exposure to study medication, and 59% of patients in the EC-MPS and 61% in the MMF group received 30 days of exposure. However, 90.9% had more than or equal to 27 days of exposure. At the end of the study, the average doses (equimolar) were 1053 mg EC-MPS (the equivalent of 1465 mg MMF) and 1491 mg MMF (1102 mg as MPA).

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Primary and Secondary Efficacy Results

A numerically greater proportion of patients in the EC-MPS group (62%) had an improvement in GSRS total score of at least 0.3 compared with patients in the MMF group (55%). However, the difference in response rates was not statistically significant (P=0.15). Similarly, for the per-protocol population, a numerically greater proportion of patients in the EC-MPS group (64%) had an improvement in GSRS total score of at least 0.3 compared with patients in the MMF group (58%). However, the difference in response rates was not statistically significant (P=0.25).

One patient in the MMF group experienced BPAR (Banff type I-A) that was noted at visit 2 because of an increase in serum creatinine to 1.9 mg/dL. The patient was treated with methylprednisolone and rehydrated, and the event was considered resolved 10 days later. There were no cases of AR in the EC-MPS group.

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Secondary Safety and Tolerability Results

The Proportion of Patients With GI Adverse Events During the 30 Days of Treatment

GI adverse events (AEs) were relatively frequent (39% EC-MPS and 46% MMF) and constituted the system organ class with the highest number of AEs overall (Table 3). The proportion of patients with severe GI AEs was similar in both groups (11% EC-MPS and 13% MMF). Related GI AEs occurred at a similar frequency in both groups (20% EC-MPS and 22% MMF). Serious GI AEs occurred at a low rate in both groups (1% EC-MPS and 2.5% MMF).

TABLE 3

TABLE 3

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Change From Baseline to Day 30 in Severity of GI Symptoms

Patients in the EC-MPS group had a statistically significant (P=0.03) greater improvement in total GI symptom score from baseline to day 30 than patients in the MMF group. Patients in the EC-MPS group also had a statistically significant (P<0.05) greater improvement in GI symptom subscale symptom scores including eructation, lower GI, constipation, and flatulence, compared with patients in the MMF group (Table 4).

TABLE 4

TABLE 4

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Dose Changes or Interruptions

Dose changes or interruptions were relatively infrequent and did not significantly differ (P=0.44) between the treatment groups (11/199 [5.5%] patients in the EC-MPS group vs. 12/197 [6.1%] patients in the MMF group had dose changes or interruptions of study medication over the 30 days of treatment). Dose adjustments were most commonly made as per protocol (7 [3.5%] EC-MPS and 5 [2.5%] MMF), reflecting dose increases back to baseline levels after a decrease or interruption or because of AEs (e.g., leucopenia, thrombocytopenia, neutropenia, or anemia; 5 [2.5%] EC-MPS and 8 [4.1%] MMF), primarily affected by dose decreases in response to these laboratory values. No patients had their dose interrupted for safety reasons for more than 4 consecutive days during the first 2 weeks of the study or for more than 12 consecutive or cumulative days during the 30-day study period. The total number of patients with any amount of drug interruption was trivial. Three patients in the EC-MPS treatment arm and two patients in the MMF group interrupted the study drug for a cumulative total of 14 days among the five patients.

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Change From Baseline to Day 30 in GSRS Total and Dimension Scores and in GIQLI Total and Subscale Scores

Statistically significant (P<0.0001) decreases from baseline in overall GSRS were seen in both the EC-MPS (mean decrease from baseline to day 30: −0.6±0.9) and MMF (−0.5±1.0) treatment groups. Between-group differences in change from baseline at day 30 were not statistically significant (P>0.05). GSRS dimension scores were similar for the EC-MPS and MMF groups at baseline and declined in both groups at day 30 compared with baseline. A statistically significant (P=0.02) greater decrease for the indigestion syndrome was seen in the EC-MPS group compared with the MMF group (mean change: EC-MPS: −0.7±1.2 and MMF: −0.5±1.4). Statistically significant changes from baseline to day 30 were not observed for diarrhea, constipation, abdominal pain, or reflux.

The baseline GIQLI scores were similar between the treatment groups (P>0.05). The mean overall and subscale scores significantly (P≤0.003) improved in both treatment groups compared with baseline with no statistically significant difference between the EC-MPS and MMF groups in the change from baseline.

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Proportion of Patients at Day 30 Who Were Free of at Least One of the GI Symptoms That Were Present at Baseline

There were no statistically significant (P=0.62) differences between treatment groups in the proportion of patients who were free of diarrhea, dyspepsia, acid reflux, or abdominal pain that was present at baseline (% free of symptom at day 30: EC-MPS: 65% and MMF: 62%). For diarrhea specifically, the proportion of patients who were symptom free was numerically greater in the EC-MPS group (42%) compared with the MMF group (35%), but the difference was not statistically significant (P=0.33). The proportion of patients whose diarrhea improved (EC-MPS: 64% and MMF: 67%), remained the same (EC-MPS: 30% and MMF: 30%), or worsened (EC-MPS: 6% and MMF: 3%) since baseline was similar in both groups (P=0.28). A greater proportion of patients in the MMF (43%) versus the EC-MPS (37%) group had a new or worsening GI AE during the study; however, the difference was not statistically significant (P=0.10).

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OTE-HRQoL Scores at Day 30

The mean OTE-HRQoL score declined in both the EC-MPS (mean decrease: −1.7±3.2) and the MMF (mean decrease: −1.9±2.7) treatment groups compared with baseline, but there was no statistically significant difference between the treatment groups (P=0.57). Categorical changes from baseline (better: EC-MPS=43% and MMF=48%; same: EC-MPS=50% and MMF=46%; worse: EC-MPS=7% and MMF=6%) at day 30 were also similar between the groups (P=0.32).

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Efficacy Results: Planned Subgroup and Post Hoc Analyses

Because CNIs can contribute significantly to GI side effects and are more likely in patients taking tacrolimus, a separate analysis was performed for cyclosporine versus tacrolimus patients. If CNIs played a role in the patient's GI symptoms at baseline, they would have been randomized equally to the EC-MPS and MMF arms. No significant difference in response rate was observed between EC-MPS and MMF patients using tacrolimus (61.4% EC-MPS and 54.3% MMF, P=0.32), patients using cyclosporine (66.7% EC-MPS and 60.0% MMF, P=0.60), patients not taking steroids (53.0% EC-MPS and 77.0% MMF, P=0.10), patients without diabetes (58.6% EC-MPS and 62.0% MMF, P=0.97), patients with transplant dates less than or equal to 6 months (58.5% EC-MPS and 56.5% MMF, P=0.91) or more than 12 months of study start (60.4% EC-MPS and 55.9% MMF, P=0.74), or between EC-MPS, and MMF African American patients (63.3% EC-MPS and 52.3% MMF, P=0.29).

A statistically significantly better response rate was observed for EC-MPS versus MMF patients in the subgroup of patients with diabetes (EC-MPS: n=70 and MMF: n=76) present pretransplantation (EC-MPS: 69.6% vs. MMF: 44.7%, P=0.009). There were no differences in time since transplant, study drug dosing, MPA levels, GI medication, or insulin use between the EC-MPS- and MMF-treated patients with diabetes. Other subgroups with statistically significant better response rates included patients who had a transplant date between more than 6 months and less than or equal to 12 months of the study start date (EC-MPS: 75.8% vs. MMF: 50.0%, P=0.035) and patients taking steroids (EC-MPS: 65.0% vs. MMF: 50.6%, P=0.012; Fig. 2).

FIGURE 2.

FIGURE 2.

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DISCUSSION

This is the first randomized, double-blinded study to compare GI symptom burden between maintenance renal transplant patients with MMF-related GI symptoms converted to EC-MPS and patients maintained on MMF. In this study, 62% of patients converted from MMF to EC-MPS reached the primary efficacy endpoint of a clinically important improvement in GSRS score of at least 0.3 compared with 55% of patients maintained on MMF. However, the difference between the groups was not statistically significant (P=0.15). Patients converted to EC-MPS did have a statistically significant greater decrease in the GSRS indigestion syndrome dimension. In addition, patients converted to EC-MPS had a statistically significant improvement in severity of overall and specific GI symptoms (eructation, lower GI, constipation, and flatulence) during the 30-day course of the study compared with patients maintained on MMF. Patients in the EC-MPS group had numerically lower frequencies of GI-related AEs, new or worsening GI AEs during the study, and a numerically greater frequency of freedom from GI symptoms present at baseline. The pattern of data regarding improvements in GI-related outcomes tended to favor conversion from MMF to EC-MPS, despite that some of these differences were not statistically significant. This improvement in GI outcomes with EC-MPS is consistent with previously published open-label studies (16, 17). Similar to other studies, the incidence of AR was low and comparable between the EC-MPS and MMF groups.

Independent of anticipated confounding variables, a significantly greater proportion of patients with diabetes in the EC-MPS conversion group had an improvement in GSRS score of at least 0.3 compared with those in the MMF- maintained group. Diabetes was the second leading primary cause of kidney failure for kidney transplants performed between 1997 and 2006. Within the deceased-donor, expanded criteria donor-kidney population, diabetes is the leading primary cause of kidney failure (27). The true prevalence of diabetes in the renal transplant population may be higher, as a significant proportion of recipients reported as having a primary underlying condition of glomerular disease (the leading underlying condition) likely have diabetes. Thus, the population of kidney transplant recipients with pretransplant diabetes represents a large segment of the kidney transplant population that could uniquely benefit from the tolerability of an EC-MPS-based immunosuppressive regimen. Analysis of three clinical trials of EC-MPS versus MMF found that clinical efficacy outcomes (BPAR, death, and graft loss) were comparable between EC-MPS-treated and MMF-treated renal transplant recipients with diabetes (28).

The lack of statistical significance between the ITT EC-MPS and MMF groups for the primary efficacy endpoint may reflect a true lack of difference between EC-MPS and MMF in GI effects, or alternatively true differences may have been masked by factors that were not anticipated a priori. Post hoc subgroup analysis based on time since transplant identified a potential bias that may have precluded finding statistically significant improvements in the primary endpoint between the EC-MPS and MMF groups. Within the subgroup of patients who were transplanted between more than 6 months and less than or equal to 12 months of their enrollment in the study, a statistically significant greater proportion of EC-MPS-converted patients had an improvement in GSRS score of at least 0.3. It is possible that the patients with a transplant date between more than 6 months and less than or equal to 12 months of study enrollment may represent the patients with GI symptoms most clearly attributable to MMF, and therefore, the subgroup most likely to benefit from a conversion to EC-MPS. No significant difference in the primary endpoint was observed between the EC-MPS and MMF groups for patients transplanted 1 to 6 months or those transplanted more than 12 months from their study enrollment date. There was a wide range of time since transplantation in the group of patients with a transplant date more than 12 months of study enrollment; in fact, some patients were several years posttransplant at the time of enrollment. It is hypothesized that these patients may have had GI complaints because of reasons other than, or in addition to, MMF. This supposition stems from the notion that MMF-related GI symptoms would likely occur and lead to MMF dose changes or cessation with the early use of MMF (i.e., within the first year) and that patients more than a year posttransplant would have already had their immunosuppressive regimens altered in response to MMF intolerability. An analysis of the Scientific Registry of Transplant Recipients data found that the majority of immunosuppressive regimen changes for kidney transplant recipients transplanted between 1998 and 2002 occurred within the first year posttransplantation (29). Conversely, GI complaints of patients who are newly transplanted (<6 months) are often because of the use of other medications with GI side effects that are ultimately tapered or removed. Magnesium and phosphorous supplementation, with their innate GI toxicity, will wane in the majority of transplant patients the further they are from their date of transplantation. In addition, the target levels of the CNIs, which are inherently GI toxic, will decrease in time when target trough levels are lowered. Prophylactic antibiotics that may contribute to GI symptoms would be removed or dose reduced by 6 months at all centers. Finally, the postoperative period is fraught with GI concerns such as constipation because patients are exposed to GI slowing narcotics and nauseating anesthesia.

In addition, 55% of patients maintained on MMF achieved the primary endpoint. The high response rate suggests that many patients in the study had transient GI symptoms because of reasons other than MMF. The large number of centers participating gives strength to the overall results as it is less likely that a few centers that might make poor choices with recruitment would significantly influence the overall results. The entry criteria allowed physicians per their clinical acumen and standard of practice to exclude patients with non-MMF–related GI symptoms without dictating how this was done (e.g., stool culture or abdominal ultrasound). Previously completed open-label studies (PROGIS and MyTime) used this entry criteria, and MyGain was designed to confirm in a double-blind study the results observed in these studies.

The double-blind, randomized nature of this study was a strength of this study over the two previous studies that evaluated changes in GI complaints after conversion from MMF to EC-MPS (16, 17). However, some patients may have experienced a placebo benefit from the possibility of being switched to another medication or from their participation in a clinical trial. Finally, we evaluated changes in GI symptoms and HRQoL at 1 month postconversion to MMF. It is possible that additional significant differences between the groups would have been realized with a longer follow-up period. This was suggested in MyTime where the majority of improvements in GI complaints were seen in the first month; however, the decrease in GSRS score was found to further decline at 3 months (17). In PROGIS, the follow-up occurred at 4 to 6 weeks posttransplant, and in fact, GI improvements in some patients were captured at 6 weeks (16).

A positive effect of myfortic was observed in patients taking steroids. Although the study was not stratified for steroid use, the majority of patients were taking steroids (80% EC-MPS and 82% MMF), and the steroid analysis was planned before the study initiation. Results from this trial indicate that intervention in patients with self-reported and personally concerning GI symptoms that are considered to be related to the use of MMF is associated with improvements in the presence and severity of GI symptoms and that conversion from MMF to EC-MPS shows a numerical advantage that does not reach significance. Statistically significant improvements in the presence and severity of GI symptoms were detected in patients with pretransplant diabetes and in patients converted to EC-MPS between 6 and 12 months posttransplantation. The results from the post hoc analyses suggest future modifications to the experimental design that may potentially lead to better characterization of patients with GI symptoms who may benefit from conversion of MMF to EC-MPS. It should be emphasized that these statistically significant benefits were discovered on post hoc analysis and might not prove to hold true whether these specific populations are vetted in a prospective study.

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MATERIALS AND METHODS

Study Design and Conduct

MyGAIN (Myfortic [Novartis, East Hanover, NJ] and MMF [CellCept, Nutley, NJ] when administered in combination with calcineurin inhibitors [CNI] in renal transplant recipients experiencing GI intolerance) was a 4-week, multicenter, randomized, prospective, double-blind, parallel-group trial in which MMF-treated and EC-MPS-treated adult renal transplant patients were evaluated for GI symptom burden and health-related quality of life (HRQoL) (clinical trial NCT00400400). The follow-up of 4 weeks was chosen because it was adequate in the PROGIS and US02 (myTIME) studies to demonstrate a statistical change in response.

Patients with self reported and personally distressing GI complaints, which the investigators determined to be related to MMF, were randomly assigned to one of the following two treatment arms in a 1:1 ratio: group 1: equimolar dose of EC-MPS+MMF placebo+CNI±steroids; group 2: MMF+EC-MPS placebo+CNI±steroids (Fig. 1). Twelve-hour trough MPA concentrations in peripheral blood were measured at baseline and day 30 to monitor compliance with study medication.

FIGURE 1.

FIGURE 1.

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Randomization

Study medications were double blinded. Patients, investigator staff, persons performing the assessments, and data analysts were blinded to the identity of the treatment from the time of randomization until database lock, using the following methods: (1) randomization data were kept strictly confidential until the time of unblinding and (2) the identity of the treatments was concealed by using study drugs with matching placebos that were identical in packaging, labeling, schedule of administration, appearance, and odor. A double-dummy design was used because the identity of the study drugs could not be disguised because of their different forms.

At the baseline visit, all patients who fulfilled the inclusion or exclusion criteria for the study and provided informed consent were assigned a randomization number in the order in which they were enrolled, each successive patient receiving the lowest number available at the site. The randomization list was generated by Novartis Drug Supply Management using a validated system that automated random assignment of treatment arms to randomization numbers in a 1:1 ratio. The randomization numbers ranged from 1001 to 2268 and were assigned to sites in blocks of 4; numbers were entered on the randomization case report form only. On all other case report forms, patients were identified only by their 9-digit patient identification number.

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Patient Population

Eligible patients were those aged 18 to 75 years who had undergone renal transplants at least 4 weeks from baseline and had been receiving an immunosuppressive regimen that included MMF (up to 3 g/day dosage allowed)+Neoral (Novartis, East Hanover, NJ) (or its generic equivalent, cyclosporine United States Pharmacopeia [MODIFIED]) or tacrolimus, with or without corticosteroids, and with self-reported but personally distressing GI symptoms determined to be associated with MMF therapy. The study was not stratified for steroid use, and steroid doses were permitted to be altered during the study. Major exclusion criteria included: multiorgan transplant patients, severe GI disorder, preexisting significant GI conditions without a presumed causal relationship with MMF, modification of GI medication or MMF dose within 1 week before baseline, evidence of graft rejection, treatment of acute rejection (AR), unstable renal function within 4 weeks before the baseline visit, inability to self-administer the study questionnaires, and patients receiving generic formulations of MMF.

The intent-to-treat (ITT) population, defined as all enrolled patients who took at least one dose of blinded study medication, was the primary population for analysis; the safety population was identical to the ITT population. The per-protocol population included all patients who received at least 17 days of study drug and completed the study without any major deviations from the protocol. Planned subgroup analyses were conducted by specific CNI (tacrolimus and cyclosporine) and for patients with and without steroids; post hoc analysis was conducted for patients with pretransplant diabetes, African American patients, and by time since transplantation to study enrollment (i.e., ≤6 months, >6 to ≤12 months, and >12 months).

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Patient-Reported Outcomes

Three self-administered questionnaires were used: the Gastrointestinal Symptom Rating Scale (GSRS) (18–20), the Gastrointestinal Quality of Life Index (GIQLI) (18, 21), and the Overall treatment effect (OTE) in HRQoL (22–25) (Fig. 1); each have been previously validated in renal transplant recipients (18). The severity of any GI condition was also assessed by the attending physician.

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Primary and Secondary Efficacy Outcomes

The primary efficacy outcome was the proportion of EC-MPS versus MMF patients with MMF-associated GI intolerance that responded to the intervention of conversion of MMF to EC-MPS therapy. Response to intervention was defined as meeting or exceeding the minimal important difference of 0.3 in change from baseline in GSRS total score at day 30. The minimal important difference is the smallest difference in score in the domain of interest (i.e., subscales of questionnaires) that patients or clinicians perceive to be important, as beneficial or harmful (26). The secondary efficacy outcomes were the proportion of EC-MPS versus MMF patients with biopsy-proven acute rejection (BPAR) and treated AR.

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Secondary Safety Outcomes

Secondary safety outcomes included: the proportion of patients with no new or worsening GI symptoms within 30 days, the change from baseline in the severity of GI symptoms at day 30, the proportion of patients with dose changes or interruptions of study medication within 30 days, the change from baseline in GSRS total and subscale scores at day 30, the change from baseline in GIQLI total and subscale scores at day 30, the proportion of patients at day 30 who were free of at least one GI symptoms that was present at baseline (diarrhea, dyspepsia, acid reflux, and abdominal pain), the proportion of patients at day 30 who were free of diarrhea that was present at baseline, HRQoL OTE scores at day 30, and the change in the severity of diarrhea from baseline to day 30.

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Statistical Analyses

For the primary efficacy outcome, response rates were summarized as number and percent of responders in each treatment group. A Cochran-Mantel-Haenszel test, adjusting for center was used to test for a significant difference between groups in response to treatment. For the secondary efficacy evaluations, the proportion of patients with BPAR or AR-treated patients at day 30, the number and percent of AR per patient, and the severity of BPAR, assessed according to the Banff '97 criteria, were summarized descriptively.

For the continuous secondary safety evaluations, the change from baselines were compared between treatment groups using an analysis of covariance model with baseline measurement as a covariate and treatment and center as main effects. The statistical significance of the mean change from baseline was assessed using a paired t test. HRQoL OTE scores at day 30 were compared between treatment groups using an ANOVA model with treatment and center as main effects when analyzing the score and by Cochran-Mantel-Haenszel test for association, adjusting for centers, when analyzing the categorical outcome of better, about the same, or worse. The categorical secondary safety evaluations were compared between treatment groups using Cochran-Mantel-Haenszel tests adjusting for center.

The sample size was calculated to detect at least a 15% difference in response rates between the EC-MPS treatment group and the MMF treatment group using a two-sided, chi-square test with a significance level of 0.05 and 80% power. Chi-square was chosen because of the larger sample size and not the Fisher's exact test, which can be used for 2×2 tables if the population number were smaller. Assuming an MMF response rate of 45%, 173 patients per treatment group would be needed. Assuming a dropout rate of 10%, 384 randomized patients would ensure approximately 346 completed patients.

Statistical analyses were performed using SAS, version 9.1 (SAS, Inc., Cary, NC) and were based on the pooled data from the individual study centers. All statistical tests were conducted under a two-sided alternative hypothesis, using a significance level of 0.05. Institutional review board approval was obtained at each participating center, and informed consent was obtained from all patients. The study was undertaken in accordance with the The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use's Harmonized Tripartite Guidelines for Good Clinical Practice and with the ethical principles laid down in the Declaration of Helsinki.

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ACKNOWLEDGMENT

The authors thank Kevin McCague from Novartis for statistical support in the MyGain manuscript.

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APPENDIX

The members of MyGAIN Study Group are as follows: Rafel Reyes Acevedo, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico; Kenneth Andreoni, The University of North Carolina School of Medicine, Chapel Hill, NC; Ahmed Awad, St. Luke's Hospital of Kansas City, Kansas City, MO; Mary T. Behrens, Mid-Atlantic Nephrology Associates, Baltimore, MD; Kenneth A. Bodziak, University Hospitals of Cleveland, Cleveland, OH; Paul Bolin, East Carolina University Brody School of Medicine, Greenville, NC; Daniel C. Brennan, Barnes Jewish Hospital Plaza, St. Louis, MO; Suphamai Bunnapradist, UCLA Kidney and Pancreas Transplant Research Office, Los Angeles, CA; Laurence Chan, University of Colorado Health Sciences Center, Denver, CO; Edward Cole, University Health Network, Toronto, ON, Canada; Matthew Cooper, University of Maryland, Baltimore, MD; Bryan Curtis, Memorial University Eastern Regional Health Authority St. John's, NL, Canada; Randall Detwiler, The University of North Carolina School of Medicine, Chapel Hill, NC; M. Francesca Egidi, Medical University of South Carolina, Charleston, SC; Mohamed El-Ghoroury, Saint Clair Specialty Physicians, PC, Detroit, MI; Richard Fatica, Cleveland Clinic, Cleveland, OH; George Francos, Thomas Jefferson University, Philadelphia, PA; Steven Gabardi, Brigham and Women's Hospital, Boston, MA; Brian Gallay, University of California, Davis Medical Center, Sacramento, CA; Eric M. Gibney, Virginia Commonwealth University, Richmond, VA; John S. Gill, St. Paul's Hospital, Vancouver, BC, Canada; Muralikrishna Golconda, Oregon Health & Science University, Portland, OR; Sita Gourishankar, University of Alberta Hospitals, Edmonton, AB, Canada; Stuart Greenstein, Montefiore Medical Center, Bronx, NY; Kristene Gugliuzza, University of Texas Medical Branch Galveston, Galveston, TX; Marquis E. Hart, University of California, San Diego, San Diego, CA; David Robb Holt, Loyola University Medical Center, Maywood, IL; Isabelle Houde, Centre Hospitalier Universitaire de Quebec, Quebec City, QC, Canada; Raja Kandaswamy, University of Minnesota, Minneapolis, MN; Paul Keown, Vancouver General Hospital, Vancouver, BC, Canada; Anthony Langone, Vanderbilt University Medical Center, Nashville, TN; David Laskow, Robert Wood Johnson University Hospital, New Brunswick, NJ; Edgardo Laurel, Arizona Kidney Disease & Hypertension Center Medical Research Services, LLC, Phoenix, AZ; Nicolae Leca, University of Washington Medical Center, Seattle, WA; Jimmy A. Light, Washington Hospital Center, WA, DC; James Lim, Robert Wood Johnson University Hospital, New Brunswick, NJ; Melissa L. Lynn, Northwest Louisiana Nephrology Research, Shreveport, LA; Gustavo Martinez-Mier, Hospital Regional de Alta Expecialidad de Veracruz, Veracruz, Mexico; Rodrigo Mateo, Keck School of Medicine of the University of Southern California, Los Angeles, CA; Herwig-Ulf Meier-Kriesche, University of Florida College of Medicine, Gainesville, FL; Joseph Keith Melancon, Johns Hopkins Hospital, Baltimore, MD; David F. Mercer, University of Nebraska Medical Center, Omaha, NE; Shamkant Mulgaonkar, St. Barnabus Medical Center, Livingston, NJ; Laura L. Mulloy, Medical College of Georgia, Augusta, GA; Ali Olyaei, Oregon Health & Science University, Portland, OR; Alice Peng, Cedars-Sinai Medical Center, Los Angeles, CA; Yasir Qazi, Keck School of Medicine of the University of Southern California, Los Angeles, CA; Carlos Gaston Ramirez, Hospital Christus Muguerza del Parque, Chihuahua, Mexico; Tariq Shah, National Institute of Transplantation, Los Angeles, CA; Fuad Shihab, University of Utah Health Sciences Center, Salt Lake City, UT; Steven M. Steinberg, California Institute of Renal Research, San Diego, CA; Timothy Taber, Clarian Health Partners-Methodist Campus, Indianapolis, IN; Bekir Tannover, Dallas Transplant Institute, Dallas, TX; J. Richard Thistlethwaite, The University of Chicago, Chicago, IL; Stephen J. Tomlanovich, University of California, San Francisco, San Francisco, CA; Eduardo Mancilla Urrea, Instituto Nacional de Cardiologia “Ignacio Chavez,” Mexico City, Tlalpan, Mexico; Thomas Waid, University of Kentucky Chandler Medical Center, Lexington, KY; Connie Wang, University of Kansas Medical Center, Kansas City, KS; Harold C. Yang, Pinnacle Health System Harrisburg Hospital, Harrisburg, PA; Angelito Yango, Rhode Island Hospital, Providence, RI; Carlos Zayas, Piedmont Hospital, Atlanta, GA; Gazi Zibari, Louisiana State University Health Sciences Center Willis Knighton Health System Regional Transplant Center, Shreveport, LA.

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REFERENCES

1. Allison AC, Eugui EM. Immunosuppressive and other effects of mycophenolic acid and an ester prodrug, mycophenolate mofetil. Immunol Rev 2006; 136: 5.
2. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1996; 61: 1029.
3. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995; 60: 225.
4. Ojo AO, Meier-Kriesche HU, Hanson JA, et al. Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation 2000; 69: 2405.
5. Meier-Kriesche HU, Steffen BJ, Hochberg AM, et al. Long-term use of mycophenolate mofetil is associated with a reduction in the incidence and risk of late rejection. Am J Transplant 2003; 3: 68.
6. Knoll GA, MacDonald I, Khan A, et al. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol 2003; 14: 2381.
7. Tierce JC, Porterfield-Baxa J, Petrilla AA, et al. Impact of mycophenolate mofetil (MMF)-related gastrointestinal complications and MMF dose alterations on transplant outcomes and healthcare costs in renal transplant recipients. Clin Transplant 2005; 19: 779.
8. Pelletier RP, Akin B, Henry ML, et al. The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation. Clin Transplant 2003; 17: 200.
9. Hardinger KL, Brennan DC, Lowell J, et al. Long-term outcome of gastrointestinal complications in renal transplant patients treated with mycophenolate mofetil. Transpl Int 2004; 17: 609.
10. Bunnapradist S, Lentine KL, Burroughs TE, et al. Mycophenolate mofetil dose reductions and discontinuations after gastrointestinal complications are associated with renal transplant graft failure. Transplantation 2006; 15: 102.
11. Johnston A, He X, Holt D. Bioequivalence of enteric-coated mycophenolate sodium and mycophenolate mofetil: A meta-analysis of three studies in stable renal transplant recipients. Transplantation 2006; 82: 1413.
12. Salvadori M, Holzer H, de Mattos A, et al. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2004; 4: 231.
13. Budde K, Curtis J, Knoll G, et al. Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: Results of a 1-year study. Am J Transplant 2004; 4: 237.
14. Salvadori M, Holzer H, Civati G, et al. Long-term administration of enteric-coated mycophenolate sodium (EC-MPS; myfortic) is safe in kidney transplant patients. Clin Nephrol 2006; 66: 112.
15. Hardinger KL, Hebbar S, Bloomer T, et al. Adverse drug reaction driven immunosuppressive drug manipulations: A single-center comparison of enteric-coated mycophenolate sodium vs. mycophenolate mofetil. Clin Transplant 2008; 22: 555.
16. Chan L, Mulaongkar S, Walker R, et al. Patient-reported gastrointestinal symptom burden and health related quality of life following conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium. Transplantation 2006; 81: 1290.
17. Bolin P, Tanriover B, Zibari GB, et al. Improvement in 3-month patient-reported gastrointestinal symptoms after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in renal transplant patients. Transplantation 2007; 84: 1443.
18. Kleinman L, Faull R, Walker R, et al. Gastrointestinal-specific patient-reported outcome instruments differentiate between renal transplant patients with or without GI complications. Transplant Proc 2005; 37: 846.
19. Dimenas E, Glise H, Hallerback B, et al. Quality of life in patients with upper gastrointestinal symptoms. An improved evaluation of treatment regimens? Scand J Gastroenterol 1993; 28: 681.
20. Revicki DA, Wood M, Wiklund I, et al. Reliability and validity of the Gastrointestinal Symptom Rating Scale in patients with gastroesophageal reflux disease. Qual Life Res 1998; 7: 75.
21. Eypasch E, Williams JI, Wood-Dauphinee S, et al. Gastrointestinal Quality of Life Index: Development, validation and application of a new instrument. Br J Surg 1995; 82: 216.
22. Jaeschke R, Singer J, Guyatt GH. Measurement of health status; ascertaining the minimal clinically important difference. Control Clin Trials 1989; 10: 407.
23. Guyatt GH, Juniper EF, Walter SD, et al. Interpreting treatment effects in randomised trials. BMJ 1998; 316: 690.
24. Juniper EF, Guyatt GH, Willian A, et al. Determining a minimal important change in a disease-specific quality of life questionnaire. J Clin Epidemiol 1994; 47: 81.
25. Talley NJ, Fullerton S, Junghard O, et al. Quality of life in patients with endoscopy-negative heartburn: Reliability and sensitivity of disease-specific instruments. Am J Gastroenterol 2001; 96: 1998.
26. Guyatt GH, Osoba D, Wu AW, et al; Clinical Significance Consensus Meeting Group. Methods to explain the clinical significance of health status measures. Mayo Clinic Proc 2002; 77: 371.
27. 2007 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1997–2006. Rockville, MD, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation.
28. Pietruck F, Budde K, Salvadori M, et al. Efficacy and safety of enteric-coated mycophenolate sodium in renal transplant patients with diabetes mellitus: Post hoc analyses from three clinical trials. Clin Transplant 2007; 21: 117.
29. Meier-Kriesche HU, Chu AH, David KM, et al. Switching immunosuppression medications after renal transplantation—A common practice. Nephrol Dial Transplant 2006; 21: 2256.
Keywords:

Gastrointestinal; Quality of life; HRQoL; Mycophenolate mofetil; Mycophenolate sodium

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