Enteric-coated Mycophenolate Sodium (EC-MPS) and Mycophenolate Mofetil (MMF) in Renal Transplant Patients With Gastrointestinal (GI) Intolerance

Study Overview
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Brief Summary
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Treatment with the immunosuppressive drug mycophenolate mofetil (MMF) may result in gastrointestinal (GI) complications in some patients. This study will investigate the safety and tolerability of converting kidney transplant recipients with gastrointestinal symptoms from their current treatment of mycophenolate mofetil (MMF) to treatment with enteric-coated mycophenolate sodium (EC-MPS).

Official Title
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A 4-week, Multicenter, Double-blind, Double-dummy, Randomized, Parallel Group Study to Compare the Gastrointestinal Safety and Tolerability of EC-MPS & MMF When Administered in Combination With Calcineurin Inhibitors in Renal Transplant Recipients Experiencing Gastrointestinal Intolerance

Conditions
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Renal Transplantation

Intervention / Treatment
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* Drug: Enteric-coated mycophenolate sodium (EC-MPS)
* Drug: Mycophenolate mofetil
* Drug: Placebo to mycophenolate sodium
* Drug: Placebo to mycophenolate mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Males and females aged 18-75 years, Recipients of first or second cadaveric, living unrelated or living related kidney transplant Recipients who are at least 4 weeks post renal transplantation with stable renal function, Patients currently receiving MMF (all dosages are allowed) and either cyclosporine USP (MODIFIED) or tacrolimus with or without corticosteroids as part of their immunosuppressive regimen for at least 2 weeks prior to study start Patients with at least one mild and/or moderate and/or severe upper or lower gastrointestinal (GI) complaints clearly associated with MMF therapy as determined by the treating physician. Additional mild GI complaints may coexist Patients' immunosuppressive regimen other than steroids (doses and type) as well as medication for treatment of GI symptoms must be unchanged for at least 1 week prior to study start Females of childbearing potential must have a negative pregnancy test prior to the inclusion period. The test should be performed locally at Baseline visit. If positive, the patient will not be included. Effective contraception must be used during the trial, and for 4 weeks following discontinuation of the study medication Patients who are willing and able to participate in the full course of the study and from whom written informed consent has been obtained. Exclusion criteria: Multi-organ transplant patients (e.g. kidney and pancreas) or previous transplant with any other organ different from kidney (second kidney transplant is allowed) History of GI disorder (diarrhea, Gastroesophageal Reflux Disease (GERD), dyspepsia, Inflammatory Bowel Disease (IBD) or Irritable Bowel Syndrome (IBS) prior to transplantation Evidence of any GI disorder induced by an infection, underlying medical condition, or concomitant medication other than MMF, Modification of GI medication or MMF dose within last 1 week Evidence of graft rejection, treatment of acute rejection, or unstable renal function within 4 weeks prior to the Baseline visit, Patients who have received an investigational immunosuppressive drug within 4 weeks prior to study entry Patients with a history of malignancy within the last five years, except excised squamous or basal cell carcinoma of the skin Pregnant or nursing (lactating) women, Women of child-bearing potential (WOCBP) not using an acceptable method of contraception such as: surgical sterilization, hormonal contraception, or double-barrier methods. Contraception should be maintained throughout the study and for 4 weeks after study drug discontinuation. Other protocol defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enteric-coated mycophenolate sodium<br>Enteric-coated mycophenolate sodium tablets taken orally twice a day (in the morning and in the evening) at a dose equimolar to the dose of mycophenolate mofetil the participant was taking prior to start of the study + Placebo to mycophenolate mofetil capsules taken orally twice a day for 30 days. Participants remained on their standard immunosuppressive regimen of calcineurin inhibitors (CNI) (Cyclosporin A or Tacrolimus) administered with or without corticosteroids throughout the study. | Drug: Enteric-coated mycophenolate sodium (EC-MPS)<br>* Enteric-coated mycophenolate sodium supplied as 180 mg tablets.<br>* Other names: Myfortic®;Drug: Placebo to mycophenolate mofetil<br>* Placebo to mycophenolate mofetil matching capsules.<br>|
| Active Comparator: Mycophenolate mofetil<br>Mycophenolate mofetil capsules taken orally twice a day (in the morning and in the evening) at the dose the participant was taking prior to study start + Placebo to mycophenolate sodium tablets taken twice a day for 30 days. Participants remained on their standard immunosuppressive regimen of calcineurin inhibitors (CNI) (Cyclosporin A or Tacrolimus) administered with or without corticosteroids throughout the study. | Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil supplied as 250 mg capsules.<br>Drug: Placebo to mycophenolate sodium<br>* Placebo to mycophenolate sodium matching tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants Who Responded to the Conversion to Mycophenolate Sodium (EC-MPS) Therapy | Response assessed using the Gastrointestinal Symptom Rating Scale (GSRS), designed to assess common symptoms with gastrointestinal (GI) disorders. The GSRS has 5 subscales (reflux, diarrhea, constipation, abdominal pain and indigestion) producing a mean subscale score ranging from 1 (no discomfort) to 7 (very severe discomfort). The total score is an average of scores across all 15 items; a higher score indicates more GI symptoms. Response was defined as Day 30 improvement in the GSRS Total Score (change from baseline) of greater than or equal to 0.3. Minimum score is 1; maximum score is 7. | Baseline, Day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Biopsy-proven Acute Rejection (BPAR) and Treated Acute Rejection (TAR) | TAR was defined as an episode of acute rejection that was suspected on clinical grounds and was treated and confirmed by the investigator according to the patient's response to therapy. BPAR was defined a treated acute rejection that was confirmed by biopsy. A graft core biopsy was performed before or within 24 hours of initiation of anti-rejection therapy and was assessed by the pathologist at the center according to the BANFF 1997 criteria. | 30 days | 
| Change From Baseline to Day 30 in the Severity of Gastrointestinal Symptoms Overall Total Score | The Severity Score for each GI symptom for each participant was calculated based on the physician's evaluation of current GI symptoms recorded at Baseline and Day 30. For each of the 16 individual GI symptoms the severity score ranged from 0 (absent) to 3 (severe). The Overall Total Score is the Mean of severity ratings of the 16 individual symptoms. | Baseline, Day 30 | 
| Number of Participants With Reported Dose Changes or Interruption of Study Medication During the 30 Days of Treatment | The number of participants with reported dose changes or interruption of study medication during the 30 days of treatment.The most common dose adjustments were dose increases back to baseline levels following a decrease or interruption and decreases due to abnormal laboratory value Adverse Events (leucopenia, thrombocytopenia, neutropenia, or anemia). | 30 days | 
| Change From Baseline in Lower and Upper GI Symptom Burden Measured by GI Symptom Rating Scale Score | This is reflected by the total score. The total score incorporates lower and upper GI elements. GSRS overall score is the mean of 15 individual GI symptom scores, each rated on a 7- point scale: 1 = no discomfort, 2= minor discomfort, 3 = mild discomfort, 4 = moderate discomfort, 5 = moderately sever discomfort, 6 = severe discomfort and 7 = very severe discomfort. Change from Baseline was calculated using ANCOVA, model includes GSRS, center and treatment group. | Baseline, Day 30 | 
| Change in Gastrointestinal Symptom Rating Scale Subscale Scores After 30 Days of Treatment | The GSRS has five subscales (reflux, diarrhea, constipation, abdominal pain, indigestion) producing a mean subscale score ranging from 1 (=no discomfort at all) to 7 (very severe discomfort). The mean score at baseline (BL), the mean score at Day 30 and the mean Change from BL to Day 30 is presented for each of the five subscales. | Baseline to Day 30 | 
| Change From Baseline (BL) to Day 30 in the Gastrointestinal Quality of Life Index (GIQLI) Total Score and Subscale Scores | The GIQLI is a 36-item questionnaire to assess the impact of GI disease on daily life. The GIQLI has 5 different subscales (GI symptoms, emotional status, physical and social functions, and stress of medical treatment) that are rated on a 5-point scale from 0 to 4. The individual scores are summed to produce a total score of the 36 items for a total possible score of 0 to 144. Lower scores represent greater dysfunction. | Baseline, Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RenalTransplantation, KidneyTransplantation, MPA, EC-MPS