Multicenter, Randomized, Open-label Study to Assess Whether Treatment With Mycophenolate Sodium (MPS) Allows Higher Dose Optimization Versus Mycophenolate Mofetil (MMF) Leading to a Dose Reduction of Tacrolimus. Maximiza Study.

Study Overview
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Brief Summary
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Multicenter, Randomized, Open-label Study to Assess Whether Treatment With Mycophenolate sodium (MPS) Allows Higher Dose Optimization Versus Mycophenolate mofetil (MMF) Leading to a Dose Reduction of Tacrolimus. Maximiza Study.

Official Title
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Multicenter, Randomized, Open-label Study to Assess Whether Treatment With Mycophenolate Sodium (MPS) Allows Higher Dose Optimization Versus Mycophenolate Mofetil (MMF) Leading to a Dose Reduction of Tacrolimus. Maximiza Study.

Conditions
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Prophilaxis of Acute Rejection in Patients Receiving a Renal Allograft

Intervention / Treatment
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* Drug: 1
* Drug: 2


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Renal transplant recipients ≥ 1 year and ≤ 5 years prior1 to inclusion in the study. Patients who were receiving an immunosuppressive regimen including MMF ≤1000 mg/day and ≥ 250 mg/day 4 and Prograf®1 or Advagraf®6 (levels ≥7 ng/ml). Patients who had been receiving the current maintenance immunosuppressive regimen with stable doses of MMF for at least the past 3 months.2 Patients included must have had Prograf® or Advagraf® levels ≥ 7ng/ml4 for at least one month prior to inclusion in the trial.2 Patients with low immunological risk, in the investigator's opinion. Patients with an estimated glomerular filtration rate based on the MDRD formula of > 30 ml/min x 1.73 m2.1 Patients over 18 years of age.1 Patients who were able to understand the study information and give written informed consent. Patients who were able to meet all study requirements, including completing questionnaires and attending study visits. Exclusion criteria Patients with GI symptoms known or assumed not to be caused by mycophenolic acid (MPA) treatment (e.g. oral bisphosphonate-induced infectious diarrhoea). Patients with chronic inflammatory bowel disease. Diabetic patients. Acute rejection < 1 month prior to inclusion in the study. Patients with leukopenia (< 3500 cells/mm3) or thrombocytopenia (< 100,000 cells/mm3). Women of childbearing potential who were planning to become pregnant, were pregnant and/or breastfeeding, or who did not wish to use effective contraception [hormonal contraceptives (implantation, patches, oral) and double-barrier methods (any double combination of: IUD, male or female condoms with spermicidal gel, diaphragm, contraceptive sponge, cervical cap)]. Presence of psychiatric illness (such as schizophrenia, major depression) that, in the investigator's opinion, could interfere with study requirements. Patients who were undergoing surgery for an acute condition or who were hospitalised. Any other medical condition that, in the investigator's opinion based on blood counts or chart review, could interfere with completion of the study, including but not limited to visual problems or cognitive impairment. Patients who were receiving or had received any investigational medicinal product during the 30 days prior to inclusion in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Mycophenolate mofetil | Drug: 1<br>* Continue with same dose of MMF as patient was taking before randomisation<br>|
| Experimental: 2<br>Miycophenolate sodium | Drug: 2<br>* Increase MPS by 180mg every 12h based on investigator's judgement up to a maximum of 720 mg of MPS every 12 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving at Least Two Mycophenolic Acid (MPA) Dose Steps Higher and Reducing Tacrolimus Dose at the End of the Study |  | at 12 months from baseline | 
| Number of Participants That Achieved One Dose Step Higher With Mycophenolic Acid (MPA) or Mycophenolate Mofetil (MMF), According to the Treatment Group Assigned at the End of the Study (Final Visit) Compared to Baseline Dose |  | at 12 months from baseline | 
| Participants With Reduction in Tacrolimus or Tacrolimus Extended Release Levels at the End of the Study (Final Visit) Compared to Baseline Dose. |  | at 12 months from baseline | 
| Mean Mycophenolic Acid (MPA) Doses at the End of the Study (Final Visit) Compared to Baseline Dose. |  | at 12 months from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Renal Function Measured Using Cockcroft-Gault Creatinine Clearance (CrCl) |  | Visit 1 (30 days +/-4), visit 2 (90 days +/- 15), visit 3 (150 days +/- 15), visit 4 (210 days +/- 15), visit 5 (365 days +/- 15) | 
| Glomerular Filtration Rate (GFR) Using Abbreviated MDRD | Calculated GFR (MDRD formula): GFR [mL/min/1.73m2] = 186.3*(C-1.154)*(A-0.203)*G*R where C is the serum concentration of creatinine [mg/dL], A is age [years], G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1 | Visit 1 (30 days +/-4), visit 2 (90 days +/- 15), visit 3 (150 days +/- 15), visit 4 (210 days +/- 15), visit 5 (365 days +/- 15) | 
| Gastrointestinal Symptom Rating Scale (GSRS) Item Score | The GSRS is a 15-item instrument design to assess the symptoms associated to gastrointestinal disorders. It has 5 subscales (reflux, diarrhoea, constipation, abdominal pain and indigestion) with scores rating from 1 to 7 (with a higher score representing more gastrointestinal symptoms) | Visit 1 (30 days +/-4), visit 2 (90 days +/- 15), visit 3 (150 days +/- 15), visit 4 (210 days +/- 15), visit 5 (365 days +/- 15) | 
| Gastrointestinal Symptom Rating Scale (GSRS) Subscale Score | The GSRS is a 15-item instrument design to assess the symptoms associated to gastrointestinal disorders. It has 5 subscales (reflux, diarrhoea, constipation, abdominal pain and indigestion) with scores rating from 1 to 7 (with a higher score representing more gastrointestinal symptoms) | Visit 1 (30 days +/-4), visit 2 (90 days +/- 15), visit 3 (150 days +/- 15), visit 4 (210 days +/- 15), visit 5 (365 days +/- 15) | 
| Health-related Quality of Life (HRQoL): Impact of Gastrointestinal Symptoms on Quality Of Life (SIGIT)-QoL Questionnaire. Total Score. | The SIGIT-QoL scale is a 17 items instrument, the score of each item ranges from 0 (always) to 4 (never). The scale score is obtained by adding the scores of the 17 items. Therefore, the total score ranges from 0 to 68 points. Higher score means, less impairment of Health Related QoL of the patient and vice versa, the lower the score, the greater severity of symptoms and worse perceived by the patient | Visit 1 (30 days +/-4), visit 2 (90 days +/- 15), visit 3 (150 days +/- 15), visit 4 (210 days +/- 15), visit 5 (365 days +/- 15) | 
| Change in Gastrointestinal Symptom Rating Scale (GSRS) Score From Baseline to Visit 2 Stratified on the Basis of the Presence or Absence of Single-nucleotide Polymorphisms (SNPs) in the UGT1A9 Gene for the ITT Population | Sub-study primary endpoint. The GSRS is a 15-item instrument design to assess the symptoms associated to gastrointestinal disorders. It has 5 subscales (reflux, diarrhoea, constipation, abdominal pain and indigestion) with scores rating from 1 to 7 (with a higher score representing more gastrointestinal symptoms) | at 12 months from baseline | 
| Change in Gastrointestinal Symptom Rating Scale (GSRS) Score From Baseline to Visit 4 Stratified on the Basis of the Presence or Absence of Single-nucleotide Polymorphisms (SNPs) in the UGT1A9 Gene for the ITT Population | Sub-study primary endpoint. The GSRS is a 15-item instrument design to assess the symptoms associated to gastrointestinal disorders. It has 5 subscales (reflux, diarrhoea, constipation, abdominal pain and indigestion) with scores rating from 1 to 7 (with a higher score representing more gastrointestinal symptoms) | at 12 months from baseline | 
| Change in Gastrointestinal Symptom Rating Scale (GSRS) Score From Baseline to Visit 5 Stratified on the Basis of the Presence or Absence of Single-nucleotide Polymorphisms (SNPs) in the UGT1A9 Gene for the ITT Population | Sub-study primary endpoint. The GSRS is a 15-item instrument design to assess the symptoms associated to gastrointestinal disorders. It has 5 subscales (reflux, diarrhoea, constipation, abdominal pain and indigestion) with scores rating from 1 to 7 (with a higher score representing more gastrointestinal symptoms) | at 12 months from baseline | 
| Change in Gastrointestinal Symptom Rating Scale (GSRS) Score From Baseline to Visit 2 Stratified on the Basis of the Presence or Absence of Single-nucleotide Polymorphisms (SNPs) in the MRP2 Gene for the ITT Population | Sub-study primary endpoint. The GSRS is a 15-item instrument design to assess the symptoms associated to gastrointestinal disorders. It has 5 subscales (reflux, diarrhoea, constipation, abdominal pain and indigestion) with scores rating from 1 to 7 (with a higher score representing more gastrointestinal symptoms) | at 12 months from baseline | 
| Change in Gastrointestinal Symptom Rating Scale (GSRS) Score From Baseline to Visit 4 Stratified on the Basis of the Presence or Absence of Single-nucleotide Polymorphisms (SNPs) in the MRP2 Gene for the ITT Population | Sub-study primary endpoint. The GSRS is a 15-item instrument design to assess the symptoms associated to gastrointestinal disorders. It has 5 subscales (reflux, diarrhoea, constipation, abdominal pain and indigestion) with scores rating from 1 to 7 (with a higher score representing more gastrointestinal symptoms) | at 12 months from baseline | 
| Change in Gastrointestinal Symptom Rating Scale (GSRS) Score From Baseline to Visit 5 Stratified on the Basis of the Presence or Absence of Single-nucleotide Polymorphisms (SNPs) in the MRP2 Gene for the ITT Population | Sub-study primary endpoint. The GSRS is a 15-item instrument design to assess the symptoms associated to gastrointestinal disorders. It has 5 subscales (reflux, diarrhoea, constipation, abdominal pain and indigestion) with scores rating from 1 to 7 (with a higher score representing more gastrointestinal symptoms) | at 12 months from baseline | 
| Change in SIGIT-QoL Score From Baseline to Visit 2 Stratified on the Basis of the Presence or Absence of SNP in the UGT1A9 Gene for the ITT Population | Sub-study primary endpoint. The SIGIT-QoL scale is a 17 items instrument, the score of each item ranges from 0 (always) to 4 (never). The scale score is obtained by adding the scores of the 17 items. Therefore, the total score ranges from 0 to 68 points. Higher score means, less impairment of Health Related QoL of the patient and vice versa, the lower the score, the greater severity of symptoms and worse perceived by the patient | at 12 months from baseline | 
| Change in SIGIT-QoL Score From Baseline to Visit 4 Stratified on the Basis of the Presence or Absence of SNP in the UGT1A9 Gene for the ITT Population | Sub-study primary endpoint. The SIGIT-QoL scale is a 17 items instrument, the score of each item ranges from 0 (always) to 4 (never). The scale score is obtained by adding the scores of the 17 items. Therefore, the total score ranges from 0 to 68 points. Higher score means, less impairment of Health Related QoL of the patient and vice versa, the lower the score, the greater severity of symptoms and worse perceived by the patient | at 12 months from baseline | 
| Change in SIGIT-QoL Score From Baseline to Visit 5 Stratified on the Basis of the Presence or Absence of SNP in the UGT1A9 Gene for the ITT Population | Sub-study primary endpoint. The SIGIT-QoL scale is a 17 items instrument, the score of each item ranges from 0 (always) to 4 (never). The scale score is obtained by adding the scores of the 17 items. Therefore, the total score ranges from 0 to 68 points. Higher score means, less impairment of Health Related QoL of the patient and vice versa, the lower the score, the greater severity of symptoms and worse perceived by the patient | at 12 months from baseline | 
| Change in SIGIT-QoL Score From Baseline to Visit 2 Stratified on the Basis of the Presence or Absence of SNP in the MRP2 Gene for the ITT Population | Sub-study primary endpoint. SIGIT-QoL scale is a 17 items instrument, the score of each item ranges from 0 (always) to 4 (never). The scale score is obtained by adding the scores of the 17 items. Therefore, the total score ranges from 0 to 68 points. Higher score means, less impairment of Health Related QoL of the patient and vice versa, the lower the score, the greater severity of symptoms and worse perceived by the patient | at 12 months from baseline | 
| Change in SIGIT-QoL Score From Baseline to Visit 4 Stratified on the Basis of the Presence or Absence of SNP in the MRP2 Gene for the ITT Population | Sub-study primary endpoint. The SIGIT-QoL scale is a 17 items instrument, the score of each item ranges from 0 (always) to 4 (never). The scale score is obtained by adding the scores of the 17 items. Therefore, the total score ranges from 0 to 68 points. Higher score means, less impairment of Health Related QoL of the patient and vice versa, the lower the score, the greater severity of symptoms and worse perceived by the patient | at 12 months from baseline | 
| Change in SIGIT-QoL Score From Baseline to Visit 5 Stratified on the Basis of the Presence or Absence of SNP in the MRP2 Gene for the ITT Population | Sub-study primary endpoint. The SIGIT-QoL scale is a 17 items instrument, the score of each item ranges from 0 (always) to 4 (never). The scale score is obtained by adding the scores of the 17 items. Therefore, the total score ranges from 0 to 68 points. Higher score means, less impairment of Health Related QoL of the patient and vice versa, the lower the score, the greater severity of symptoms and worse perceived by the patient | at 12 months from baseline | 
| Duration of Exposure to the Study Medicinal Product, Mycophenolate Sodium Descriptive Statistics. Safety Population Per Treatment Group | Exposure to study drug (MPS). Data presented only for safety population on the study treatment arm (not applicable for MMF arm) | at 12 months from baseline | 
| Dose of the Study Medicinal Product Mycophenolate Sodium (MPS) | Safety population per visit and per treatment group | at 12 months from baseline | 
| Dose of the Study Medicinal Product Mycophenolate Mofetil (MMF) | Safety population per visit and per treatment group (missings not included) | at 12 months from baseline |