OPERA Study: A Study of Two Dosing Regimens of CellCept (Mycophenolate Mofetil) in Kidney Transplant Patients.

Study Overview
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Brief Summary
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This study will compare the incidence of acute clinical or subclinical rejection between immunosuppression with CellCept at a starting dose of 3mg po daily with therapeutic drug monitoring and standard immunosuppression with CellCept and a fixed dose of 2g po daily, in kidney transplant recipients receiving induction by anti-IRL2, cyclosporine therapy, and early discontinuation of steroids. Patients will be randomized to one of the two treatment arms. The anticipated time on study treatment is 52 weeks.

Official Title
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A Randomized Study Comparing the Incidence of Acute Clinical or Subclinical Rejection With Two Dosing Regimens of CellCept in de Novo Renal Transplant Recipients Receiving Induction, Cyclosporine and Brief Steroid Therapy

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: mycophenolate mofetil
* Drug: mycophenolate mofetil
* Drug: anti-IL-2R
* Drug: methylprednisolone
* Drug: cyclosporine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients, aged 18-75 years of age; in receipt of first donor kidney; eligible to receive immunosuppressive treatment comprising IRL2, CellCept, cyclosporine and steroids; eligible to receive oral treatment from the first day post-transplantation. Exclusion Criteria: patients receiving a second or subsequent kidney transplant, or multi-organ transplant; history of malignancy in the last 5 years (except successfully treated squamous cell or basal cell cancer and cervical cancer in situ); patients with active hepatitis B and/or hepatitis C, or HIV infection.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mycophenolate Mofetil, Adapted Dose<br>Participants received 3 grams (g) mycophenolate mofetil (MMF) tablets per os (p.o.) in divided doses (every 12 hours [q12h]) adapted to mycophenolic acid (MPA) by area under the curve (AUC) beginning on the day of renal transplant, Day 0, or the day before, Day -1, and continuing through Week 52. In addition, induction by interleukin-2R (IL-2R) was administered at Day 0 per standard of care at the site at the investigator's discretion. At 72 hours post-transplantation, participants received cyclosporine 100-1500 nanograms (ng) per (/) milliliter (mL) from Day 0 to (-) Week 4, 800-1200 ng/mL from Week 4 - Week 12 and 500-800 ng/mL from Week 12 - Week 52. Solumedrol 500 mg intravenously (i.v.) was administered before or after the transplantation, and 0.5 milligrams (mg) per kilogram (kg) p.o. daily from Day 1 - Day 7. | Drug: mycophenolate mofetil<br>* 3 g p.o. in divided doses q12h beginning on the day of renal transplant, Day 0, or the day before, Day -1, and continuing to Week 52, adapted to MPA by AUC on Weeks 2, 6, 12, 26, and 52 to obtain AUC0-12 of 50 milligrams (mg) multiplied by (*) height (h)/ liter(L).<br>* Other names: CellCept;Drug: anti-IL-2R<br>* Induction by IL-2R was administered at Day 0 per standard of care at the site at the investigators discretion.<br>Drug: methylprednisolone<br>* 500 mg intravenous (i.v.) was administered before or after the transplantation, and 0.5 mg/kg p.o. daily from Day 1 to Day 7.<br>* Other names: Solumedrol;Drug: cyclosporine<br>* 100-1500 nanograms (ng) per milliliter (mL) from Day 0 to Week 4, 800-1200 ng/mL from Week 4 to Week 12 and 500-800 ng/mL from Week 12 to Week 52<br>|
| Active Comparator: Mycophenolate Mofetil, Fixed Dose<br>Participants received 2 g MMF tablets p.o. in divided doses q12h beginning on the day of renal transplant, Day 0, or the day before, Day -1, and continuing through Week 52. In addition, induction by IL-2R was administered at Day 0 per standard of care at the site at the investigators discretion. At 72 hours post-transplantation, participants received cyclosporine 100-1500 ng/mL from Day 0 - Week 4, 800-1200 ng/mL from Week 4 - Week 12 and 500-800 ng/mL from Week 12 - Week 52. Solumedrol 500 mg i.v. was administered before or after the transplantation, and 0.5 mg/kg p.o. daily from Day 1 - Day 7. | Drug: mycophenolate mofetil<br>* 2 g p.o. in divided doses q12h beginning on the day of renal transplant, Day 0, or the day before, Day -1, and continuing to Week 52.<br>* Other names: CellCept;Drug: anti-IL-2R<br>* Induction by IL-2R was administered at Day 0 per standard of care at the site at the investigators discretion.<br>Drug: methylprednisolone<br>* 500 mg intravenous (i.v.) was administered before or after the transplantation, and 0.5 mg/kg p.o. daily from Day 1 to Day 7.<br>* Other names: Solumedrol;Drug: cyclosporine<br>* 100-1500 nanograms (ng) per milliliter (mL) from Day 0 to Week 4, 800-1200 ng/mL from Week 4 to Week 12 and 500-800 ng/mL from Week 12 to Week 52<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR) Before Week 12 or Acute Subclinical Rejection on Protocol Biopsy at Week 12 | BPAR was defined as the presence of clinical signs and kidney biopsy that confirmed the rejection before Week 12. Subclinical acute rejection was defined as an increase of serum creatinine at Week 12 strictly less than 10 percent (%) compared to baseline (BL) values and BPAR of Grade greater than or equal to (≥) 1 according to Banff 1997 classification at Week 12. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Creatinine Values [Micromoles Per Liter (µmol/L)] | The mean serum creatinine values at Weeks 2, 4, 6, 12, 16, 26, 39, and 52. | Weeks 2, 4, 6, 12, 16, 26, 39, and 52 | 
| Creatinine Clearance Values Estimated With the Cockcroft-Gault Equation (Milliliters Per Minute [mL/Min]) | The mean creatinine clearance values at Weeks 2, 4, 6, 12, 16, 26, 39, and 52 estimated using the Cockcroft-Gault equation. | Weeks 2, 4, 6, 12, 16, 26, 39, and 52 | 
| Creatinine Clearance Values Estimated With the Modification of Diet in Renal Disease (MDRD) Simplified Equation | The mean creatinine clearance values at Weeks 2, 4, 6, 12, 16, 26, 39, and 52 estimated using the MDRD simplified equation. For males, the MDRD simplified equation was defined as MDRD (mL/min/1.73 square meters [m^2]) =186 multiplied by (*) serum creatinine in mg/L raised to the power of (^) -1.154 * age ^ -0.203. For females, the MDRD simplified equation was defined as MDRD (mL/min/1.73 m^2) = males formula * 0.742. | Weeks 2, 4, 6, 12, 16, 26, 39, and 52 | 
| Time to Occurrence of First BPAR Between Day 0 and Week 52 - Percentage of Participants With an Event | BPAR was defined as the presence of clinical signs and kidney biopsy that confirmed the rejection before Week 12. Subclinical acute rejection at Week 12 was included in the analysis. Subclinical acute rejection was defined as an increase of serum creatinine at Week 12 strictly less than 10% compared to BL values and BPAR of Grade ≥1 according to Banff 1997 classification at Week 12. The occurrence of the first BPAR was defined as the time from randomization to the first recorded BPAR between Day 0 and Week 52. The results of protocol biopsies at Week 12 were taken into account. Participants were censored at the date of last treatment, date of last contact or withdrawal, and date of death. | Day 0, Weeks 2, 4, 6, 12, 16, 26, 39, and 52 | 
| Time to Occurrence of First BPAR Between Day 0 and Week 52 | BPAR was defined as the presence of clinical signs and kidney biopsy that confirmed the rejection before Week 12. Subclinical acute rejection at Week 12 was included in the analysis. Subclinical acute rejection was defined as an increase of serum creatinine at Week 12 strictly less than 10% compared to BL values and BPAR of Grade ≥1 according to Banff 1997 classification at Week 12. The occurrence of the first BPAR was defined as the time from randomization to the first recorded BPAR between Day 0 and Week 52. The results of protocol biopsies at Week 12 were taken into account. Participants were censored at the date of last treatment, date of last contact or withdrawal, and date of death. | Day 0, Weeks 2, 4, 6, 12, 16, 26, 39, and 52 | 
| Percentage of Participants With at Least One BPAR at Week 12 and Week 52 | BPAR was defined as the presence of clinical signs and kidney biopsy that confirmed the rejection before Week 12. Participants were censored at the date of last treatment, date of last contact or withdrawal, and date of death. | Weeks 12 and 52 | 
| Graft Histology - Percentage of Participants With at Least One Borderline Lesion at Week 12 and Week 52 | Participants were censored at the date of last treatment, date of last contact or withdrawal, and date of death. | Weeks 12 and 52 | 
| Graft Histology - Percentage of Participants With at Least One Chronic Graft Nephropathy at Week 12 and Week 52 | Participants were censored at the date of last treatment, date of last contact or withdrawal, and date of death. | Weeks 12 and 52 | 
| Graft Loss - Percentage of Participants With an Event | Graft loss was defined as physical loss (nephrectomy), functional loss [necessitating maintenance dialysis for greater than (>)8 weeks], retransplant or death. Participants were censored at the date of last treatment, date of last contact or withdrawal, and date of death. | Day 0, Weeks 2, 4, 6, 12, 16, 26, 39, and 52 | 
| Time to Graft Loss | The median time, in days, from randomization to graft loss event. Participants were censored at the date of last treatment, date of last contact or withdrawal, and date of death. | Day 0, Weeks 2, 4, 6, 12, 16, 26, 39, and 52 | 
| Participant Survival | Participants survival was defined as the percentage of participants living with or without a functioning graft between Weeks 0 and 52. Participants were censored at the date of last treatment, date of last contact or withdrawal, and date of death. | Day 0, Weeks 2, 4, 6, 12, 16, 26, 39, and 52 |