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sirolimus

cyclosporine or tacrolimus

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The purpose of this study is to determine the effect of sirolimus on the prevention of new non-melanoma skin cancer (NMSC) in kidney transplant recipients.

Study Evaluating the Effect of Sirolimus on Non-Melanoma Skin Cancer in Kidney Transplant Recipients

A Randomized, Open-Label Study to Compare the Rate of New Non-Melanoma Skin Cancer in Maintenance Renal Allograft Recipients Converted to a Sirolimus-based Regimen Versus Continuation of a Calcineurin Inhibitor-based Regimen

The number of new biopsy-confirmed NMSC lesions per subject per year was calculated by summarizing the total number of new BCC and SCC lesions reported over the observation period and standardizing it to an annual rate by multiplying by 365 and dividing by days on study.

The time to first biopsy confirmed new NMSC lesion starts at 1 day post randomization to biopsy and/or treatment of newly confirmed NMSC lesion.

The overall number of subjects who were lesion free were compared between treatment groups with the Cochran Mantel Haenszel test stratified by baseline NMSC stratum. Within each stratum, the Fisher exact test was used to compare the proportions of lesion free subjects between treatment groups.

Number of subjects with at least 1 biopsy-confirmed new squamous cell carcinoma (SCC) or basal cell carcinoma (BCC).

Recurrent NMSC lesions is defined as recurring at the site of a previously treated lesion.

The number of subjects with metastatic disease related to NMSC.

GFR is an index of kidney function. GFR describes the flow rate of filtered fluid through the kidney. GFR can be measured directly or estimated using established formulas. For this study, GFR was calculated using Nankivell. A normal GFR is \> 90 mL/min, although children and older people usually have a lower GFR. Lower values indicate poor kidney function. A GFR \<15 is consistent with kidney failure.

Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatinine, commonly found in blood, urine, and muscle tissue. It is removed from the blood by the kidneys and excreted in urine. An increased level of creatinine in the blood indicates decreased kidney function. Normal adult blood levels of creatinine are 0.5 to 1.1 mg/dL for females and 0.6 to 1.2 mg/dL for males, however the normal values are age-dependent as elderly patients typically have smaller muscle mass.

Graft loss was defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for \>8 consecutive weeks), retransplant, or death.

Subjects' urine protein:creatinine ratios were summarized by each scheduled visit, and the nonparametric Wilcoxon rank sum test was used to compare the difference between groups.

Wyeth is now a wholly owned subsidiary of Pfizer

All subjects discontinued Calcineurin inhibitors (CNI) after the morning dose on day 1. SRL was initiated with a loading dose of 6-12mg on day 1, followed by 2-4mg daily and was adjusted to maintain a whole blood trough concentration of 5-15ng/mL (high performance liquid chromatography \[HPLC\]). Once the SRL trough concentration was ≥ 5ng/mL, subjects receiving mycophenolate mofetil (MMF), mycophenolate sodium (MPS), or azathioprine (AZA) at randomization had doses reduced to ≤1.5 g/day, ≤1080 mg/day or ≤75 mg/day respectively. If warranted subjects could be switched between MMF, MPS, or AZA or their doses decreased, temporarily withheld, or discontinued. Subjects receiving corticosteroids (CS) at time of randomization or if MMF, MPS, or AZA was discontinued, had to receive CS ≥2.5mg/day of prednisone. Subjects not receiving MMF, MPS, or AZA at time of randomization remained on a minimum of double therapy (SRL and CS). Addition of MMF, MPS, or AZA was permitted.

Sirolimus (SRL) Based Regimen

Baseline CNI therapy was continued after randomization and doses could be adjusted throughout the study as indicated, but therapy could not be withdrawn. Cyclosporine could be switched to tacrolimus, and vice versa. If warranted subjects could be switched between MMF, MPS, or AZA or their doses could be decreased, temporarily withheld, or discontinued. Subjects undergoing discontinuation of MMF, MPS, or AZA had to receive CS ≥2.5 mg/day of prednisone or the equivalent thereof. If subjects were not receiving MMF, MPS, or AZA at the time of randomization, the addition of MMF, MPS, or AZA was permitted if clinically indicated. If subjects were receiving CS at the time of randomization, CS was maintained at ≥2.5 mg/day of prednisone or the equivalent thereof. CS withdrawal was prohibited. If subjects were not receiving CS at the time of randomization, treatment could be initiated during the conduct of the study if clinically indicated.

Calcineurin Inhibitor (CNI) Based Regimen

Total

Age Continuous

Sex: Female, Male

0-5 Lesions in 12 months prior

6-20 Lesions in 12 months prior

Stratification Group

Time from Current Transplantation to Randomization

A blinded review of data in May 2007 determined there was minimal added power in follow-up through 2 years vs. 1 year. The study was then amended to require at least 1 year of follow-up instead of 2 years.

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Intention to Treat: All randomly assigned subjects with at least 1 dose of study medication, includes data of subjects on therapy, those off therapy, and those who completed follow-up.

New Biopsy-Confirmed Nonmelanoma Skin Cancer (NMSC) Lesions Per Subject Per Year

Time to First Biopsy Confirmed New NMSC Lesion.

Number of Lesion Free Subjects

Percentage of Patients With New Biopsy-confirmed NMSC: Squamous Cell Carcinoma (SCC) and Basal Cell Carcinoma (BCC)

SCC Well differentiated

SCC Moderately differentiated

SCC Poorly differentiated

SCC Invasive

SCC In Situ

SCC Invasive with Perineural Invasion

SCC Invasive without Perineural Invasion

BCC Superficial

BCC Nodular

BCC Infiltrative

Grade Distribution of NMSC Lesions

Number of Recurrent NMSC Lesions Per Subject-year

Subjects Reporting Incidence of Metastatic Disease Related to NMSC.

Death Due to NMSC

Number of Subjects Who Discontinue Assigned Therapy

Intention to Treat: All randomly assigned subjects with at least 1 dose of study medication, includes data of subjects on therapy, those off therapy, and those who completed follow-up. For the intention to treat analysis, a GFR of 0 was imputed for graft loss or death, and last observation carried forward (LOCF) for missing values.

Nankivell-Calculated Glomerular Filtration Rate (GFR)

Intention to Treat: All randomly assigned subjects with at least 1 dose of study medication, includes data of subjects on therapy, those off therapy, and those who completed follow-up. All available data, no imputations.

Serum Creatinine Level

Number of Participants That Died

Graft Survival Measured by Graft Loss

Number of Subjects With Biopsy-Confirmed Acute Rejection

Intention to Treat: All randomly assigned subjects with at least 1 dose of study medication, includes data of subjects on therapy, those off therapy, and those who completed follow-up. Available data, no imputations.

Spots Global Cancer Trial Database for Study Evaluating the Effect of Sirolimus on Non-Melanoma Skin Cancer in Kidney Transplant Recipients

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