Skin Neoplasms, Kidney Transplantation
Conditions
Keywords
Kidney, Transplant, Skin Cancer
Brief summary
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.
Interventions
DRUGsirolimus
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Kidney transplant at least 1 year prior * Subjects with a functioning renal allograft with calculated glomerular filtration rate (GFR) ≥40mL/min (Nankivell method) and proteinuria ≤500mg/day. * Stable on cyclosporine or tacrolimus-based multi-drug immunosuppressive regimen * History of NMSC within last 3 years
Exclusion criteria
* History of other cancer within last 3 years * NMSC with metastatic disease or more than 20 NMSC lesions in last 12 months * Multiple organ transplant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| New Biopsy-Confirmed Nonmelanoma Skin Cancer (NMSC) Lesions Per Subject Per Year | up to 24 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Lesion Free Subjects | up to 24 months | 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. |
| Percentage of Patients With New Biopsy-confirmed NMSC: Squamous Cell Carcinoma (SCC) and Basal Cell Carcinoma (BCC) | up to 24 months | — |
| Grade Distribution of NMSC Lesions | up to 24 months | Number of subjects with at least 1 biopsy-confirmed new squamous cell carcinoma (SCC) or basal cell carcinoma (BCC). |
| Number of Recurrent NMSC Lesions Per Subject-year | up to 24 months | Recurrent NMSC lesions is defined as recurring at the site of a previously treated lesion. |
| Subjects Reporting Incidence of Metastatic Disease Related to NMSC. | up to 24 months | The number of subjects with metastatic disease related to NMSC. |
| Death Due to NMSC | up to 24 months | — |
| Time to First Biopsy Confirmed New NMSC Lesion. | up to 24 months | 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. |
| Nankivell-Calculated Glomerular Filtration Rate (GFR) | At 24 months (week 104) | 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 Level | At 24 months (Week 104) | 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. |
| Number of Participants That Died | up to 24 months | — |
| Graft Survival Measured by Graft Loss | up to 24 months | Graft loss was defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for \>8 consecutive weeks), retransplant, or death. |
| Number of Subjects With Biopsy-Confirmed Acute Rejection | up to 24 months | — |
| Spot Urine Protein:Creatinine Ratio | At 24 months (Week 104) | 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. |
| Number of Subjects Who Discontinue Assigned Therapy | up to 24 months | — |
Countries
Australia, Canada, New Zealand, United States
Participant flow
Recruitment details
Subjects were recruited in Australia, New Zealand and North America from August 2005 (first subject randomized September 2005) through October 2007.
Pre-assignment details
Screening and baseline evaluations were performed within 4 weeks prior to randomization. Randomization assignments by site were stratified by the number of new NMSC lesions in the 12 months prior to enrollment (0-5 lesions vs 6-20 lesions).
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus (SRL) Based Regimen 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. | 39 |
| Calcineurin Inhibitor (CNI) 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. | 47 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Missing Record | 0 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Sponsor | 14 | 20 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Sirolimus (SRL) Based Regimen | Calcineurin Inhibitor (CNI) Based Regimen | Total |
|---|---|---|---|
| Age Continuous | 59.08 years | 58.98 years | 59.02 years |
| Sex: Female, Male Female | 8 Participants | 13 Participants | 21 Participants |
| Sex: Female, Male Male | 31 Participants | 34 Participants | 65 Participants |
| Stratification Group 0-5 Lesions in 12 months prior | 33 subjects | 39 subjects | 72 subjects |
| Stratification Group 6-20 Lesions in 12 months prior | 6 subjects | 8 subjects | 14 subjects |
| Time from Current Transplantation to Randomization | 114.98 Months STANDARD_DEVIATION 57.63 | 109.57 Months STANDARD_DEVIATION 55.08 | 112.02 Months STANDARD_DEVIATION 55.98 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 39 | 40 / 47 |
| serious Total, serious adverse events | 15 / 39 | 21 / 47 |
Outcome results
Primary
New Biopsy-Confirmed Nonmelanoma Skin Cancer (NMSC) Lesions Per Subject Per Year
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.
Time frame: up to 24 months
Population: 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.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Sirolimus (SRL) Based Regimen | New Biopsy-Confirmed Nonmelanoma Skin Cancer (NMSC) Lesions Per Subject Per Year | 1.31 Standardized Yearly Rate of NMSC | 0.52 |
| Calcineurin Inhibitor (CNI) Based Regimen | New Biopsy-Confirmed Nonmelanoma Skin Cancer (NMSC) Lesions Per Subject Per Year | 2.48 Standardized Yearly Rate of NMSC | 0.69 |
p-value: 0.022Poisson regression
Secondary
Death Due to NMSC
Time frame: up to 24 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus (SRL) Based Regimen | Death Due to NMSC | 0 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Death Due to NMSC | 0 participants |
Secondary
Grade Distribution of NMSC Lesions
Number of subjects with at least 1 biopsy-confirmed new squamous cell carcinoma (SCC) or basal cell carcinoma (BCC).
Time frame: up to 24 months
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus (SRL) Based Regimen | Grade Distribution of NMSC Lesions | SCC Well differentiated | 5 participants |
| Sirolimus (SRL) Based Regimen | Grade Distribution of NMSC Lesions | SCC Moderately differentiated | 9 participants |
| Sirolimus (SRL) Based Regimen | Grade Distribution of NMSC Lesions | SCC Poorly differentiated | 1 participants |
| Sirolimus (SRL) Based Regimen | Grade Distribution of NMSC Lesions | SCC Invasive | 10 participants |
| Sirolimus (SRL) Based Regimen | Grade Distribution of NMSC Lesions | SCC In Situ | 12 participants |
| Sirolimus (SRL) Based Regimen | Grade Distribution of NMSC Lesions | SCC Invasive with Perineural Invasion | 2 participants |
| Sirolimus (SRL) Based Regimen | Grade Distribution of NMSC Lesions | SCC Invasive without Perineural Invasion | 8 participants |
| Sirolimus (SRL) Based Regimen | Grade Distribution of NMSC Lesions | BCC Superficial | 7 participants |
| Sirolimus (SRL) Based Regimen | Grade Distribution of NMSC Lesions | BCC Nodular | 11 participants |
| Sirolimus (SRL) Based Regimen | Grade Distribution of NMSC Lesions | BCC Infiltrative | 2 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Grade Distribution of NMSC Lesions | BCC Superficial | 16 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Grade Distribution of NMSC Lesions | SCC Well differentiated | 17 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Grade Distribution of NMSC Lesions | SCC Invasive with Perineural Invasion | 1 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Grade Distribution of NMSC Lesions | SCC Moderately differentiated | 14 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Grade Distribution of NMSC Lesions | BCC Infiltrative | 6 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Grade Distribution of NMSC Lesions | SCC Poorly differentiated | 1 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Grade Distribution of NMSC Lesions | SCC Invasive without Perineural Invasion | 24 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Grade Distribution of NMSC Lesions | SCC Invasive | 24 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Grade Distribution of NMSC Lesions | BCC Nodular | 15 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Grade Distribution of NMSC Lesions | SCC In Situ | 27 participants |
Comparison: SCC Well differentiatedp-value: 0.014Cochran-Mantel-Haenszel
Comparison: SCC Moderately differentiatedp-value: 0.491Cochran-Mantel-Haenszel
Comparison: SCC Poorly differentiatedp-value: 0.905Cochran-Mantel-Haenszel
Comparison: SCC Invasivep-value: 0.018Cochran-Mantel-Haenszel
Comparison: SCC In Situp-value: 0.012Cochran-Mantel-Haenszel
Comparison: SCC Invasive with Perineural Invasionp-value: 0.463Cochran-Mantel-Haenszel
Comparison: SCC Invasive without Perineural Invasionp-value: 0.004Cochran-Mantel-Haenszel
Comparison: BCC Superficialp-value: 0.094Cochran-Mantel-Haenszel
Comparison: BCC Nodularp-value: 0.72Cochran-Mantel-Haenszel
Comparison: BCC Infiltrativep-value: 0.227Cochran-Mantel-Haenszel
Secondary
Graft Survival Measured by Graft Loss
Graft loss was defined as physical loss (nephrectomy), functional loss (necessitating maintenance dialysis for \>8 consecutive weeks), retransplant, or death.
Time frame: up to 24 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus (SRL) Based Regimen | Graft Survival Measured by Graft Loss | 2 graft loss |
| Calcineurin Inhibitor (CNI) Based Regimen | Graft Survival Measured by Graft Loss | 1 graft loss |
p-value: 0.588Fisher Exact
Secondary
Nankivell-Calculated Glomerular Filtration Rate (GFR)
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.
Time frame: At 24 months (week 104)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus (SRL) Based Regimen | Nankivell-Calculated Glomerular Filtration Rate (GFR) | 72.49 units on scale | Standard Deviation 24.41 |
| Calcineurin Inhibitor (CNI) Based Regimen | Nankivell-Calculated Glomerular Filtration Rate (GFR) | 68.42 units on scale | Standard Deviation 19.91 |
p-value: 0.604ANCOVA
Secondary
Number of Lesion Free Subjects
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.
Time frame: up to 24 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus (SRL) Based Regimen | Number of Lesion Free Subjects | 17 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Number of Lesion Free Subjects | 9 participants |
p-value: 0.015Cochran-Mantel-Haenszel
Secondary
Number of Participants That Died
Time frame: up to 24 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus (SRL) Based Regimen | Number of Participants That Died | 1 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Number of Participants That Died | 1 participants |
p-value: 0.999Fisher Exact
Secondary
Number of Recurrent NMSC Lesions Per Subject-year
Recurrent NMSC lesions is defined as recurring at the site of a previously treated lesion.
Time frame: up to 24 months
Population: 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.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Sirolimus (SRL) Based Regimen | Number of Recurrent NMSC Lesions Per Subject-year | 0.107 lesions per participant year | 0.09 |
| Calcineurin Inhibitor (CNI) Based Regimen | Number of Recurrent NMSC Lesions Per Subject-year | 0.134 lesions per participant year | 0.1 |
p-value: 0.748Poisson regression
Secondary
Number of Subjects Who Discontinue Assigned Therapy
Time frame: up to 24 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus (SRL) Based Regimen | Number of Subjects Who Discontinue Assigned Therapy | 31 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Number of Subjects Who Discontinue Assigned Therapy | 23 participants |
Secondary
Number of Subjects With Biopsy-Confirmed Acute Rejection
Time frame: up to 24 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus (SRL) Based Regimen | Number of Subjects With Biopsy-Confirmed Acute Rejection | 0 subjects |
| Calcineurin Inhibitor (CNI) Based Regimen | Number of Subjects With Biopsy-Confirmed Acute Rejection | 1 subjects |
p-value: 0.999Fisher Exact
Secondary
Percentage of Patients With New Biopsy-confirmed NMSC: Squamous Cell Carcinoma (SCC) and Basal Cell Carcinoma (BCC)
Time frame: up to 24 months
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus (SRL) Based Regimen | Percentage of Patients With New Biopsy-confirmed NMSC: Squamous Cell Carcinoma (SCC) and Basal Cell Carcinoma (BCC) | SCC | 67 Percentage of Participants |
| Sirolimus (SRL) Based Regimen | Percentage of Patients With New Biopsy-confirmed NMSC: Squamous Cell Carcinoma (SCC) and Basal Cell Carcinoma (BCC) | BCC | 33 Percentage of Participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Percentage of Patients With New Biopsy-confirmed NMSC: Squamous Cell Carcinoma (SCC) and Basal Cell Carcinoma (BCC) | SCC | 69 Percentage of Participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Percentage of Patients With New Biopsy-confirmed NMSC: Squamous Cell Carcinoma (SCC) and Basal Cell Carcinoma (BCC) | BCC | 31 Percentage of Participants |
p-value: 0.799Chi-squared
Secondary
Serum Creatinine Level
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.
Time frame: At 24 months (Week 104)
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sirolimus (SRL) Based Regimen | Serum Creatinine Level | 139.35 μmol/L | Standard Deviation 41.63 |
| Calcineurin Inhibitor (CNI) Based Regimen | Serum Creatinine Level | 135.23 μmol/L | Standard Deviation 37.84 |
p-value: 0.672ANCOVA
Secondary
Spot Urine Protein:Creatinine Ratio
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.
Time frame: At 24 months (Week 104)
Population: 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.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Sirolimus (SRL) Based Regimen | Spot Urine Protein:Creatinine Ratio | 0.14 ratio (mg/mg) | Full Range 0.28 |
| Calcineurin Inhibitor (CNI) Based Regimen | Spot Urine Protein:Creatinine Ratio | 0.12 ratio (mg/mg) | Full Range 0.08 |
p-value: 0.03Wilcoxon (Mann-Whitney)
Secondary
Subjects Reporting Incidence of Metastatic Disease Related to NMSC.
The number of subjects with metastatic disease related to NMSC.
Time frame: up to 24 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sirolimus (SRL) Based Regimen | Subjects Reporting Incidence of Metastatic Disease Related to NMSC. | 1 participants |
| Calcineurin Inhibitor (CNI) Based Regimen | Subjects Reporting Incidence of Metastatic Disease Related to NMSC. | 3 participants |
p-value: 0.425Cochran-Mantel-Haenszel
Secondary
Time to First Biopsy Confirmed New NMSC Lesion.
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.
Time frame: up to 24 months
Population: 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.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Sirolimus (SRL) Based Regimen | Time to First Biopsy Confirmed New NMSC Lesion. | 380 number of days | 95% Confidence Interval 42.42 |
| Calcineurin Inhibitor (CNI) Based Regimen | Time to First Biopsy Confirmed New NMSC Lesion. | 163 number of days | 95% Confidence Interval 42.32 |
p-value: 0.047Regression, Cox