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

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Prevention
Conditions:	Skin Neoplasms Kidney Transplantation
Interventions:	Drug: sirolimus Drug: cyclosporine or tacrolimus

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Subjects were recruited in Australia, New Zealand and North America from August 2005 (first subject randomized September 2005) through October 2007.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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).

Reporting Groups

	Description
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.
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continued after randomization and doses could be adjusted throughout the study as indicated, but therapy could not be withdrawn.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.

Description

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.

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.

Participant Flow: Overall Study

	Sirolimus (SRL) Based Regimen	Calcineurin Inhibitor (CNI) Based Regimen
STARTED	39	47
COMPLETED	20	24
NOT COMPLETED	19	23
Adverse Event	1	0
Death	1	1
Withdrawal by Sponsor	14	20
Physician Decision	1	0
Withdrawal by Subject	2	1
Missing Record	0	1

Baseline Characteristics

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Reporting Groups

	Description
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.
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.

Description

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.

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.

Baseline Measures

	Sirolimus (SRL) Based Regimen	Calcineurin Inhibitor (CNI) Based Regimen	Total
Number of Participants [units: participants]	39	47	86
Age [units: years] Mean ( Full Range )	59.08 ( 36 to 76 )	58.98 ( 37 to 78 )	59.02 ( 36 to 78 )
Gender [units: subjects]
Female	8	13	21
Male	31	34	65
Stratification Group [units: subjects]
0-5 Lesions in 12 months prior	33	39	72
6-20 Lesions in 12 months prior	6	8	14
Time from Current Transplantation to Randomization [units: Months] Mean ± Standard Deviation	114.98 ± 57.63	109.57 ± 55.08	112.02 ± 55.98

Outcome Measures

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1. Primary:

New Biopsy-Confirmed Nonmelanoma Skin Cancer (NMSC) Lesions Per Subject Per Year [ Time Frame: up to 24 months ]

Show Outcome Measure 1

2. Secondary:

Time to First Biopsy Confirmed New NMSC Lesion. [ Time Frame: up to 24 months ]

Show Outcome Measure 2

3. Secondary:

Number of Lesion Free Subjects [ Time Frame: up to 24 months ]

Show Outcome Measure 3

4. Secondary:

Percentage of Patients With New Biopsy-confirmed NMSC: Squamous Cell Carcinoma (SCC) and Basal Cell Carcinoma (BCC) [ Time Frame: up to 24 months ]

Show Outcome Measure 4

5. Secondary:

Grade Distribution of NMSC Lesions [ Time Frame: up to 24 months ]

Show Outcome Measure 5

6. Secondary:

Number of Recurrent NMSC Lesions Per Subject-year [ Time Frame: up to 24 months ]

Show Outcome Measure 6

7. Secondary:

Subjects Reporting Incidence of Metastatic Disease Related to NMSC. [ Time Frame: up to 24 months ]

Show Outcome Measure 7

8. Secondary:

Death Due to NMSC [ Time Frame: up to 24 months ]

Show Outcome Measure 8

9. Secondary:

Number of Subjects Who Discontinue Assigned Therapy [ Time Frame: up to 24 months ]

Show Outcome Measure 9

10. Secondary:

Nankivell-Calculated Glomerular Filtration Rate (GFR) [ Time Frame: At 24 months (week 104) ]

Show Outcome Measure 10

11. Secondary:

Serum Creatinine Level [ Time Frame: At 24 months (Week 104) ]

Show Outcome Measure 11

12. Secondary:

Number of Participants That Died [ Time Frame: up to 24 months ]

Show Outcome Measure 12

13. Secondary:

Graft Survival Measured by Graft Loss [ Time Frame: up to 24 months ]

Show Outcome Measure 13

14. Secondary:

Number of Subjects With Biopsy-Confirmed Acute Rejection [ Time Frame: up to 24 months ]

Show Outcome Measure 14

15. Secondary:

Spot Urine Protein:Creatinine Ratio [ Time Frame: At 24 months (Week 104) ]

Show Outcome Measure 15

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The PIs agreed to allow the sponsor 60 days to review and require changes to presentations or publications but only to protect confidential information and intellectual property, and for the sponsor to file a patent application, as applicable. The PIs also agreed for data to be presented first as a joint, multi-center publication.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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.

Results Point of Contact:

Name/Title: U. S. Contact Center
Organization: Wyeth
e-mail: clintrialresults@wyeth.com

No publications provided

Responsible Party:	Wyeth is now a wholly owned subsidiary of Pfizer
ClinicalTrials.gov Identifier:	NCT00129961 History of Changes
Other Study ID Numbers:	0468H1-407
Study First Received:	August 1, 2005
Results First Received:	January 29, 2010
Last Updated:	April 9, 2012
Health Authority:	Australia: Department of Health and Ageing Therapeutic Goods Administration