Study Comparing Effect On Carotid Atherosclerosis Following Conversion From Tacrolimus To Sirolimus Post-Transplant In Kidney Transplant Patients

This study has been terminated.

(See termination reason in detailed description.)

Sponsor:

Information provided by (Responsible Party):

Pfizer

ClinicalTrials.gov Identifier:

NCT00311311

First received: April 3, 2006

Last updated: May 15, 2012

Last verified: May 2012

History of Changes

Purpose

The purpose of this study is to determine whether immunosuppression by tacrolimus, mycophenolate mofetil, and prednisone compared to conversion to sirolimus, mycophenolate mofetil, and prednisone affect the progression of atherosclerosis in renal transplant recipients.

Condition	Intervention	Phase
Atherosclerosis Kidney Failure	Drug: tacrolimus Drug: mycophenolate mofetil Drug: prednisone Drug: sirolimus	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Prospective, Randomized, Open-Label, Pilot Study To Compare The Effect On Carotid Atherosclerosis Of A Tacrolimus-Based Regimen With Conversion From A Tacrolimus- To A Sirolimus-Based Regimen At 3-4 Months Post-Transplant In De Novo Renal Transplant Recipients

Resource links provided by NLM:

MedlinePlus related topics: Atherosclerosis Kidney Transplantation Steroids

Drug Information available for: Prednisone Mycophenolic acid Mycophenolate sodium Sirolimus Tacrolimus Mycophenolate mofetil hydrochloride Mycophenolate mofetil Everolimus Temsirolimus

U.S. FDA Resources

Further study details as provided by Pfizer:

Primary Outcome Measures:

Total Plaque Volume (TPV) Annual Rate of Change From Pre-conversion Baseline to 12 Months Post Transplant [ Time Frame: 12 Months Post-Transplant ] [ Designated as safety issue: Yes ]
Annual rate of change in TPV in the left and right distal common carotid arteries from the pre-conversion baseline to 12 months post kidney transplant as determined by ultrasound. Annual change rate equals (=) (TPV at month 12 post-transplant minus [-] TPV at pre-conversion baseline) divided (/) by imaging interval in years. TPV is the sum of assessment in left and right distal common carotid arteries.
TPV at Pre-conversion Baseline [ Time Frame: Pre-Conversion Baseline ] [ Designated as safety issue: Yes ]
TPV is the sum of the assessment in left and right distal common carotid arteries.

Secondary Outcome Measures:

Carotid Intima Media Thickness (CIMT) Annual Rate of Change From Pre-conversion Baseline at 12, 18, 24 and 36 Months Post-transplant [ Time Frame: 12, 18, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: Yes ]
Annual rate of change in the distal common carotid arteries as determined by ultrasound. Mean CIMT=average of left CIMT and right CIMT. Annual CIMT Change Rate (mm/year) = (CIMT at Month x Post-transplant Visit - CIMT at Conversion Baseline) / Imaging Interval. Further data will be reported.
Change From Pre-conversion Baseline in Carotid Plaque Roughness at 12 and 24 Months Post-transplant [ Time Frame: Pre-Conversion Baseline, 12, and 24 Months Post-Transplant or ET ] [ Designated as safety issue: Yes ]
Carotid plaque roughness as determined by ultrasound. Change equals (=) value at post-transplant month x minus (-) pre-conversion baseline.
Change From Pre-conversion Baseline in Fasting Lipid Parameters at 12 Months Post-transplant [ Time Frame: Pre-conversion baseline and 12 Months Post-Transplant ] [ Designated as safety issue: Yes ]
Total Cholesterol (TC), Low Density Lipoprotein (LDL), High Density Lipoprotein (HDL) and Triglyceride (Tg) blood concentrations. Higher levels of TC, LDL and Tg are less desirable. Lower levels of HDL are less desirable. Change for each parameter = value at 12 months post transplant - value at preconversion baseline.
Change From Pre-conversion Baseline in Glucose at 12, 24, and 36 Months Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: Yes ]
Fasting plasma glucose. Change = value at month x post-transplant - pre-conversion baseline values.
Change From Pre-conversion Baseline in Insulin at 12, 24, and 36 Months Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: Yes ]
Fasting insulin. Change = value at month x post-transplant - pre-conversion baseline.
Change From Pre-conversion Baseline in Hemoglobin (Hb) A1C at 12, 24, and 36 Months Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: Yes ]
Hb A1C, change = value at month x post-transplant - pre-conversion baseline.
Change From Pre-conversion Baseline in Adiponectin at Months 12, 24 and 36 Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: No ]
Adiponectin is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates less risk. Change = month x post-transplant values - pre-conversion baseline values.
Change From Pre-conversion Baseline in High Sensitivity C-Reactive Protein (hsCRP) at Months 12, 24 and 36 Post-transplant. [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: No ]
hsCRP is a biomarker of cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values.
Change From Pre-conversion Baseline in Tumor Necrosis Factor Alpha (TNF-alpha) at Months 12, 24 and 36 Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: No ]
TNF-alpha is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values.
Change From Pre-conversion Baseline in Endothelin-1 at Months 12, 24 and 36 Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: No ]
Endothelin-1 is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates greater risk. Change = month x post-transplant values - pre-conversion baseline values.
Change From Pre-conversion Baseline in Interleukin-6 (IL-6) at Months 12, 24 and 36 Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: No ]
IL-6 is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion values.
Change From Pre-conversion Baseline in Homocysteine at Months 12, 24 and 36 Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: No ]
Homocysteine is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values.
Change From Pre-conversion Baseline in Lipoprotein (a) at Months 12, 24 and 36 Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: No ]
Lipoprotein (a) is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values.
Change From Pre-conversion Baseline in Fibrinogen at Months 12, 24 and 36 Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: No ]
Fibrinogen is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values.
Change From Pre-conversion Baseline in Vitamin B12 at Months 12, 24 and 36 Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: No ]
Vitamin B12 is a biomarker for cardiovascular disease and atherosclerosis risk. A lower level indicates a greater risk. Change = month x post-transplant values - pre-conversion values.
Change From Pre-conversion Baseline in Uric Acid at Months 12, 24 and 36 Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: No ]
Uric Acid is a biomarker for cardiovascular disease and atherosclerosis risk. A higher level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values.
Change From Pre-conversion Baseline in Folate at 12, 24 and 36 Months Post-transplant [ Time Frame: Pre-conversion baseline, 12, 24 and 36 Months Post-Transplant or ET ] [ Designated as safety issue: No ]
Folate is a biomarker for cardiovascular disease and atherosclerosis risk. A lower level indicates a greater risk. Change = month x post-transplant values - pre-conversion baseline values.
Number of Participants Who Used Lipid Lowering or Anti-hypertensive Therapies [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
Participants who reported "yes" to taking a lipid lowering therapy or an anti-hypertensive medication as a concomitant medication.
CIMT at Pre-conversion Baseline [ Time Frame: Pre-Conversion Baseline ] [ Designated as safety issue: Yes ]
Mean CIMT=average of left CIMT and right CIMT.
Change From Pre-conversion Baseline in Fasting Lipid Parameters at 24 Months Post-transplant [ Time Frame: 24 Months Post-Transplant ] [ Designated as safety issue: Yes ]
TC, LDL, HDL and Tg blood concentrations. Higher levels of TC, LDL and Tg are less desirable. Lower levels of HDL are less desirable. Change for each parameter = value at 24 months post transplant-value at pre-conversion baseline.
Change From Pre-conversion Baseline in Fasting Lipid Parameters at 36 Months Post-transplant [ Time Frame: 36 Months Post-Transplant or ET ] [ Designated as safety issue: Yes ]
TC, LDL, HDL and Tg blood concentrations. Higher levels of TC, LDL and Tg are less desirable. Lower levels of HDL are less desirable. Change for each parameter = value at 36 months post transplant - value at pre-conversion baseline.
TPV Annual Rate of Change From Pre-conversion Baseline to 18, 24 and 36 Months Post Transplant [ Time Frame: Pre-Conversion Baseline, 18, 24, and 36 Month Post-Transplant or Early Termination (ET) ] [ Designated as safety issue: Yes ]
Annual rate of change in TPV in the left and right distal common carotid arteries from the pre-conversion baseline to x months post kidney transplant as determined by ultrasound. Annual change rate equals (=) (TPV at month x post-transplant - TPV at baseline) divided (/) by imaging interval in years. TPV is the sum of assessment in left and right distal common carotid arteries.

Enrollment:	72
Study Start Date:	April 2006
Study Completion Date:	January 2012
Primary Completion Date:	December 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: 1 Tacrolimus + MMF + Steroids	Drug: tacrolimus The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol TAC should be initiated within 24 hours before or after transplantation or within 14 days of transplantation as per local standard of care and tapered to a target trough level of 3-10 ng/mL by the Pre-Conversion visit at month 3-4 post-transplantation. The target trough level of TAC will be maintained at 3-10 ng/mL through to the end of the study. Other Name: CNI Drug: mycophenolate mofetil The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol MMF or MPS should be initiated within 24 hours before or after transplantation or within 14 days of transplantation per local standard of care and tapered to a minimum oral dose of MMF ≥ 500 mg/day or MPS ≥ 360 mg/day by the Pre-Conversion visit at month 3-4 post-transplantation. At the discretion of the investigator, MMF may be changed to MPS, or MPS may be changed to MMF. MMF is to be continued at ≥ 500 mg/day dose or MPS is to be continued at ≥ 360 mg/day dose through to the end of study. Other Name: MMF, MPS Drug: prednisone The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol CCS should be initiated within 24 hours before or after transplantation or within 14 days of transplantation per local standard of care and tapered to a minimum of 5 mg/day of prednisone orally or the alternate day equivalent by the Pre-Conversion visit at month 3-4 post-transplant. Continue administration of prednisone as per local standard of care to a minimum dose of 2.5 mg/day or alternate day equivalent dose to the end of the study. Withdrawal of CCS is prohibited. Other Name: CCS
Experimental: 2 Tacrolimus + MMF + Steroids with conversion from Tacrolimus to Sirolimus at 3-4 months post-transplant	Drug: sirolimus The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol. On study Day 1 Conversion, the daily dose of TAC will not be taken, and SRL is initiated as a single 5-10 mg loading dose, followed by 3 mg/day on subsequent days, adjusted to maintain a SRL target trough level of 8-15 ng/mL through to month 24 post-transplant, then 5-12 ng/mL to the end of month 36 post-transplant. Drug: tacrolimus The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol TAC should be initiated within 24 hours before or after transplantation or within 14 days of transplantation as per local standard of care and tapered to a target trough level of 3-10 ng/mL by the Pre-Conversion visit at month 3-4 post-transplantation. Reintroduction of TAC or introduction of CsA is not permitted in the SRL Therapy group. Other Name: CNI Drug: mycophenolate mofetil The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol MMF or MPS should be initiated within 24 hours before or after transplantation or within 14 days of transplantation per local standard of care and tapered to a minimum oral dose of MMF ≥ 500 mg/day or MPS ≥ 360 mg/day by the Pre-Conversion visit at month 3-4 post-transplantation. At the discretion of the investigator, MMF may be changed to MPS, or MPS may be changed to MMF. MMF is to be continued at ≥ 500 mg/day dose or MPS is to be continued at ≥ 360 mg/day dose through to the end of study. Other Name: MMF, MPS Drug: prednisone The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol CCS should be initiated within 24 hours before or after transplantation or within 14 days of transplantation per local standard of care and tapered to a minimum of 5 mg/day of prednisone orally or the alternate day equivalent by the Pre-Conversion visit at month 3-4 post-transplant. Continue administration of prednisone as per local standard of care to a minimum dose of 2.5 mg/day or alternate day equivalent dose to the end of the study. Withdrawal of CCS is prohibited. Other Name: CCS

Arms

Assigned Interventions

Active Comparator: 1

Tacrolimus + MMF + Steroids

Drug: tacrolimus

The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol TAC should be initiated within 24 hours before or after transplantation or within 14 days of transplantation as per local standard of care and tapered to a target trough level of 3-10 ng/mL by the Pre-Conversion visit at month 3-4 post-transplantation. The target trough level of TAC will be maintained at 3-10 ng/mL through to the end of the study.

Other Name: CNI

Drug: mycophenolate mofetil

The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol MMF or MPS should be initiated within 24 hours before or after transplantation or within 14 days of transplantation per local standard of care and tapered to a minimum oral dose of MMF ≥ 500 mg/day or MPS ≥ 360 mg/day by the Pre-Conversion visit at month 3-4 post-transplantation. At the discretion of the investigator, MMF may be changed to MPS, or MPS may be changed to MMF. MMF is to be continued at ≥ 500 mg/day dose or MPS is to be continued at ≥ 360 mg/day dose through to the end of study.

Other Name: MMF, MPS

Drug: prednisone

The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol CCS should be initiated within 24 hours before or after transplantation or within 14 days of transplantation per local standard of care and tapered to a minimum of 5 mg/day of prednisone orally or the alternate day equivalent by the Pre-Conversion visit at month 3-4 post-transplant. Continue administration of prednisone as per local standard of care to a minimum dose of 2.5 mg/day or alternate day equivalent dose to the end of the study. Withdrawal of CCS is prohibited.

Other Name: CCS

Experimental: 2

Tacrolimus + MMF + Steroids with conversion from Tacrolimus to Sirolimus at 3-4 months post-transplant

Drug: sirolimus

On study Day 1 Conversion, the daily dose of TAC will not be taken, and SRL is initiated as a single 5-10 mg loading dose, followed by 3 mg/day on subsequent days, adjusted to maintain a SRL target trough level of 8-15 ng/mL through to month 24 post-transplant, then 5-12 ng/mL to the end of month 36 post-transplant.

Drug: tacrolimus

The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol TAC should be initiated within 24 hours before or after transplantation or within 14 days of transplantation as per local standard of care and tapered to a target trough level of 3-10 ng/mL by the Pre-Conversion visit at month 3-4 post-transplantation. Reintroduction of TAC or introduction of CsA is not permitted in the SRL Therapy group.

Other Name: CNI

Drug: mycophenolate mofetil

The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol MMF or MPS should be initiated within 24 hours before or after transplantation or within 14 days of transplantation per local standard of care and tapered to a minimum oral dose of MMF ≥ 500 mg/day or MPS ≥ 360 mg/day by the Pre-Conversion visit at month 3-4 post-transplantation. At the discretion of the investigator, MMF may be changed to MPS, or MPS may be changed to MMF. MMF is to be continued at ≥ 500 mg/day dose or MPS is to be continued at ≥ 360 mg/day dose through to the end of study.

Other Name: MMF, MPS

Drug: prednisone

The daily dosage and formulation for each study treatment will be chosen by the investigator as medically appropriate for each individual subject, in order to achieve the target levels specified in the protocol CCS should be initiated within 24 hours before or after transplantation or within 14 days of transplantation per local standard of care and tapered to a minimum of 5 mg/day of prednisone orally or the alternate day equivalent by the Pre-Conversion visit at month 3-4 post-transplant. Continue administration of prednisone as per local standard of care to a minimum dose of 2.5 mg/day or alternate day equivalent dose to the end of the study. Withdrawal of CCS is prohibited.

Other Name: CCS

Detailed Description:

A decision to terminate the study was taken in November 2011 and a communication to that effect sent to all participating sites on November 18. All sites were asked to have patients returned to the sites and have all end of study procedures performed by Dec 31, 2011.

The decision to terminate this study was made following the conduct of an interim analysis which demonstrated that the study did not reach its primary endpoint. The termination of this study was not driven by any safety concerns and had no impact on subject safety and well-being.

Eligibility

Ages Eligible for Study:	35 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

At least one of the following characteristics:

History of dialysis for at least 3 years.
History of diabetes for at least 5 years.
Hypertension or ischemic nephropathy as a cause of the end stage renal disease or loss of the first transplant.
History of coronary artery disease, stroke, myocardial infarction, or amputation for vascular disease.

Exclusion Criteria:

History of malignancy within the last 5 years (except adequately treated skin cancer).
Recipients of non-renal organ transplant.
Active gastrointestinal disease that may interfere with drug absorption.
Active HIV, hepatitis B or C infection.
Women who are pregnant or breastfeeding.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00311311

Locations

United States, New York
Pfizer Investigational Site
Rochester, New York, United States, 14642
Canada, Alberta
Pfizer Investigational Site
Calgary, Alberta, Canada, T2N 2T9
Pfizer Investigational Site
Edmonton, Alberta, Canada, T6G 2B7
Canada, Ontario
Pfizer Investigational Site
Hamilton, Ontario, Canada, L8N 4A6
Pfizer Investigational Site
London, Ontario, Canada, N6A 5A5
Pfizer Investigational Site
Toronto, Ontario, Canada, M5B 1W8
Pfizer Investigational Site
Toronto, Ontario, Canada, M5C 2T2
Canada, Quebec
Pfizer Investigational Site
Montreal, Quebec, Canada, H1T 2M4

Sponsors and Collaborators

Pfizer

Investigators

Study Director:

Pfizer CT.gov Call Center

Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Pfizer
ClinicalTrials.gov Identifier:	NCT00311311 History of Changes
Other Study ID Numbers:	0468H1-319
Study First Received:	April 3, 2006
Results First Received:	December 12, 2011
Last Updated:	May 15, 2012
Health Authority:	Canada: Health Canada

Keywords provided by Pfizer:

Kidney transplant
Renal transplant
Immunosuppression

Atherosclerosis
Graft Rejection
Kidney Transplant

Additional relevant MeSH terms:

Atherosclerosis
Renal Insufficiency
Carotid Artery Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Kidney Diseases
Urologic Diseases
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Mycophenolate mofetil
Sirolimus

Everolimus
Tacrolimus
Mycophenolic Acid
Prednisone
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Glucocorticoids
Hormones

ClinicalTrials.gov processed this record on June 18, 2013

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