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Sirolimus usage discontinued since black box warning
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Pharmacokinetics of Tacrolimus and Sirolimus alone and in combination in liver transplant recipients.
Liver transplant patients receiving tacrolimus, and who experience side effects such as hypertension and renal dysfunction, will be converted to sirolimus with low-dose tacrolimus, or Tacrolimus withdrawal. This study will evaluate allograft function by serial clinical lab testing, the pharmacokinetics of sirolimus and tacrolimus, the glomerular filtration rate (GFR) and the potential side effect of sirolimus, such as marrow suppression and hyperlipidemia. Two pharmacokinetic evaluations are planned: once around the third post-transplant month and another one at about 12 months. Expected outcomes are, a better understanding of sirolimus pharmacokinetic parameters over time in pediatric/adult liver recipients and early efficacy and safety data of the sirolimus as a non-nephrotoxic alternative to tacrolimus.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sirolimus | Experimental |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sirolimus | Drug | Single dose SRL pharmacokinetics and TAC steady state pharmacokinetics: This phase is applicable to both sets of patients: those with nephrotoxicity and those with hypertension. Patients will receive a single dose of SRL of 2 mg/m2. Blood sampling will be performed over a 24 hour stay in the Children's Hospital of Pittsburgh's Pediatric Clinical and Translational Research Center (PCTRC) - See more at: http://www.chp.edu/research/our-facilities/pctrc, and the sampling for 48 hour and 72 hour PK studies can be done at the outpatient lab. This phase can either be performed immediately after the 12-hour iothalamate GFR evaluation, or a few days later at the convenience of the subject. |
| Measure | Description | Time Frame |
|---|---|---|
| Early and Late Pharmacokinetics of Sirolimus (SRL) | To evaluate early and late pharmacokinetics of Sirolimus (SRL) , and safety and efficacy of conversion from tacrolimus (TAC) to sirolimus in liver transplant recipients who have been stable for at least 3 months, and who have early nephrotoxicity and/or hypertension due to use of tacrolimus. | 1 year |
| Measure | Description | Time Frame |
|---|---|---|
| PK Parameters for Tacrolimus and Sirolimus | pharmacokinetics (PK) of SRL after a single dose and after steady state has been achieved; and the pharmacokinetics of tacrolimus once at steady state | 12 months |
| SRL Can Substitute TAC |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Rakesh Sindhi | UPitt | Principal Investigator |
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| ID | Title | Description |
|---|---|---|
| FG000 | Sirolimus | Sirolimus: Single dose SRL pharmacokinetics and TAC steady state pharmacokinetics: This phase is applicable to both sets of patients: those with nephrotoxicity and those with hypertension. Patients will receive a single dose of SRL of 2 mg/m2. Blood sampling will be performed over a 24 hour stay in the Children's Hospital of Pittsburgh Pediatric Clinical and Translational Research Center (PCTRC) - See more at: http://www.chp.edu/research/our-facilities/pctrc, and the sampling for 48 hour and 72 hour PK studies can be done at the outpatient lab. This phase can either be performed immediately after the 12-hour iothalamate Glomerular Filtration Rate (GFR) evaluation, or a few days later at the convenience of the subject. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Sirolimus | Sirolimus: Single dose SRL pharmacokinetics and TAC steady state pharmacokinetics: This phase is applicable to both sets of patients: those with nephrotoxicity and those with hypertension. Patients will receive a single dose of SRL of 2 mg/m2. Blood sampling will be performed over a 24 hour stay in the PCTRC , and the sampling for 48 hour and 72 hour PK studies can be done at the outpatient lab. This phase can either be performed immediately after the 12-hour iothalamate GFR evaluation, or a few days later at the convenience of the subject. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Secondary | PK Parameters for Tacrolimus and Sirolimus | pharmacokinetics (PK) of SRL after a single dose and after steady state has been achieved; and the pharmacokinetics of tacrolimus once at steady state | We were able to preform 3 pharmacokinetics (PK) profiles, one in each of three patients enrolled. However, due to emerging data and blackbox warnings from FDA suggesting that use of Sirolimus in liver transplant recipients be circumspect (risk of thrombosis and death), the study was terminated early and data analysis was not able to be completed. | Posted | 12 months |
|
1 year
There have been no adverse events or unanticipated events during the course of this study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sirolimus | Sirolimus: Single dose SRL pharmacokinetics and TAC steady state pharmacokinetics: This phase is applicable to both sets of patients: those with nephrotoxicity and those with hypertension. Patients will receive a single dose of SRL of 2 mg/m2. Blood sampling will be performed over a 24 hour stay in the PCTRC , and the sampling for 48 hour and 72 hour PK studies can be done at the outpatient lab. This phase can either be performed immediately after the 12-hour iothalamate GFR evaluation, or a few days later at the convenience of the subject. |
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Complete follow-up failed, due to early study termination as a result of FDA black box warning (6/11/2009) about Sirolimus in liver transplant recipients (risk of thrombosis and death).
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Rakesh Sindhi, MD | Children's Hospital of Pittsburgh | 412-692-6110 | rakesh.sindhi@chp.edu |
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| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D016559 | Tacrolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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|
|
Whether Sirolimus can substitute Tacrolimus in the stable post-transplant state, without compromising allograft function
| 12 months |
| SRL Prevent TAC-related Side Effects | Whether SRL can prevent or minimize progression of selected TAC-related side-effects such as renal dysfunction as measured by clearance of iothalamate (Glomerular filtration rate < 80 mL/min/1.73 m2) and hypertension (blood pressure > 140/90 mm Hg) | 1 year |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
|
| Secondary | SRL Can Substitute TAC | Whether Sirolimus can substitute Tacrolimus in the stable post-transplant state, without compromising allograft function | Due to FDA blackbox warnings (6/11/09) about Sirolimus in liver transplant recipients (risk of thrombosis and death), the study was terminated early. Due to the early termination of this study and small number of subjects enrolled (3), data analysis was not able to be completed. | Posted | 12 months |
|
|
| Primary | Early and Late Pharmacokinetics of Sirolimus (SRL) | To evaluate early and late pharmacokinetics of Sirolimus (SRL) , and safety and efficacy of conversion from tacrolimus (TAC) to sirolimus in liver transplant recipients who have been stable for at least 3 months, and who have early nephrotoxicity and/or hypertension due to use of tacrolimus. | Three pharmacokinetics (PK) profiles were performed, one in each of three patients who were enrolled. However, due to FDA blackbox warnings (6/11/2009) about Sirolimus in liver transplant recipients be circumspect (risk of thrombosis and death), the study was terminated early and data analysis was not able to be completed. | Posted | 1 year |
|
|
| Secondary | SRL Prevent TAC-related Side Effects | Whether SRL can prevent or minimize progression of selected TAC-related side-effects such as renal dysfunction as measured by clearance of iothalamate (Glomerular filtration rate < 80 mL/min/1.73 m2) and hypertension (blood pressure > 140/90 mm Hg) | Due to FDA blackbox warnings from FDA (6/11/2009) about Sirolimus in liver transplant recipients (risk of thrombosis and death), the study was terminated early and data analysis was not able to be completed. | Posted | 1 year |
|
|
| 0 |
| 3 |
| 0 |
| 3 |
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