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Pharmacokinectics of Sirolimus and Tacrolimus in Liver Transplant Recipients With Tacrolimus Toxicity

This study has been terminated.
(Sirolimus usage discontinued since black box warning)
Sponsor:
Information provided by:
University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT01709136
First received: June 29, 2010
Last updated: October 16, 2012
Last verified: August 2011
History of Changes
  Purpose

Liver transplant patients treated with tacrolimus, who are clinically stable for at least 3 months, who are on antihypertensive drug treatment, and/or have renal dysfunction due to tacrolimus use, will be eligible for conversion to sirolimus and withdrawl of Tacrolimus. The study will include 60 subjects, both male and female, age 5-30. This study will evaluate allograft function by serial clinical lab testing, the pharmacokinetics of sirolimus and tacrolimus, the glomerular filtration rate (GFR) as measured clearance of iothalamate, and the potential side effect of sirolimus, such as marrow suppression and hyperlipidemia. Two pharmacokinetic evlauations 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.


Condition Intervention Phase
Hypertension
 Drug: Sirolimus
 Phase 2
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pharmacokinectics of Sirolimus and Tacrolimus in Liver Transplant Recipients With Early Nephrotoxicity and/or Hypertension Due to Tacrolimus

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • Acute rejection - incidence and severity- [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Acute rejection - incidence and severity- [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Acute rejection - incidence and severity- [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Incidence of infection- [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Incidence of infection- [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Incidence of infection- [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Leukopenia [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Leukopenia [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Leukopenia [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • thrombocytopenia [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • thrombocytopenia [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • thrombocytopenia [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Hyperlipidemia [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Hyperlipidemia [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Hyperlipidemia [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • diabetes mellitus [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • diabetes mellitus [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • diabetes mellitus [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Malignancy [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Malignancy [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Malignancy [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Adverse events requiring discontinuation of any immunosuppressive agent [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Adverse events requiring discontinuation of any immunosuppressive agent [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Adverse events requiring discontinuation of any immunosuppressive agent [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Discontinuation/decrease in antihypertensive medications- [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Discontinuation/decrease in antihypertensive medications- [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Discontinuation/decrease in antihypertensive medications- [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Hypertension requiring treatment [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Hypertension requiring treatment [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Hypertension requiring treatment [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Resolution of renal dysfunction [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • Resolution of renal dysfunction [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Resolution of renal dysfunction [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • PK parameters for tacrolimus and sirolimus [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
  • PK parameters for tacrolimus and sirolimus [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • PK parameters for tacrolimus and sirolimus [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Enrollment: 3
Study Start Date: December 2005
Study Completion Date: January 2010
Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sirolimus Drug: 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.
Other Names:
  • Sirolimus (Rapamycin)
  • Tacrolimus (FK506)

Detailed Description:

The study plans to collect Pharmacokinetic data for Tacrolimus and Sirolimus alone and in combination.

  Eligibility

Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Recipients of primary liver (cadaver/liver, whole/segmental) transplants 5- 30 years old.
  • Rejection-free post-transplant course for at least 3 months
  • Renal dysfunction (15% decrease in age-adjusted calculated creatinine clearance)
  • Hypertension requiring anti-hypertensive mediations.
  • Informed consent.
  • Weight ≥15 kg.

Exclusion Criteria:

  • Rejection or infections within 3 months of enrollment.
  • Intent to continue TAC
  • Active participation in ongoing studies of immunosuppressive agents.
  • Lack of informed consent.
  • Pregnant or breast feeding
  • HIV positive
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01709136

Sponsors and Collaborators
University of Pittsburgh
Investigators
Principal Investigator: Rakesh Sindhi UPitt
  More Information

No publications provided

Responsible Party: Rakesh Sindhi, MD, FACS, Children's Hospital of Pittsburgh of UPMC
ClinicalTrials.gov Identifier: NCT01709136     History of Changes
Other Study ID Numbers: 07100379
Study First Received: June 29, 2010
Last Updated: October 16, 2012
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Sirolimus
Everolimus
Tacrolimus
Antibiotics, Antineoplastic
Antineoplastic Agents
 Therapeutic Uses
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on May 22, 2013