Evaluation Of Switching From Twice Daily Tacrolimus To Once Daily Formulation On Cardiovascular Risk (ESTTEROD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01702207
Recruitment Status : Completed
First Posted : October 5, 2012
Last Update Posted : January 8, 2018
Astellas Pharma Canada, Inc.
Information provided by (Responsible Party):
AShoker, University of Saskatchewan

Brief Summary:

Current standard prophylactic immunosuppression in renal transplantation includes tacrolimus, a calcineurin inhibitor, dosed twice daily. In Canada, oral tacrolimus has been available as a twice daily formulation marketed as Prograf® since 1997. It has recently become available in an extended release formulation called Advagraf®, which is dosed once daily. Advagraf® has been demonstrated to be therapeutically equivalent to Prograf® in the renal transplant maintenance population, and as a result it has been is approved as an alternative to the twice daily formulation in these patients. There is an evolving and expanding positive clinical experience with Advagraf® in kidney transplantation and it has shown to be preferred by many patients, due to the diminished dosing frequency. In clinical trials, Advagraf® has been shown to have other potential benefits over Prograf® such as less inter and intra-patient variability, improved cardiovascular profiles, and improved kidney function. Compared to Prograf®, Advagraf® also has a lower Cmin or 'trough' concentration as well as a lower Cmax or 'peak' concentration. The purpose of this study is to convert stabilized renal transplant patients currently receiving Prograf® to Advagraf®, to investigate these potential therapeutic benefits.

The Framingham Risk Score and the Reynold's Risk Score are currently recommended by the Canadian Cardiovascular Society (CCS) to predict 10-year cardiovascular risk in the general population. Surrogate markers are widely used in clinical trials to shorten follow-up durations. In this study, the investigators will use the Framingham Risk Score and Reynold's Risk Score to quantify changes in estimated cardiovascular risk. The investigators also intend to examine novel inflammatory markers to investigate cardiovascular risk.

The investigators hypothesize that the more consistent drug exposure and lower Cmax noted with Advagraf® will decrease Framingham Risk Score, Reynolds Risk score as well as markers of inflammation in kidney transplant recipients.

Condition or disease Intervention/treatment Phase
Immunosuppression Cardiovascular Diseases Kidney Transplantation Drug: Once Daily Tacrolimus Drug: Twice Daily Tacrolimus Phase 4

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Supportive Care
Official Title: A One-Year, Prospective, Randomized, Controlled Study Evaluating The Efficacy Of Switching From The Twice Daily Tacrolimus Formulation To The Extended Release, Once Daily Formulation To Reduce The Framingham Cardiovascular Risk Scores.
Actual Study Start Date : October 2012
Actual Primary Completion Date : December 2017
Actual Study Completion Date : December 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Tacrolimus
U.S. FDA Resources

Arm Intervention/treatment
Active Comparator: Once Daily Tacrolimus
Treatment Arm - Subjects are switched from the tacrolimus twice daily (Prograf®) to the once daily formulation (Advagraf®) to maintain a trough tacrolimus level of 5-8.
Drug: Once Daily Tacrolimus
Subjects switched from the tacrolimus twice daily (Prograf®) to the once daily formulation (Advagraf®) to maintain a trough tacrolimus level of 5-8.
Other Name: Advagraf®
Active Comparator: Twice Daily Tacrolimus
Control Arm - Subjects are kept on Prograf® which is the Twice Daily Tacrolimus
Drug: Twice Daily Tacrolimus
Subjects are kept on Prograf® which is the Twice Daily Tacrolimus
Other Name: Prograf®

Primary Outcome Measures :
  1. Change in the Framingham risk scores and change in the Reynolds Risk Score. [ Time Frame: Visit 1, Visit 3 (12 months) ]

Secondary Outcome Measures :
  1. Comparison in GFR between the two groups. [ Time Frame: Visit 1, Visit 3 (12 months) ]
  2. Effect of therapy on CV biomarkers, insulin resistance and lipid profile. [ Time Frame: Visit 1, Visit 3 (12 months) ]
    CV biomarkers will be assessed by luminex and insulin resistance and lipid profile will be assessed by the Metabolic Syndrome

  3. To look at change in the glomerular filtration rate (GFR) over the duration of the study. [ Time Frame: Vist 1, Visit 3 (12 months) ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 74 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Kidney transplant patients currently stable on the twice-daily formulation and who are followed as outpatients.
  • Stability is defined as change in serum creatinine of less than 10% over the last two months
  • Age 18-74 years old
  • At least six months after transplantation
  • Lack of rejection within the last 12 weeks
  • Serum creatinine less than 300 umol/L at enrolment
  • Negative urine pregnancy test for female patients of childbearing potential
  • Consent to the study
  • Not included in a clinical trial within the last 90 days

Exclusion Criteria:

  • Patients with other types of solid organ transplants
  • Patients with any form of substance abuse or psychiatric disorder.
  • Patients with acute or chronic diarrhea
  • Patients receiving anti-lymphocyte treatment for rejection within the last six months
  • Patients on cyclosporine and or not receiving a mycophenolate derivative.
  • Patients with significant liver disease defined as having an elevated bilirubin by at least two times the upper value of the normal range
  • Patients who have any unstable medical condition that could interfere with the study
  • Patients with chronic viral infection with HIV, Hep C and HCV.
  • Presence of any acute illness requiring admission to the hospital for the last 4 weeks
  • Pregnancy
  • Significant cardiovascular event such as MI, stroke or TIA within the last 12 weeks or uncontrolled hypertension.
  • Immunosuppressant changes within the last month.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01702207

Canada, Saskatchewan
St Paul's Hospital
Saskatoon, Saskatchewan, Canada, S7M0Z9
Sponsors and Collaborators
University of Saskatchewan
Astellas Pharma Canada, Inc.
Principal Investigator: Ahmed Shoker, MD University of Saskatchewan

Responsible Party: AShoker, M.D., University of Saskatchewan Identifier: NCT01702207     History of Changes
Other Study ID Numbers: ESTTEROD
First Posted: October 5, 2012    Key Record Dates
Last Update Posted: January 8, 2018
Last Verified: January 2018

Keywords provided by AShoker, University of Saskatchewan:
kidney transplant
renal transplant
cardiovascular risk
Framingham Risk
Reynolds Risk

Additional relevant MeSH terms:
Cardiovascular Diseases
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action