Influence of Pharmaceutical Care on the Intraindividual Variability of Tacrolimus Concentrations (PharmCare)

A Prospective Randomized Trial Investigating the Influence of Pharmaceutical Care on the Intraindividual Variability of Tacrolimus Concentrations Early After Kidney Transplant.

Primary end-point

The primary end-point was the influence of pharmaceutical intervention in tacrolimus intra-subject variability during the first 3 months after kidney transplant. Coefficients of variation were calculated from the average of dose-corrected tacrolimus blood concentration(CV= Standard Deviation (SD) x 100/mean) of study visits day 10, 14, 21, 30, 60 and 90 post kidney transplant.

Secondary end-points

1. Secondary outcomes included evaluate percentage of patients who achieved target levels of tacrolimus in day study visits 7, 10, 14, 21, 28, 60 e 90 days after kidney transplant;
2. Tacrolimus bioavailability profile during the period of 3 months,characterized by mean and standard deviation (SD) of dose corrected tacrolimus blood concentration(ng/ml/mg);
3. Assess patient adherence through validated questionnaire "Portuguese version of Basel Scale Adherence Rating Immunosuppressive Drugs (BAASIS) scale". It consists of a four-item questionnaire measuring nonadherence to immunosuppressives over the past four weeks. This questionnaire assesses omission of single doses or successive doses, timing deviations >2h and dose reductions. Responses are given on a six-point scale: never, once per month, every second week, every week, more than once per week and every day. Patients that answer different from "never" in any of the four questions are considered as nonadherent;
4. We evaluated renal function eGFR by Modification of Diet in Renal Disease (MDRD);
5. We evaluated Incidence of Infections;
6. We evaluated Treated acute rejection episodes;
7. We evaluated Death cases;
8. We evaluated Graft loss cases;
9. We evaluated Discontinuation of immunosuppressive treatment;
10. We evaluated Hospital readmissions.

Study Design

This was a single-center, prospective, randomized and controlled study to evaluate the influence of pharmaceutical intervention in tacrolimus intra-subject variability during the first 3 months after transplantation. The authors designed the protocol, acquired and maintained the data, and conducted the statistical analysis. The protocol was approved by an independent ethics committee. All subjects signed a written informed consent before enrollment and the study was conducted according to good clinical practices and declaration of Helsinki. This study was conducted at Hospital do Rim between February 2014 and December 2014, 128 randomized and were followed for 3 months after transplantation.

Study Overview

• Status: Completed
• Conditions: Renal Transplant Graft Failure
• Intervention / Treatment: Other: Pharmaceutical Intervention

Detailed Description

Population

Inclusion criteria were patients who underwent renal transplantation aged ≥18 years old, who signed the informed consent, who underwent follow-up post transplant clinic at the Hospital do Rim for 3 months, receiving immunosuppressive drugs tacrolimus, prednisone and sodium mycophenolate or tacrolimus, azathioprine, and prednisone. Exclusion criteria were patients who underwent second kidney transplant, which did not follow the Hospital do Rim after transplant and who were participating in some other study with pharmaceutical intervention.

Randomization The randomization plan was carried out in blocks and stratified by immunosuppressive drugs tacrolimus, prednisone and mycophenolate sodium or tacrolimus, prednisone and azathioprine.

Opaque envelopes were made from a table of random numbers and they were open on the day of randomization to determine the group to which each patient was allocated group 1 with pharmaceutical intervention or group 2 without pharmaceutical intervention.

• Study Type: Interventional
• Enrollment (Actual): 128
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• patients who underwent renal transplantation aged ≥18 years old,
• who signed the informed consent,
• who underwent follow-up post transplant clinic at the Hospital do Rim for 3 months,
• receiving immunosuppressive drugs tacrolimus, prednisone and sodium mycophenolate or tacrolimus, azathioprine, and prednisone.

Exclusion Criteria:

• were patients who underwent second kidney transplant,
• which did not follow the Hospital do Rim after transplant and who were participating in some other study with pharmaceutical intervention.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1 with pharmaceutical intervention; Patients allocated to group 1 with pharmaceutical intervention received instructions on the proper use of immunosuppressants as dosage, frequency and administration schedules, importance of immunosuppressive drugs and the risk of rejection. No more interventions were applied.	Other: Pharmaceutical Intervention; Patients allocated to group 1, with pharmaceutical intervention, received instructions on the proper use of immunosuppressants as doses, frequency, importance, schedules on the following days 3, 5, 7, 10, 14, 21, 28, 60 and 90 after kidney transplant. Teaching materials were designed to assist in the pharmaceutical guidelines that understood the importance of immunosuppressive drugs, the risk of rejection, the schedules and the most appropriate way for the administration. In addition to these guidelines, pharmacists helped patients in filling out the patient diary. This diary contains all the medications that the patient administers and encourages them to write down daily doses in order to remind them. This was a standardized pharmacist intervention.
No Intervention: 2 without pharmaceutical intervention; Standard following of the Hospital do Rim, without pharmaceutical intervention. This group was just followed by the nurses of the hospital, but without a standardized intervention. It was not a intervention, it was the control group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary end-point was the influence of pharmaceutical intervention in tacrolimus intra-subject variability during the first 3 months after kidney transplant. variability during the first 3 months after transplantation.	Coefficients of variation were calculated from the average of dose-corrected tacrolimus blood concentration(CV= SD x 100/mean) of study visits day 10, 14, 21, 30, 60 and 90 post kidney transplant.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess patient adherence through validated questionnaire "Portuguese version of BAASIS scale (Basel Scale Adherence Rating Immunosuppressive Drugs)";	It consists of a four-item questionnaire measuring nonadherence to immunosuppressives over the past four weeks. This questionnaire assesses omission of single doses or successive doses, timing deviations >2h and dose reductions. Responses are given on a six-point scale: never, once per month, every second week, every week, more than once per week and every day. Patients that answer different from "never" in any of the four questions are considered as nonadherent.	3 months
Secondary outcomes included evaluate percentage of patients who achieved target levels of tacrolimus in day study visits day 7, 10, 14, 21, 28, 60 e 90 post kidney transplant		3 months
We also evaluated renal function (eGFR by MDRD formula)		3 months
Tacrolimus bioavailability profile during the period of 3 months	Characterized by mean and standard deviation of dose corrected tacrolimus blood concentrations(ng/ml/mg)	3 months
We evaluated the incidence of Infections		3 months
We evaluated treated acute rejection episodes		3 months
We evaluated death cases		3 months
We evaluated graft loss cases		3 months
We evaluated discontinuation of immunosuppressive treatment		3 months
We evaluated hospital readmissions.		3 months

Collaborators and Investigators

• Sponsor: Hospital do Rim e Hipertensão
• Investigators: Principal Investigator: Adrieli BA Bessa, Pharmacist, Hospital do Rim

Publications and helpful links

General Publications

• Mellon L, Doyle F, Hickey A, Ward KD, de Freitas DG, McCormick PA, O'Connell O, Conlon P. Interventions for increasing immunosuppressant medication adherence in solid organ transplant recipients. Cochrane Database Syst Rev. 2022 Sep 12;9(9):CD012854. doi: 10.1002/14651858.CD012854.pub2.

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: March 6, 2015
• First Submitted That Met QC Criteria: March 27, 2015
• First Posted (Estimate): March 30, 2015

Study Record Updates

• Last Update Posted (Estimate): November 3, 2015
• Last Update Submitted That Met QC Criteria: October 30, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: pharmaceutical intervention; tacrolimus blood concentration; intrasubject variability
• Other Study ID Numbers: Hospital do Rim