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Functional Genetic Variants Affecting Tacrolimus Trough Levels and Side Effects in Chinese Renal Transplantation.

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.
 
ClinicalTrials.gov Identifier: NCT03083769
Recruitment Status : Completed
First Posted : March 20, 2017
Results First Posted : November 20, 2019
Last Update Posted : November 20, 2019
Sponsor:
Collaborators:
Third Affiliated Hospital, Sun Yat-Sen University
181 Central Hospital of the Chinese PLA
Information provided by (Responsible Party):
Liang Li, Southern Medical University, China

Brief Summary:
The purpose of this study is to determine whether functional genetic variants can affect tacrolimus dose corrected trough levels and associate with the side effects in Chinese renal transplant recipients.

Condition or disease
Transplantation

Detailed Description:

Tacrolimus is an effective immunosuppressive drug widely used in solid organ transplantation to prevent rejection. It is characterized by a narrow therapeutic range and large inter- and intra- individual variability in its pharmacokinetics. Many factors are associated with the variability. Of these factors, genetic factor play an important role. Full understanding of this mechanism is important for the personalized use of tacrolimus and reducing the risk of side effects.The CYP3A5*3 (A6986G) resulting in a splicing defect and the absence of protein activity, was identified as a functional variant (Kuehl P.2001). The CYP3A4*1G was also reported as a functional variant (Richards-Waugh LL. 2014). In addition, other functional variants will also be identified and analyzed in our project.

Our project has two parts:first, retrospective study, 839 renal transplant recipients using tacrolimus as immunosuppressive drug were recruited from Nanfang Hospital. Fifty-eight SNPs from GWAS, GTEx and promoter region of CYP3A gene were genotyped. The association of 58 SNPs on the dose corrected tacrolimus trough levels and side effects (acute rejection, nephrotoxicity and neurotoxicity) were analyzed. Luciferase reporter gene assay were used to identify the functional variants. Second, in this part, there is another renal transplantation cohort. For this cohort, it was a retrospective cohort. All the patients will be stratified to different groups according to the different genotypes. The side effects (acute rejection, nephrotoxicity and neurotoxicity) will be observed.During the study period, all the therapeutic procedures of the patients are as usual.

This will be the largest cohort of this kind of study in Chinese population. The findings will be useful for the patients to improve the therapeutic efficacy and reduce the side effects.

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Study Type : Observational
Actual Enrollment : 1502 participants
Observational Model: Cohort
Time Perspective: Other
Actual Study Start Date : January 1, 1998
Actual Primary Completion Date : July 30, 2019
Actual Study Completion Date : August 1, 2019

Group/Cohort
Cohort 1
The retrospective cohort consists of about 839 kidney transplant recipients from Nanfang Hospital. These patients used tacrolimus as immunosuppressive drug for preventing the rejection.The side effects (acute rejection, nephrotoxicity and neurotoxicity) will be recorded.
Cohort 2
The retrospective cohort consists of about 663 kidney transplant recipients from Guilin No. 924 Hospital. These patients used tacrolimus as immunosuppressive drug for preventing the rejection.The side effects (acute rejection, nephrotoxicity and neurotoxicity) will be recorded.



Primary Outcome Measures :
  1. Number of Participants With Acute Rejection [ Time Frame: Day 1 to Day 61 ]
    We will measure the number of participants with acute rejection during the day 1 to day 61 after transplantation. Kaplan-Meier analyses were performed for acute rejection in participants with different genotypes.

  2. Number of Participants With Tacrolimus-related Nephrotoxicities [ Time Frame: Day1 to Day 61 ]
    We will measure the number of participants with tacrolimus-related nephrotoxicities during the day 1 to day 61 after transplantation. Kaplan-Meier analyses were performed for tacrolimus-related nephrotoxicities in participants with different genotypes.

  3. Number of Participants With Tacrolimus-related Neurotoxicities [ Time Frame: Day1 to Day 61 ]
    We will measure the number of participants with tacrolimus-related neurotoxicities during the day 1 to day 61 after transplantation. Kaplan-Meier analyses were performed for tacrolimus-related neurotoxicities in participants with different genotypes.


Biospecimen Retention:   Samples With DNA
Human genomic DNA was extracted from leukocytes in patients' peripheral blood.


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
The study population consists of the renal transplant recipients who received tacrolimus as immunosuppressant from Nanfang Hospital and Guilin No.924 Hospital. All the patients are Chinese.
Criteria

Inclusion Criteria:

Subject has been conducted kidney transplantation. Subject has used tacrolimus as immunosuppressant.

Exclusion Criteria:

Simultaneous liver-kidney transplantation. Patients with age less than 18 years old. Tacrolimus blood concentration monitoring less than 3 times. Failed to extract DNA.


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 ClinicalTrials.gov identifier (NCT number): NCT03083769


Locations
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China, Guangdong
Nanfang Hospital
Guangzhou, Guangdong, China, 510515
China, Guangxi
Guilin No.924 Hospital
Guilin, Guangxi, China, 541002
Sponsors and Collaborators
Southern Medical University, China
Third Affiliated Hospital, Sun Yat-Sen University
181 Central Hospital of the Chinese PLA
  Study Documents (Full-Text)

Documents provided by Liang Li, Southern Medical University, China:
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Responsible Party: Liang Li, professor, Southern Medical University, China
ClinicalTrials.gov Identifier: NCT03083769    
Other Study ID Numbers: NFEC-2016-176
First Posted: March 20, 2017    Key Record Dates
Results First Posted: November 20, 2019
Last Update Posted: November 20, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Liang Li, Southern Medical University, China:
tacrolimus
genetic variants
side effects