Immunosuppression, Kidney Disease, Chronic, Transplant Recipient (Kidney)
Conditions
Keywords
Tacrolimus, Kidney transplant, Cost-effectiveness, Pharmacogenetic, Phase IV Clinical Trial
Brief summary
This is a phase IV multicentre adaptive single-blinded randomized clinical trial to evaluate if preemptively genotyping populations at pretransplant chronic kidney disease susceptible of receiving tacrolimus therapy is effective, cost-effective, and feasible within the Spanish National Health System when compared to the current standard of care. This trial is nested within the iPHARMGx master protocol.
Detailed description
This is a nation-wide, multicentre, randomised, controlled, and adaptive phase IV clinical trial that aims to assess the effectiveness and cost-effective of pre-emptive pharmacogenetic testing strategies, including those impacted by genetic variants associated with adverse drug reactions (ADRs) or limited efficacy. The clinical trials will evaluate the effective and cost-effective of pre-emptive genotyping by defining a drug-gene-endpoint triad. Study subjects will be pre-emptively genotyped and, if found to have an actionable gene variant, randomly allocated to either a test group where guideline-based treatment modifications will be initiated or a control group that will be managed according to healthcare provider standard of care (SoC). Subsequently, subjects will be prospectively followed at prespecified timepoints. Detailed information on drug-gene-endpoint triads, allocation schemes, and follow-up visits will be provided in each of the subprotocols. A Data Monitoring Committee (DMC), composed of physician experts, will be appointed for each nested trial to review the data on an ongoing basis, ensuring the safety of participants and scientific validity of the study.
Interventions
DRUGTacrolimus
Tacrolimus at the dosage reccomended by the Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing based on the subjects pharmacogenetic phenotype.
Sponsors
Instituto de Salud Carlos III
Instituto de Investigación Hospital Universitario La Paz
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Subjects will remain blinded to arm assigned because pharmacogenetic phenotype and tacrolimus dose-guidance will only be exclusively accesible to the attending physician
Intervention model description
Phase IV, multicentre, controlled, randomized, parallel and single-blind adaptive clinical trial nested within the iPHARMGx master protocol study
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Participants must be willing and able to provide written informed consent prior the initiation of any study procedures. 2. Subject or their legally authorized representative has voluntarily signed the informed consent document. 3. Participant is on the waiting list for a kidney transplant. 4. Subject is able and willing to take part and be followed-up for the majority of the study duration, and adhere to the procedures specified in this protocol. 5. Subjects must be naïve to any genotyping test of the following genes: CYP3A5.
Exclusion criteria
1. Known hypersensitivity/allergy reaction to tacrolimus or any of the excipients. 2. History of renal, heart, and/or liver transplant. 3. History or clinical evidence of any disease and/or existence of any surgical or medical condition, which might interfere in a relevant manner with the absorption, distribution, metabolism, or excretion of the study treatment, except for renal disease. 4. Any condition or situation precluding or interfering the compliance with the protocol. 5. Any condition at medical discretion for which renal transplantation and/or study treatment should not be received.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tacrolimus concentrations levels | 4 days | Number and percentage of patients achieving tacrolimus target plasma concentrations at visit 3. Tacrolimus concentrations levels at day 4 (+/-1d) will be the effectiveness surrogate outcome. It will be considered therapeutic range levels between 7-10 ng/ml. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number and percentage of patients with transplant rejection. | Though study completion, on average 18 months | Transplant rejection will be considered if there is histological confirmation and/or the patient initiates any type of therapy aimed at treating rejection (e.g. corticosteroids). |
| Incremental cost-effectiveness ratio (ICER) | Though study completion, on average 18 months | Cost-effectiveness ratio that divides the differences in costs between both treatments by the difference in effectiveness between both treatments. |
| Rate of AE associated to treatment. | Though study completion, on average 18 months | All adverse events associated to tacrolimus will be recorded during the study |
| Healthcare expenditure related to predefined events of interest | Though study completion, on average 18 months | Any costs made as a result of an AE |
| Incidence of discontinuation or treatment modification | Though study completion, on average 18 months | Incidence of discontinuation or treatment modification due to lack of effective related to the drug of inclusion. |
| Number and percentage of patients achieving tacrolimus target plasma concentrations at visit 4, 5 and 6. | Week 4, 15 and 26 | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Novel prognostic and predictive genetic biomarkers of tacrolimus safety and effectiveness | Though study completion, on average 18 months | All participants DNA sample will be susceptible of deep sequencing analysis assessed trough techniques only available at Nation Centre of Oncological Investigations (CNIO) and genome-wide association studies when applicable |
| Identification of new actionable genes/relevant polymorphisms within the predefined population subsets | Though study completion, on average 18 months | — |
Countries
Spain
Contacts
Primary ContactAlberto M. Borobia, MD, PhD
Outcome results
None listed