Personalization of Maintenance Immunosuppression Based on TTV Viral Load to Prevent Long-term Complications in Renal Transplantation
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 600
- 试验地点
- 8
- 主要终点
- Compare the time from inclusion to first complication of inadequate immunosuppression between the experimental group, whose treatment is tailored on quarterly TTV viral load results, and the control group.
研究概览
简要总结
Long-term outcomes in kidney transplantation remain a significant challenge, as complications such as donor-specific antibodies (DSA), antibody-mediated rejection, infections, and cancer increasingly threaten graft and patient survival over time. The development of non-invasive biomarkers to guide the management of therapeutic immunosuppression beyond the first year post-transplantation is therefore a crucial unmet need.
Torque Teno Virus (TTV), a non-pathogenic virus with a high prevalence worldwide, has emerged as a promising biomarker in this context. Its replication inversely reflects immune control by T cells, correlating with the depth of therapeutic immunosuppression. Additionally, its slow replication kinetics make TTV DNAemia a useful marker for evaluating patient adherence to immunosuppressive treatments.
The TAOIST study tests whether longitudinal monitoring of TTV DNAemia every six months, starting from the second year after transplantation, can guide the personalization of immunosuppressive therapy. The primary endpoint is the time to the first occurrence of complications linked to inadequate immunosuppression, including dnDSA, biopsy-proven rejection, infection, cancer, or graft loss. Secondary objectives include evaluating the acceptability of TTV DNAemia among healthcare professionals and assessing its cost-effectiveness compared to standard care. An ancillary objective examines the link between TTV DNAemia and the immunosuppressant possession ratio (IPR) to explore its potential as a marker of treatment adherence.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Single (Investigator)
盲法说明
TTV DNAemia will be measured every 6 months for all patients but the results will not be communicated to the physicians for patients from the control group.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult ≥ 18 years-old
- •Recipient of a kidney allograft (third graft at most)
- •12 to 48 months post-transplantation
- •Stable graft function (defined as: delta creatininemia over the previous 6 months < 20% and proteinuria < 30mg/mmol)
- •On maintenance immunosuppression, which includes CNI (cyclosporin or tacrolimus) and MMF (Cellcept or Myfortic) with or without corticosteroids
- •Detectable TTV DNAemia at enrollment
- •No circulating DSA in solid phase assay
- •Undetectable BKV DNAemia at enrollment
- •Written informed consent
排除标准
- •Recipient of an HLA identical graft
- •Mutiple organ transplantation or functional transplant other than kidney
- •Maintenance immunosuppression that includes a mTOR inhibitor, belatacept or imurel
- •Presence of histological sign of active rejection (i+t > 2 and g+cpt > 2) on graft biopsy performed within 3 months before enrollment
- •Uncontrolled infection at inclusion
- •Infection requiring hospitalization within 3 months before inclusion
- •Diagnosis of a cancer of interest between the (current) transplantation and inclusion
- •Pregnant, unwillingness to practice adequate contraception or patient with a pregnancy plan during 3 years of study
- •Person not affiliated to a social security scheme or beneficiary of a similar scheme
- •Person subject to a legal protection measure (guardianship, curatorship) or deprived of liberty
研究组 & 干预措施
TTV-guided immunosuppression
The adaptation of the dose of maintenance immunosuppressive drugs will be based on TTV DNAemia measured on site in the plasma of patients every 6 months (at distance of an infection or a vaccination). The physicians will be free to change the dose of calcineurin inhibitors (CNI) and/or the mycophenolate mofetil (MMF) to maintain TTV DNAemia between 3.8 and 5.1 log10 cp/mL as long as the trough levels remain between 3-12 ng/mL for tacrolimus (50-250 ng/mL for cyclosporin) and the daily dose of MMF is comprise between 250 and 1500 mg bid for Cellcept (180 and 900 mg for Myfortic).
干预措施: TTV DNAemia (Biological)
Standard Immunosuppression
TTV DNAemia will also be measured every 6 months but the results will not be communicated to the physicians. Instead, the adaptation of the dose of maintenance immunosuppressive drugs will be performed according to the current standard of care: i) the dose of the CNI will be adapted to maintain the trough levels, monitored in the circulation every 3 month, between 5-10 ng/mL for tacrolimus (75-150 ng/mL for cyclosporin) and ii) the dose of MMF will be adjusted to maintain the AUC, measured every year, between 30-60 h.mg/L.
干预措施: TTV DNAemia (Biological)
Standard Immunosuppression
TTV DNAemia will also be measured every 6 months but the results will not be communicated to the physicians. Instead, the adaptation of the dose of maintenance immunosuppressive drugs will be performed according to the current standard of care: i) the dose of the CNI will be adapted to maintain the trough levels, monitored in the circulation every 3 month, between 5-10 ng/mL for tacrolimus (75-150 ng/mL for cyclosporin) and ii) the dose of MMF will be adjusted to maintain the AUC, measured every year, between 30-60 h.mg/L.
干预措施: EQ-5D-5L questionnaire (Other)
TTV-guided immunosuppression
The adaptation of the dose of maintenance immunosuppressive drugs will be based on TTV DNAemia measured on site in the plasma of patients every 6 months (at distance of an infection or a vaccination). The physicians will be free to change the dose of calcineurin inhibitors (CNI) and/or the mycophenolate mofetil (MMF) to maintain TTV DNAemia between 3.8 and 5.1 log10 cp/mL as long as the trough levels remain between 3-12 ng/mL for tacrolimus (50-250 ng/mL for cyclosporin) and the daily dose of MMF is comprise between 250 and 1500 mg bid for Cellcept (180 and 900 mg for Myfortic).
干预措施: EQ-5D-5L questionnaire (Other)
TTV-guided immunosuppression
The adaptation of the dose of maintenance immunosuppressive drugs will be based on TTV DNAemia measured on site in the plasma of patients every 6 months (at distance of an infection or a vaccination). The physicians will be free to change the dose of calcineurin inhibitors (CNI) and/or the mycophenolate mofetil (MMF) to maintain TTV DNAemia between 3.8 and 5.1 log10 cp/mL as long as the trough levels remain between 3-12 ng/mL for tacrolimus (50-250 ng/mL for cyclosporin) and the daily dose of MMF is comprise between 250 and 1500 mg bid for Cellcept (180 and 900 mg for Myfortic).
干预措施: Biological tests (Biological)
Standard Immunosuppression
TTV DNAemia will also be measured every 6 months but the results will not be communicated to the physicians. Instead, the adaptation of the dose of maintenance immunosuppressive drugs will be performed according to the current standard of care: i) the dose of the CNI will be adapted to maintain the trough levels, monitored in the circulation every 3 month, between 5-10 ng/mL for tacrolimus (75-150 ng/mL for cyclosporin) and ii) the dose of MMF will be adjusted to maintain the AUC, measured every year, between 30-60 h.mg/L.
干预措施: Biological tests (Biological)
结局指标
主要结局
Compare the time from inclusion to first complication of inadequate immunosuppression between the experimental group, whose treatment is tailored on quarterly TTV viral load results, and the control group.
时间窗: through study completion, an average of 6 years
Time from inclusion to occurrence of the first complication of inadequate immunosuppression: development of dnDSA, biopsy-proven rejection, infection, cancer, graft loss. Patients lost to follow-up or died without an event before will be right censored at this date.
次要结局
- Proportion of patients with at least one complication of inadequate immunosuppression between the experimental and control groups at 36 months(through study completion, an average of 6 years)
- Compare the rate of complications of inadequate immunosuppression between patients in the experimental and control groups.(through study completion, an average of 6 years)
- Describe the nature and timing of various complications of inadequate immunosuppression in the experimental and control groups.(through study completion, an average of 6 years)
- Compare the proportion of patients with adequate immunosuppressive therapy between the experimental and control groups.(through study completion, an average of 6 years)
- Compare the proportion of quarterly systematic checks of TTV DNAemia in the target between patients in the experimental and control groups.(Every 3 months)
- Model the impact of variations in dose and residual rates (pre-dose trough levels or AUC) of the various immunosuppressive drugs on TTV viral load.(every 3 months)
- Evaluate how nephrologists and biologists feel about using the new test in clinical practice.(6th year)
- Assess the cost-effectiveness of the intervention compared to standard care at 36 months from the French Health care System perspective(through study completion, an average of 6 years)