Optimal Dose of Anti-lymphocyte Globulin in Kidney Transplant Recipients With Low Immunological Risk

Обзор

Antithymocyte globulins (ATG) are the gold standard of induction therapies and are currently used to prevent or treat acute rejection in solid organ transplantation. They induce rapid depletion of immune cells, particularly T lymphocytes. The time to immune reconstitution after ATG is characterized by significant intra- and inter-individual variability in reconstitution of immune cell subpopulations (T and B cells, NK cells, dendritic cells). This variability explains the prolonged T cell lymphopenia observed in some patients, which is a surrogate immune biomarker associated with an increased risk of death after 2 years of renal transplantation and more infections, cancers and atheromatous events. However, ATG also promotes an increase in the proportion of Treg cells. Although the underlying mechanisms are still debated, data from experimental animal models confirm the tolerogenic properties of ATG. ATGs are associated with improved allograft survival without rejection in patients at high immunological risk and are therefore indicated as first-line therapy in this population. In patients at low immunological risk, anti-CD25 monoclonal antibodies (anti-CD25mAb) are recommended as first-line therapy because ATGs are associated with a higher incidence of infections despite their equivalent efficacy in this population compared to anti-CD25mAb. However, neither the dosages nor the treatment duration of ATGs are clearly defined (recommended Grafalon® dosages range from 5 to 2 mg/kg/day for 5 to 21 days) and ATGs remain widely prescribed to allow early withdrawal of corticosteroids. Determination of optimal non-depleting doses of ATG could be of great interest because, in vitro, ATG is able to induce regulatory polarization of naïve T cells even at non-depleting doses. Thus, the use of such doses in patients with low immunological risk may be of interest in clinical practice with respect to anti-CD25mAb, particularly for their pro-regulatory properties and their low cost. This question must be clearly addressed in a pilot clinical study. The purpose of this study is to find the optimal non-depleting dose (Maximum Tolerated Dose; MTD) of rabbit anti-human T-lymphocyte immunoglobulin (Grafalon®) to prevent the complications associated with prolonged CD4 T cell lymphopenia in low immunological risk renal transplant recipients. The primary outcome for the de-escalation study is the Dose Limiting Toxicity (DLT) defined by a T cell (CD3+) relative depletion above 30 % compared to baseline (Day 0) at the end of the Grafalon® induction treatment (Day 4). The patients under study are adult receiving first kidney transplantation without a high immunological risk of rejection (african-American ethnicity, presence of a donor-specific antibody, blood group incompatibility, delayed onset of graft function (i.e donor after cardiac death), cold ischemia time \>24 hours, anti-HLA immunization (Flow PRA \> or = 20%, presence of donor specific antibody before and/or at time of transplantation and with a positive CDC and FXM with historical and/or transplant day sera), bacterial, viral or mycotic and parasitic infections, history of opportunistic infection that required intensive care hospitalization in the two years preceding the transplant, related donor with two-haplotype HLA matched kidneys, multi-organ transplant, history of cancer, thrombocytopenia \< 50 000 platelets/µl, hypersensitivity to the active substance or to the excipients of Grafalon (monosodium phosphate dihydrate, phosphoric acid). The inclusion period is one year. According to the active file of the center of Besançon, it is planned to include 2 patients per month. The maximum number of patients to include is 18. With a margin of error of 20%, it is possible to include all patients in 1 year. The duration of patient participation in the study is 1 year (one-year follow-up). Consequently, the duration of the study is estimated at 2 years (1 year of inclusion and 1 year of follow-up). ODORAT is a monocenter, open-label, de-escalation phase1b controlled study. The study will be proposed to patients receiving a first kidney transplant and matching the criteria of inclusion. Recruitment will be achieved only in Besançon's transplant unit. The physician gives information on the study and collect informed consent. Then the treatment is assigned according to the dose determined by the dose de-escalation study. The first dose tested is the dose level at 2 mg/kg/day (level 3). This dose is the reference dose according to the current recommendations. The number of patients included at each dose is determined according to Bayesian optimal interval (BOIN) design. The administration of treatment begin at time of transplantation according to recommendation. The study will include 11 visits: D0 (baseline) to D4 (primary end point assessement), D7, D14, M1, M3, M6 and M12, to analyze pharmacokinetics of Grafalon and the immune phenotype.

Вмешательства

• Препарат Grafalon® administered during 5 consecutive days at 2 mg/kg/j
  This de-escalation study was planned to investigate 3 doses level of Grafalon® administered during 5 consecutive days, i.e.: Group 3 : 2 mg/kg/j, Group 2 : 1 mg/kg/j, Group 1 : 0,5 mg/kg/j. Group 3 receives treatment in accordance with health recommendations as part of prophylactic treatment for acute rejection after allogeneic solid organ transplantation, at the minimum dose, i.e., 2 to 5 mg/kg/day for 5 to 21 days.
• Препарат Grafalon® administered during 5 consecutive days at 1 mg/kg/j
  This de-escalation study was planned to investigate 3 doses level of Grafalon® administered during 5 consecutive days, i.e.: Group 3 : 2 mg/kg/j, Group 2 : 1 mg/kg/j, Group 1 : 0,5 mg/kg/j. Group 2 receive treatment at lower doses than the recommended dose for the same duration (5 days). Treatment begins on the day of transplantation immediately before the procedure at induction of sedation.
• Препарат Grafalon® administered during 5 consecutive days at 0,5 mg/kg/j
  This de-escalation study was planned to investigate 3 doses level of Grafalon® administered during 5 consecutive days, i.e.: Group 3 : 2 mg/kg/j, Group 2 : 1 mg/kg/j, Group 1 : 0,5 mg/kg/j. Group 1 receive treatment at lower doses than the recommended dose for the same duration (5 days). Treatment begins on the day of transplantation immediately before the procedure at induction of sedation

Первичные конечные точки

• The optimal non-depleting dose (Maximum Tolerated Dose; MTD) of rabbit anti-human T-lymphocyte immunoglobulin (Grafalon®) to prevent the complications associated with prolonged CD4 T cell lymphopenia in low immunological risk renal transplant recipients. [Срок оценки: From transplantation to the end of treatment at 4 days]

Вторичные конечные точки (8)

• The tolerance of Grafalon® in each dose level. [Срок оценки: From transplantation to the end of the study at 1 year.]
• Clearance of Grafalon® during the treatment period and until month-3 in each dose level. [Срок оценки: From transplantation to 3 month after first treatment.]
• Describe immune profile and immune restauration in each dose level. [Срок оценки: From transplantation to 1 year after.]
• Describe time to event clinical endpoints since transplantation at each dose level. [Срок оценки: From transplation to 1 year after.]
• The rate of patients with infection up to 1 year after transplantation in each dose level. [Срок оценки: From transplantation to 1 year after]
• The number of infections by patients up to 1 year after transplantation in each dose level [Срок оценки: From transplantation to 1 year after]
• The rate of patients with an atherosclerotic event up to 1 year after transplantation in each dose level [Срок оценки: From transplantation to year after]
• Renal function at 1 year post transplant in each dose level [Срок оценки: From transplantation to 1 year after.]

Критерии участия

Критерии включения

• Age ≥ 18 years
• Females must be using highly effective contraceptive measures (see Section V-9), and have a negative pregnancy test prior to the start of dosing if of childbearing potential, or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening :

• Post-menopausal is defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments.
• Women under the age of 50 years would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution.
• Women with documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
• Male patients with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 6 months following discontinuation of study drug. Patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing study treatment.
• Patient affiliated to or beneficiary of French social security system
• Signed and dates informed consent
• Patient receiving first kidney transplantation

Критерии исключения

• Current participation in a study of an investigational agent or in the period of exclusion
• Pregnant or breast-feeding subjects,
• Patient under guardianship, curatorship or under the protection of justice
• Subject not able to cooperate properly in the study judged by the investigator.
• Patients with bacterial, viral or mycotic and parasitic infections,History of opportunistic infection that required intensive care hospitalization in the two years preceding the transplant
• Patients with a high immunological risk of rejection:

• African-American ethnicity
• Presence of a donor-specific antibody
• Blood group incompatibility
• Delayed onset of graft function (i.e donor after cardiac death)
• Cold ischemia time >24 hours
• Anti-HLA immunization (Flow PRA > or = 20%, presence of donor specific antibody before and/or at time of transplantation and with a positive CDC and FXM with historical and/or transplant day sera)
• Related donor with two-haplotype HLA matched kidneys
• Multi-organ transplant
• Previous transplant(s)
• History of cancer
• Thrombocytopenia < 50 000 platelets/µl
• Hypersensitivity to the active substance or to the excipients of Grafalon (monosodium phosphate dihydrate, phosphoric acid).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT06744400 · 2024/874

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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