Imlifidase Prior to Kidney Transplant in Highly Sensitised Children

Официальное название

A Single-arm, Multi-centre Trial to Evaluate Efficacy and Safety of Imlifidase in Highly Sensitised Children (1-17 Years) Receiving a Kidney Transplant With Positive Crossmatch Against a Living or Deceased Donor Converted to Negative After Imlifidase Treatment

Обзор

The goal of this clinical trial is to learn about the efficacy and safety of imlifidase in highly sensitized paediatric patients, 1-17 years old, with end stage renal disease (ESRD). The main questions it aims to answer are: * Does imlifidase treatment result in crossmatch conversion that enables transplantation? * How is the function of the transplanted kidney? The participants will be hospitalised in accordance with the normal routines for transplanted patients. The patients will receive medication to prevent rejection of the donor kidney, and because such treatment make the body more vulnerable medications to prevent infections.

Подробное описание

After being informed about the study and potential risks, all patients giving written informed consent will undergo pre-screening to determine eligibility for study entry.

The trial will include highly sensitised ESRD paediatric patients (1-17 years). The patients have previously undergone desensitization unsuccessfully or have an anti-HLA antibody status deemed too difficult to make a successful desensitization using other experimental methods.

A screening visit will take place when an organ offer has been placed for a final check of the patients' eligibility for study participation.

All patients included in the trial will be desensitized with imlifidase to convert the positive XM to negative and then transplanted with either a kidney from a deceased donor (DD) or a living donor (LD).

Patients will be hospitalised in accordance with the normal routines for transplanted patients at each clinic.

Following transplantation, the patients will receive induction therapies, rejection prophylaxis, and maintenance immunosuppressive therapies.

The patients will be closely monitored for any signs of antibody-mediated rejections (AMRs).

The duration of the interventional trial period after an organ has been offered will be 6 months for each patient. The trial includes a follow-up part to collect long-term efficacy and safety data up to 5 years after the transplantation.

Вмешательства

• Препарат Imlifidase
  Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly selective towards IgG. The cleavage of IgG generates one F(ab')2- and one homodimeric Fc-fragment and efficiently neutralizes Fc-mediated activities of IgG.

Первичные конечные точки

• Proportion of patients with conversion of a positive crossmatch test to negative within 24 hours after start of imlifidase treatment [Срок оценки: From start of imlifidase administration to 24 hours]

Вторичные конечные точки (12)

• Renal function up to 5 years after transplantation as assessed by estimated glomerular filtration rate (eGFR) [Срок оценки: From pre-dose imlifidase up to 5 years]
• Renal function up to 5 years after transplantation as assessed by serum/plasma creatinine levels [Срок оценки: From pre-dose imlifidase up to 5 years]
• Renal function up to 5 years after transplantation as assessed by serum/plasma cystatin C levels [Срок оценки: From pre-dose imlifidase up to 5 years]
• Renal function up to 5 years after transplantation as assessed by proteinuria [Срок оценки: From pre-dose imlifidase up to 5 years]
• DSA levels up to 5 years after transplantation [Срок оценки: From pre-dose imlifidase up to 5 years]
• Graft survival (death censored) up to 5 year after transplantation [Срок оценки: From 6 months up to 5 years]
• Graft failure-free survival up to 5 years after transplantation [Срок оценки: From 6 months up to 5 years]
• Patient survival up to 5 years after transplantation [Срок оценки: From 6 months up to 5 years]
• Frequency of delayed graft function (DGF) [Срок оценки: From transplantation up 7 days after transplantation]
• Length of DGF [Срок оценки: From transplantation up 7 days after transplantation]
• Proportion of patients with dialysis dependency up to 5 years after transplantation [Срок оценки: From 6 months up to 5 years]
• Imlifidase Pharmacokinetics (AUC) [Срок оценки: From pre-dose imlifidase up to Day 15]

Критерии участия

Критерии включения

• Signed Informed Consent obtained from patient/parent/legal guardian/independent witness (depending on patient's age) before any trial-related procedures
• Highly sensitised patient with panel reactive antibodies (PRA) ≥80%
• Male or female patient between the age of 1 to 17 years (up to the day before the 18th birthday) at the time of screening
• Patient with end-stage renal disease (ESRD) and waiting for a renal transplant from a living or deceased donor
• Patient must be transplantable (including size mismatch) at the time of obtaining informed consent for trial participation
• Patients who have previously undergone desensitisation unsuccessfully with plasmapheresis/IVIg/anti-CD20 or have an anti-HLA antibody status deemed too difficult to make a successful desensitisation (judgement based on physicians' previous experience with similar patients)
• Positive crossmatch (XM) test determined by flow cytometry crossmatch (FCXM) and/or complement-dependent cytotoxicity crossmatch (CDCXM) tests against the donor. For the DD patients, if physical XM tests are not practically possible due to lack of time, patients may be included on a virtual crossmatch (vXM) predictive of a positive XM test.
• Willingness and ability to comply with the protocol as judged by the investigator

Критерии исключения

• Previous treatment with imlifidase
• IVIg treatment within 28 days prior to imlifidase treatment
• Desensitisation treatment(s) within 1 month prior to the current transplantation
• Hypersensitivity to the active substance (imlifidase) or to any of the excipients and to other immunosuppressive drugs specified in the protocol
• Ongoing serious infections
• Present, or history of, thrombotic thrombocytopenic purpura (TTP), or known familial history of TTP
• At the time of transplantation: severe other condition requiring treatment and close monitoring e.g. cardiac failure ≥ grade 4 (New York Heart Association), unstable coronary disease, active peripheral vascular disease, proven hypercoagulable conditions/events or oxygen dependent respiratory disease
• Malignancy within 3 years prior to transplantation
• ABO blood group incompatible transplantations (A2 and A2B kidneys will not be accepted for B recipients)
• Any other reason that, in the view of the investigator, precludes transplantation
• Breast feeding or pregnancy, if applicable
• Woman of fertile age and sexually active without adequate contraceptive measures to avoid pregnancy during the interventional trial period (i.e. up to 6 months after transplantation)
• Suspicion of Covid-19 infection or positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test
• Positive serology for human immunodeficiency virus (HIV)
• Clinical signs of hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus (CMV), or Epstein Barr virus (EBV) infection
• Donor with positive serology for HIV, HBV, HCV, CMV or EBV to a patient with negative serology (mismatch serology)
• Clinically relevant active infection(s) as judged by the investigator
• Tuberculosis or history of tuberculosis
• Use of other investigational agents within 5 terminal elimination half-lives prior to the transplantation
• Contemporaneous participation in medical device studies
• Known mental incapacity or language barriers precluding patients'/parents'/legal guardians' adequate understanding of the informed consent information and the trial activities
• Inability by the judgement of the investigator to participate in the trial for any other reason

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Финляндия · 1 центр

• HUS, Helsinki University Hospital — Helsinki

Франция · 1 центр

• Robert Debre University Hospital — Paris

Испания · 1 центр

• Hospital Unviersitari Vall d'Hebron, Nefrología Pediátrica — Barcelona

Швеция · 1 центр

• Karolinska University Hospital — Huddinge

Великобритания · 1 центр

• Great Ormond Street Hospital for Children NHS Foundation Trust — London

Публикации

• Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell LD, Clahsen-van Groningen MC, Demetris AJ, Dragun D, Duong van Huyen JP, Farris AB, Fogo AB, Gibson IW, Glotz D, Gueguen J, Kikic Z, Kozakowski N, Kraus E, Lefaucheur C, Liapis H, Mannon RB, Montgomery RA, Nankivell BJ, Nickeleit V, Nickerson P, Rabant M, Racusen L, Randhawa P, Robin B PMID 32463180

Идентификаторы

NCT: NCT05753930 · 20-HMedIdes-21 · 2022-500230-28-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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