Clinical trials

Safety is a key issue of the BIO-DrIM clinical trials. All studies are performed according to the international rules and have received ethical approval. The trials are conducted in accordance with the current ICH-GCP-guidelines. Good Clinical Practice (GCP). The trial protocols and any amendments were and will be prepared in accordance with the Declaration of Helsinki in the version of October 1996 (48th General Assembly of the World Medical Association, Somerset West, Republic of South Africa).
We will not use any non-approved drug therefore undesired toxicity is not expected.

Study I

Prospective randomised marker-based trial to assess the clinical utility and safety of biomarker-guided immunosuppression withdrawal in liver transplantation

Short title: Liver Immunospression Free Trial (LIFT)
Phase IV clinical
EudraCT number: 2014-004557-14
PI: Alberto Sanchez-Fueyo, King’s College, London, UK

Purpose of the trial: ‘LIFT’ aims to validate a biomarker test of operational tolerance to stratify liver transplant recipients before withdrawing immunosuppressive medication

dot Study duration: Enrollment phase (18 months); patient follow-up (48 months: 6-12 months drug weaning, 36 months post-weaning follow-up). Total study duration: 72 months.

dot Primary endpoint: The primary endpoint is defined as the successful discontinuation of IS with maintainance of normal allograft status as assessed by liver biopsy and liver tests 12 months after IS withdrawal (operational tolerance). For the purposes of validating the clinical usefulness of the tolerance biomarker, successful IS withdrawal is considered the Gold Standard. Since this outcome is strictly restricted to the IS withdrawal process and by definition cannot be observed in Arm B-, the analysis of the primary outcome will be restricted to Arms A and B+.

dot Secondary endpoints: rejection; graft fibrosis; graft loss; all–cause mortality; participants remaining free of rejection at 3 years post drug withdrawal; renal function; change in co-morbidities associated with drug use; anti-HLA antibodies before and after drug withdrawal; pharmacoeconomic anda qualitfy of life changes.

Study II

A France prospective randomized double-blind, multicentre parallel controlled study of CNI weaning in selected long-term kidney transplant patients

Short title: WEANING
EudraCT number: 2010-019574-33

PI: Pr. Magali Giral, Centre Hospitalier Universitaire de Nantes; France

Purpose of the trial: The WEANING trial aims to improve the graft function in clinically selected Highly Stable (HS) patients following complete weaning of calcineurin inhibitor (CNI).

dot Primary endpoint: The main objective is to demonstrate the benefit of Tacrolimus weaning (Prograf) assessing the renal function one year after the end of the weaning period.
dot Secondary endpoint: Secondary objective is to evaluate risks and consequences of CNI withdrawal. Secondary composite objectives are acute and chronic rejection, death, graft lost, anti HLA antibodies, de novo proteinuria.

Sub-study of the trial is the assessment of low and high immunological risk biomarkers (DNA chip, Phenotypes).

The study was approved in 2010 by the French regulatory agency AFSAPS.

In December 2014, the group decided to stop the study due to insufficient patient recruitment.

Study IV

Prospective donor-specific cellular alloresponse assessment for Immunosuppression minimization in de novo renal transplantation

Short title: CELLIMIN
EudraCT-Number: 2014-001325-33

PI: Prof. Dr. Josep M. Grinyó and Oriol Bestard, INSTITUT CATALA DE LA SALUT, Renal Transplant Unit, Dept. Nephrology Bellvitge Universitary Hospital, Barcelona, Spain

Sponsor: Charité - Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin
Representative of the Sponsor: Prof. Dr. Med. Petra Reinke, Department Nephrology and BCRT, Charité - Universitätsmedizin Berlin.

Clinical sites (patient recruitment centers): CHARITE (Berlin), ITUN (Nantes), ICS-HUB (Barcelona), IKEM (Prague), AMC (Amsterdam), UHREG (Regensburg), UKE (Hamburg), Hospital Central de Asturias (Oviedo), Hospital Universitario Marqués de Valdecilla (Santander). Prior to patient recruitment, all clinical sites participated in extensive lab and interlab comparision to validate the robustness and correctness of the IFN-γ ELISPOT assay.
Using the Interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISPOT) assay to assess whether negative donor-specific T-cell alloreactivity as a biomarker based IS will be non-inferior with respect to T-Cell mediated biopsy proven acute rejection (BPAR) rate at 12 months post-transplantation, comparing kidney transplant patients randomized 1:1 to receive either low (TAC monotherapy) or high IS (Standard of Care triple therapy).

The current immunosuppressive therapy consists mainly from combination of three to four immunosuppressant agents. This therapy is not only costly, but leads also to many undesirable side effects. Minimizing immunosuppression (IS), e.g. monotherapy, as early as possible without losing control of acute/chronic rejections would be of great benefit and could reduce adverse effects and costs. However, this is only possible in a minority of patients yet. Therefore, a precise evaluation of the anti-donor alloimmune response in order to identify patients likely to accept the graft with no or very low IS would be of great value.

This is a biomarker strategy design randomized trial, whereby only pre-TX ELISPOT negative patients will be enrolled into the study and randomized 1:1 to either low or high IS regimen. The study will test non-inferiority of low IS regimen compared to high IS regimen, assuming 10% of BPAR at 6-months in the control group, and allowing a non-inferiority limit of maximum 10%. The main objective of the study is to demonstrate the utility and safety of the IFN-γ ELISPOT marker for the stratification of kidney transplant recipients into low and high IS regimens.

Beside the ELISPOT, several other biomarkers are being evaluated in this trial.

Study V

Tacrolimus after rATG and infliximab induction immunosuppression

Short title: RIMINI
EudraCT-Number: 2015-005346-58

PI: Prof. Dr. Ondřej Viklický, Klinika nefrologie, Transplantační centrum Institut klinické a experimentální medicíny, Praha, Czech Republic

Sponsor: Charité - Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin
Representative of the Sponsor: Prof. Dr. Med. Petra Reinke, Department Nephrology and BCRT, Charité Berlin.

Clinical sites (patient recruitment centers): CHARITE (Berlin), ITUN (Nantes), ICS-HUB (Barcelona), IKEM (Prague), AMC (Amsterdam), UHREG (Regensburg), UKE (Hamburg)
RIMINI is an International multicenter open-label single-arm Simon’s two-stage Phase II clinical trial aiming to provide evidence for efficacy and safety of the induction regimen with rATG and infliximab and a go/no go rule for further clinical development. A total of 161 patients will receive the proposed induction regimen, accounting for a drop-out rate of 10%.

Using tolerance/rejection biomarker monitoring we aim to prove shift from high responders to low responders while using infliximab as co-induction agent to target recently activated memory/effector T cells.

dot First stage: Interim analysis will be performed after 64 patients have completed 12 months of follow-up (end of first stage). If 37 or less of them have shown clinical response the trial will stop for futility. If more than 37 patients have experienced clinical response the trial will continue into the second stage.

dot Second stage: The final analysis of the primary outcome will be performed after 146 patients have completed follow up of 12 months. If 90 or less patients have shown clinical response, the trial would not have provided sufficient evidence of efficacy to continue into further clinical development. If more than 90 patients have shown clinical response, the trial would have demonstrated that the clinical response rate of the proposed induction regimen is at least as large as the target rate of 66%, providing sufficient evidence of efficacy to continue into further clinical development.

Clinical response to the induction is determined by the absence of the following outcomes up to 12 months post transplantation (start of follow up at transplantation): acute rejection, graft loss or poor graft function defined as eGFR<40 ml/min.