The ONE Study M Reg Trial

Study Overview
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Brief Summary
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To collect evidence of the safety of administering donor-derived regulatory macrophage (M reg) preparations to living-donor renal transplant recipients in the context of an international European Union funded consortium aimed at evaluating cellular immunotherapy in solid organ transplantation (The ONE Study). It is anticipated that immune regulation induced by M reg therapy can eventually be used to reduce the need for conventional immunosuppression in transplant recipients.

Detailed Description
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Decades of immunosuppressive drug development has produced an array of powerful pharmacological agents, but the various drawbacks associated with these treatments leaves considerable room for improvement. By harnessing the power of suppressive mechanisms in the human immune system, regulatory cell therapy may be able to support peripheral tolerance and induce a level of donor-specific unresponsiveness that allows for a reduction in the use of conventional immunosuppression in organ transplant recipients. Several alternative regulatory cell types have been identified as potential adjunct immunotherapies for solid organ transplantation and are now approaching a stage of development that would allow clinical testing in an early-stage trial. The EU-funded international ONE Study consortium aims to answer the question as to whether M reg treatment, or other immunoregulatory cell-based therapies, can be advanced in the clinical management of solid organ transplant recipients. This particular M reg trial aims to explore the potential of M reg therapy as an adjunct immunosuppressive treatment in living-donor renal transplant recipients through a clinical protocol design shared by other investigators in The ONE Study group testing additional regulatory cell therapies in separate trials.

Official Title
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The ONE Study: A Unified Approach to Evaluating Cellular Immunotherapy in Solid Organ Transplantation - M Reg Trial

Conditions
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Renal Failure, End Stage

Intervention / Treatment
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* Biological: Donor M reg (Mreg_UKR)


Participation Criteria
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Eligibility Criteria
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RECIPEINT Inclusion Criteria: Chronic renal insufficiency necessitating kidney Tx Aged at least 18 years Able to commence the immunosuppressive regimen as specified Willing and able to participate in The ONE Study subprojects Signed and dated written informed consent Exclusion Criteria: Patient has previously received any tissue or organ Tx Known contraindication to the protocol-specified treatments /medications HLA 0-0-0 mismatch PRA grade >40% within 6 mo. prior to enrolment Previous desensitisation treatment Concomitant malignancy or history of malignancy <5 years before study entry (excluding successfully-treated non-metastatic skin BCC or SCC) Significant local or systemic infection HIV-positive, EBV-negative or suffering chronic viral hepatitis CMV negative and receiving a kidney from a CMV+ donor Significant liver disease Malignant or pre-malignant haematological conditions Any uncontrolled condition that could interfere with study objectives Any condition placing the subject at undue risk Ongoing treatment with systemic immunosuppressive drugs at study entry Exposure to an investigational product during the study, or within 28 days or 5 half-lives of the product before study entry Female patients of child-bearing potential with a +pregnancy test Female patients breast-feeding or that are of child bearing potential and unwilling to use effective birth control Psychological, familial, sociological or geographical factors hampering compliance Any substance abuse or psychiatric disorder Patients unable to freely give informed consent Known IgA or IgG deficiency Any pro-coagulant disposition causing undue risk Previous history of transfusion-associated disease causing undue risk Conditions resulting in substantially reduced pulmonary vasculature or increased pulmonary vascular resistance. Diseases causing substantially elevated pulmonary arterial or right heart hypertrophy or dysfunction Known atrial or ventricular septal defects posing a risk of embolism Known hypersensitivity to components of the manufactured cell product DONOR Inclusion Criteria: Eligible for live kidney donation Aged at least 18 years Willing and able to provide a blood sample for The ONE Study Subproject Willing to provide personal and medical/biological data for the trial analysis Eligible for leucapheresis prior to organ donation Signed and dated written informed consent Exclusion Criteria: Genetically identical to the prospective organ recipient at the HLA loci (0-0-0 mismatch) CMV-positive and donating to a CMV-negative recipient Exposure to an investigational product during the study, or within 28 days or 5 half-lives of the product before study entry Any form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the Investigator, may invalidate communication with the investigator and/or designated study personnel Subjects unable to freely give their informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: M reg treatment<br>Donor M reg (2.5-7.5 million cells/kg) IV infused (6-7d before Tx) into recipients of a LD renal Tx. Recipients also receive prednisolone, mycophenolate mofetil and tacrolimus, as detailed below: Prednisolone D 0: 500 mg IV D 1: 125 mg IV D 2 - 14: 20.0 mg/d (oral) Wk 3 - 4: 15.0 mg/d Wk 5 - 8: 10.0 mg/d Wk 9 - 12: 5.0 mg/d Wk 13 - 14: 2.5 mg/d Wk 15 - End: Cessation MMF (or biologic equiv.) D -7 to -2: 500 mg/d (250mg 2x/d) D -1 to 14: 2000 mg/d Wk 3 - 36: 1000 mg/d Wk 37 - 40: 750 mg/d Wk 41 - 44: 500 mg/d Wk 45 - 48: 250 mg/d Wk 49 - End: Cessation NOTE: MMF tapering will only happen if a 36-Wk biopsy shows no signs of subclinical rejection or if there is no evidence of declining renal function or if the clinician has any other concern about dose reduction. Tacrolimus (or biologic equiv.) ≤ 48 h pre-Tx to D 14: 3-12 ng/ml Wk 3 - 12: 3-10 ng/ml Wk 13 - 36: 3-8 ng/ml Wk 37 - End: 3-6 ng/ml | Biological: Donor M reg (Mreg_UKR)<br>* Experimental: M reg treatment Donor M reg (2.5-7.5 million cells/kg) IV infused (6-7d before Tx) into recipients of a living donor renal Tx. Recipients also receive prednisolone, mycophenolate mofetil and tacrolimus background immunosuppression (as described in detail in the arm description).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| biopsy-confirmed acute rejection incidence |  | 60 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time to first acute rejection episode |  | 60 weeks | 
| severity of acute rejection episodes | based on response to treatment and histological scoring | 60 weeks | 
| total immunosuppressive burden | assessed at last study visit | 60 weeks | 
| incidence of patients treated for subclinical acute rejection |  | 60 weeks | 
| prevention of chronic graft dysfunction (chronic rejection or IF/TA) | assessed by clinical (impairment of GFR) and histopathological (Banff staging) measures | 60 weeks | 
| incidence of post-transplant dialysis, inclusion on the transplant waiting list or re-transplantation following graft loss through rejection |  | 60 weeks | 
| avoidance of drug-related complications by immunosuppressant reduction | assessed by the incidence of reported adverse drug reactions | 60 weeks | 
| incidence of embolic pulmonary complications and other embolic events |  | 60 weeks | 
| incidence of immunological reactions resulting in anaphylactoid reactions, immediate cardiovascular compromise or other acute organ failure |  | 1 week | 
| biochemical disturbances caused by cell infusion |  | 1 week | 
| over-suppression of the immune system assessed by the incidence of major and/or opportunistic infections, especially CMV, EBV and polyoma virus |  | 60 weeks | 
| over-suppression of the immune system assessed by the incidence of neoplasia |  | 60 weeks | 
| immunological condition of study patients | an extensive immune monitoring program has been established in The ONE Study | 60 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal failure, end stage, renal transplantation, cell therapy, macrophages, monocyte derived, immune tolerance, ONE Study, immunotherapy