The ONE Study M Reg Trial (ONEmreg12)

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

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.

Study Overview

• Status: Terminated
• Conditions: Renal Failure, End Stage
• Intervention / Treatment: Biological: Donor M reg (Mreg_UKR)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Regensburg, Germany, 93053
    • University Hospital Regensburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: M reg treatment; 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); 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
incidence of malignancies arising directly from Mreg_UKR		60 weeks
incidence of autoimmune disorders		60 weeks
incidence of inflammatory pathologies		60 weeks
incidence of anaemia, cytopaenia or biochemical disturbances unrelated to the function of the transplanted kidney		60 weeks
A Health-Economics Subproject will evaluate the health-related quality-of-life of trial patients using patient-reported outcome measures	this subproject will also calculate the cost-effectiveness of the Mreg_UKR cell product	60 weeks

Collaborators and Investigators

• Sponsor: University of Regensburg
• Investigators: Study Director: Edward K Geissler, PhD, University Hospital Regensburg, University of Regensburg; Principal Investigator: Bernhard Banas, MD, University Hospital Regensburg, University of Regensburg; Principal Investigator: James A Hutchinson, MD, PhD, University Hospital Regensburg, University of Regensburg

Publications and helpful links

General Publications

• Sawitzki B, Harden PN, Reinke P, Moreau A, Hutchinson JA, Game DS, Tang Q, Guinan EC, Battaglia M, Burlingham WJ, Roberts ISD, Streitz M, Josien R, Boger CA, Scotta C, Markmann JF, Hester JL, Juerchott K, Braudeau C, James B, Contreras-Ruiz L, van der Net JB, Bergler T, Caldara R, Petchey W, Edinger M, Dupas N, Kapinsky M, Mutzbauer I, Otto NM, Ollinger R, Hernandez-Fuentes MP, Issa F, Ahrens N, Meyenberg C, Karitzky S, Kunzendorf U, Knechtle SJ, Grinyo J, Morris PJ, Brent L, Bushell A, Turka LA, Bluestone JA, Lechler RI, Schlitt HJ, Cuturi MC, Schlickeiser S, Friend PJ, Miloud T, Scheffold A, Secchi A, Crisalli K, Kang SM, Hilton R, Banas B, Blancho G, Volk HD, Lombardi G, Wood KJ, Geissler EK. Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials. Lancet. 2020 May 23;395(10237):1627-1639. doi: 10.1016/S0140-6736(20)30167-7. Erratum In: Lancet. 2020 Jun 27;395(10242):1972.
• Geissler EK. The ONE Study compares cell therapy products in organ transplantation: introduction to a review series on suppressive monocyte-derived cells. Transplant Res. 2012 Sep 28;1(1):11. doi: 10.1186/2047-1440-1-11. No abstract available.

Helpful Links

• One Study

Study record dates

Study Major Dates

• Study Start (Actual): July 24, 2014
• Primary Completion (Actual): December 3, 2018
• Study Completion (Actual): December 3, 2018

Study Registration Dates

• First Submitted: March 10, 2014
• First Submitted That Met QC Criteria: March 10, 2014
• First Posted (Estimate): March 13, 2014

Study Record Updates

• Last Update Posted (Actual): April 18, 2019
• Last Update Submitted That Met QC Criteria: April 16, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: immunotherapy; cell therapy; renal transplantation; immune tolerance; renal failure, end stage; macrophages, monocyte derived; ONE Study
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Renal Insufficiency
• Other Study ID Numbers: ONEmreg12; 2013-000999-15 (EudraCT Number); grant number 260687 (Other Grant/Funding Number: European Union FP7 Programme)