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The ONE Study M Reg Trial (ONEmreg12)

Primary Purpose

Renal Failure, End Stage

Status
Terminated
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
Donor M reg (Mreg_UKR)
Sponsored by
University of Regensburg
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Renal Failure, End Stage focused on measuring renal failure, end stage, renal transplantation, cell therapy, macrophages, monocyte derived, immune tolerance, ONE Study, immunotherapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University Hospital Regensburg

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

M reg treatment

Arm Description

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

Outcomes

Primary Outcome Measures

biopsy-confirmed acute rejection incidence

Secondary Outcome Measures

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

Full Information

First Posted
March 10, 2014
Last Updated
April 16, 2019
Sponsor
University of Regensburg
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1. Study Identification

Unique Protocol Identification Number
NCT02085629
Brief Title
The ONE Study M Reg Trial
Acronym
ONEmreg12
Official Title
The ONE Study: A Unified Approach to Evaluating Cellular Immunotherapy in Solid Organ Transplantation - M Reg Trial
Study Type
Interventional

2. Study Status

Record Verification Date
April 2019
Overall Recruitment Status
Terminated
Why Stopped
Insufficient rate of patient recruitment and treatment.
Study Start Date
July 24, 2014 (Actual)
Primary Completion Date
December 3, 2018 (Actual)
Study Completion Date
December 3, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Regensburg

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Failure, End Stage
Keywords
renal failure, end stage, renal transplantation, cell therapy, macrophages, monocyte derived, immune tolerance, ONE Study, immunotherapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
8 (Actual)

8. Arms, Groups, and Interventions

Arm Title
M reg treatment
Arm Type
Experimental
Arm Description
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
Intervention Type
Biological
Intervention Name(s)
Donor M reg (Mreg_UKR)
Intervention Description
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).
Primary Outcome Measure Information:
Title
biopsy-confirmed acute rejection incidence
Time Frame
60 weeks
Secondary Outcome Measure Information:
Title
time to first acute rejection episode
Time Frame
60 weeks
Title
severity of acute rejection episodes
Description
based on response to treatment and histological scoring
Time Frame
60 weeks
Title
total immunosuppressive burden
Description
assessed at last study visit
Time Frame
60 weeks
Title
incidence of patients treated for subclinical acute rejection
Time Frame
60 weeks
Title
prevention of chronic graft dysfunction (chronic rejection or IF/TA)
Description
assessed by clinical (impairment of GFR) and histopathological (Banff staging) measures
Time Frame
60 weeks
Title
incidence of post-transplant dialysis, inclusion on the transplant waiting list or re-transplantation following graft loss through rejection
Time Frame
60 weeks
Title
avoidance of drug-related complications by immunosuppressant reduction
Description
assessed by the incidence of reported adverse drug reactions
Time Frame
60 weeks
Title
incidence of embolic pulmonary complications and other embolic events
Time Frame
60 weeks
Title
incidence of immunological reactions resulting in anaphylactoid reactions, immediate cardiovascular compromise or other acute organ failure
Time Frame
1 week
Title
biochemical disturbances caused by cell infusion
Time Frame
1 week
Title
over-suppression of the immune system assessed by the incidence of major and/or opportunistic infections, especially CMV, EBV and polyoma virus
Time Frame
60 weeks
Title
over-suppression of the immune system assessed by the incidence of neoplasia
Time Frame
60 weeks
Title
immunological condition of study patients
Description
an extensive immune monitoring program has been established in The ONE Study
Time Frame
60 weeks
Other Pre-specified Outcome Measures:
Title
incidence of malignancies arising directly from Mreg_UKR
Time Frame
60 weeks
Title
incidence of autoimmune disorders
Time Frame
60 weeks
Title
incidence of inflammatory pathologies
Time Frame
60 weeks
Title
incidence of anaemia, cytopaenia or biochemical disturbances unrelated to the function of the transplanted kidney
Time Frame
60 weeks
Title
A Health-Economics Subproject will evaluate the health-related quality-of-life of trial patients using patient-reported outcome measures
Description
this subproject will also calculate the cost-effectiveness of the Mreg_UKR cell product
Time Frame
60 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Edward K Geissler, PhD
Organizational Affiliation
University Hospital Regensburg, University of Regensburg
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Bernhard Banas, MD
Organizational Affiliation
University Hospital Regensburg, University of Regensburg
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
James A Hutchinson, MD, PhD
Organizational Affiliation
University Hospital Regensburg, University of Regensburg
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Regensburg
City
Regensburg
ZIP/Postal Code
93053
Country
Germany

12. IPD Sharing Statement

Citations:
PubMed Identifier
23369457
Citation
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.
Results Reference
background
PubMed Identifier
32446407
Citation
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.
Results Reference
derived
Links:
URL
http://www.onestudy.org
Description
ONE Study

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The ONE Study M Reg Trial

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