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The ONE Study M Reg Trial (ONEmreg12)

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ClinicalTrials.gov Identifier: NCT02085629
Recruitment Status : Terminated (Insufficient rate of patient recruitment and treatment.)
First Posted : March 13, 2014
Last Update Posted : April 18, 2019
Sponsor:
Information provided by (Responsible Party):
Edward Geissler, University of Regensburg

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.

Condition or disease Intervention/treatment Phase
Renal Failure, End Stage Biological: Donor M reg (Mreg_UKR) Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 8 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The ONE Study: A Unified Approach to Evaluating Cellular Immunotherapy in Solid Organ Transplantation - M Reg Trial
Actual Study Start Date : July 24, 2014
Actual Primary Completion Date : December 3, 2018
Actual Study Completion Date : December 3, 2018

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).





Primary Outcome Measures :
  1. biopsy-confirmed acute rejection incidence [ Time Frame: 60 weeks ]

Secondary Outcome Measures :
  1. time to first acute rejection episode [ Time Frame: 60 weeks ]
  2. severity of acute rejection episodes [ Time Frame: 60 weeks ]
    based on response to treatment and histological scoring

  3. total immunosuppressive burden [ Time Frame: 60 weeks ]
    assessed at last study visit

  4. incidence of patients treated for subclinical acute rejection [ Time Frame: 60 weeks ]
  5. prevention of chronic graft dysfunction (chronic rejection or IF/TA) [ Time Frame: 60 weeks ]
    assessed by clinical (impairment of GFR) and histopathological (Banff staging) measures

  6. incidence of post-transplant dialysis, inclusion on the transplant waiting list or re-transplantation following graft loss through rejection [ Time Frame: 60 weeks ]
  7. avoidance of drug-related complications by immunosuppressant reduction [ Time Frame: 60 weeks ]
    assessed by the incidence of reported adverse drug reactions

  8. incidence of embolic pulmonary complications and other embolic events [ Time Frame: 60 weeks ]
  9. incidence of immunological reactions resulting in anaphylactoid reactions, immediate cardiovascular compromise or other acute organ failure [ Time Frame: 1 week ]
  10. biochemical disturbances caused by cell infusion [ Time Frame: 1 week ]
  11. 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 ]
  12. over-suppression of the immune system assessed by the incidence of neoplasia [ Time Frame: 60 weeks ]
  13. immunological condition of study patients [ Time Frame: 60 weeks ]
    an extensive immune monitoring program has been established in The ONE Study


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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02085629


Locations
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Germany
University Hospital Regensburg
Regensburg, Germany, 93053
Sponsors and Collaborators
University of Regensburg
Investigators
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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

Additional Information:
Publications:
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Responsible Party: Edward Geissler, Professor, University of Regensburg
ClinicalTrials.gov Identifier: NCT02085629     History of Changes
Other Study ID Numbers: ONEmreg12
2013-000999-15 ( EudraCT Number )
grant number 260687 ( Other Grant/Funding Number: European Union FP7 Programme )
First Posted: March 13, 2014    Key Record Dates
Last Update Posted: April 18, 2019
Last Verified: April 2019

Keywords provided by Edward Geissler, University of Regensburg:
renal failure, end stage
renal transplantation
cell therapy
macrophages, monocyte derived
immune tolerance
ONE Study
immunotherapy

Additional relevant MeSH terms:
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Renal Insufficiency
Kidney Failure, Chronic
Kidney Diseases
Urologic Diseases
Renal Insufficiency, Chronic
Prednisolone
Mycophenolic Acid
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action