Clinical trial NCT02085629: The ONE Study M Reg Trial
Official title: The ONE Study: A Unified Approach to Evaluating Cellular Immunotherapy in Solid Organ Transplantation - M Reg Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Renal Failure, End Stage
Keywords: renal failure, end stage
renal transplantation
cell therapy
macrophages, monocyte derived
immune tolerance
ONE Study
immunotherapy
Lead sponsor: University of Regensburg
Sponsor class: OTHER
First posted: 2014-03-13
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: biopsy-confirmed acute rejection incidence
timeFrame: 60 weeks
Secondary outcomes:
measure: time to first acute rejection episode
timeFrame: 60 weeks
measure: severity of acute rejection episodes
timeFrame: 60 weeks
measure: total immunosuppressive burden
timeFrame: 60 weeks
measure: incidence of patients treated for subclinical acute rejection
timeFrame: 60 weeks
measure: prevention of chronic graft dysfunction (chronic rejection or IF/TA)
timeFrame: 60 weeks
measure: incidence of post-transplant dialysis, inclusion on the transplant waiting list or re-transplantation following graft loss through rejection
timeFrame: 60 weeks
measure: avoidance of drug-related complications by immunosuppressant reduction
timeFrame: 60 weeks
measure: incidence of embolic pulmonary complications and other embolic events
timeFrame: 60 weeks
measure: incidence of immunological reactions resulting in anaphylactoid reactions, immediate cardiovascular compromise or other acute organ failure
timeFrame: 1 week
measure: biochemical disturbances caused by cell infusion
timeFrame: 1 week
measure: over-suppression of the immune system assessed by the incidence of major and/or opportunistic infections, especially CMV, EBV and polyoma virus
timeFrame: 60 weeks
measure: over-suppression of the immune system assessed by the incidence of neoplasia
timeFrame: 60 weeks
measure: immunological condition of study patients
timeFrame: 60 weeks
Other outcomes:
measure: incidence of malignancies arising directly from Mreg_UKR
timeFrame: 60 weeks
measure: incidence of autoimmune disorders
timeFrame: 60 weeks
measure: incidence of inflammatory pathologies
timeFrame: 60 weeks
measure: incidence of anaemia, cytopaenia or biochemical disturbances unrelated to the function of the transplanted kidney
timeFrame: 60 weeks
measure: A Health-Economics Subproject will evaluate the health-related quality-of-life of trial patients using patient-reported outcome measures
timeFrame: 60 weeks
Locations:
city: Regensburg
country: Germany
facility: University Hospital Regensburg
Study officials:
affiliation: University Hospital Regensburg, University of Regensburg
name: Edward K Geissler, PhD
role: STUDY_DIRECTOR
affiliation: University Hospital Regensburg, University of Regensburg
name: Bernhard Banas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Regensburg, University of Regensburg
name: James A Hutchinson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.