The ONE Study nTreg Trial (ONEnTreg13) (ONEnTreg13)

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

The aim of this trial is to collect evidence of the safety of administering autologous CD4+CD25+FoxP3+ natural regulatory T cells (nTregs) to living-donor renal transplant recipients. In addition, the study will determine whether post-transplant nTregs infusion allows a tapering of conventional maintenance immunosuppression within 60 weeks after transplantation.

Study Overview

• Status: Completed
• Conditions: Immunosuppressive Treatment of Living-donor Renal Transplantation
• Intervention / Treatment: Biological: autologous CD4+CD25+FoxP3+ natural regulat. T cells (nTregs)

Detailed Description

The ONE Study aims to explore the feasibility, safety and efficacy of regulatory cell therapies as adjunct immunosuppressive treatments in the context of living-donor renal transplantation.The clinical trial presented here (ONEnTreg13) will test autologous, polyclonally expanded CD4+CD25+FoxP3+ nTregs as a somatic cell-based medicinal product.

The objective of this study is to determine whether administration of nTregs to recipients of living-donor kidney transplants is safe and able to polarize the immunological response of the recipient away from graft rejection and towards graft acceptance, allowing a reduction in the doses of pharmacological maintenance immunosuppression.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13353
    • Charité University Medicine, Dept. of Nephrology and Internal Intensive Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria for organ recipients:

• Chronic renal insufficiency with a GFR < 15 ml/min, accepted by the organ transplantation conference, registered by ET (Euro Transplant) and having a positive vote from the living donor ethic commission (Lebendspendekommission) at the Berlin Medical Association.
• Willing and able to participate in The ONE Study IM and HEC Subprojects.
• Signed and dated written informed consent. For patients unable to read and/or write, oral informed consent observed by an independent witness is acceptable if the patient has fully understood oral information given by the Investigator. The witness should sign the consent form on behalf of the patient.

Exclusion Criteria for organ recipients:

• Patient has previously received any tissue or organ transplant other than the planned kidney graft.
• Known contraindication to protocol-specified treatments / medications.
• Genetically identical to the prospective organ donor at the HLA loci, the so called "full house match" (0-0-0 mismatch).
• Panel-Reactive Antibody (PRA) grade > 40% within last 6 months before transplantation.
• Previous treatment with any desensitization procedure (with or without IVIg).
• Concomitant malignancy or history of malignancy within 5 years before study entry (excluding successfully-treated non-metastatic basal/squamous cell carcinoma of the skin).
• Evidence of significant local or systemic infection.
• CMV-negative recipient receiving a kidney from a CMV-positive donor. EBV-negative recipient receiving a kidney from an EBV-positive donor.
• HIV-positive or suffering chronic viral hepatitis.
• Significant liver disease, defined as persistently elevated AST and/or ALT levels > 2 x ULN.
• Malignant or pre-malignant hematological conditions.
• Any uncontrolled medical condition or concurrent disease that could interfere with the study objectives.
• Any condition which, according to the Investigator, would place the subject at undue risk.
• Ongoing treatment with systemic immunosuppressive drugs at study entry.
• Participation in another clinical trial during the study or within 28 days prior to planned study entry.
• Female patients of childbearing potential with a positive pregnancy test at enrolment.
• Female patients who are breast-feeding.
• All female patients of childbearing potential unless the patient is willing to maintain a highly effective method of birth control for the duration of the study.
• Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up visit schedule.
• Any form of drug or alcohol abuse, psychiatric disorder, or other condition that, in the opinion of the Investigator, may invalidate communication with the Investigator and/or designated study personnel.
• Patients unable to freely give their informed consent (e.g. patients under legal guardianship).
• Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
• Known allergy/hypersensitivity to any component of the study product.

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: Treatment arm; Patients in ONEnTreg13 will be treated with four immunosuppressive agents, all of which are classified as an Investigational Medicinal Products (IMPs): nTregs; Prednisolone; MMF; Tacrolimus	Biological: autologous CD4+CD25+FoxP3+ natural regulat. T cells (nTregs); autologous CD4+CD25+FoxP3+ natural regulatory T cells (nTregs). nTregs will be infused at escalating doses of 0.5 x 10^6, 1 x 10^6, and 2.5-3 x 10^6 cells/kg body weight in cohorts of three patients each.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of biopsy-confirmed acute rejection (BCAR) within 60 weeks of organ transplantation	60 weeks
Incidence of infectious complications associated with cell administration.	60 weeks
Incidence of embolic pulmonary complications and other embolic events.	60 weeks
Incidence of immune responses resulting in anaphylactic reactions, cardiovascular compromise or other acute organ failure.	60 weeks
Biochemical disturbances associated with the cell infusion.	60 weeks
Over-suppression of the immune system assessed by the incidence of opportunistic infections, especially, CMV, EBV and polyoma virus.	60 weeks
Over-suppression of the immune system assessed by the incidence of neoplasia.	60 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of patients treated for subclinical acute rejection on the basis of histopathological findings		60 weeks
Prevention of acute rejection will be secondarily assessed by measuring	i) time to first acute rejection episode ii) severity of acute rejection episodes based on response to treatment and histological scoring iii) the level of total immunosuppression drugs at the final trial visit.	60 weeks
Prevention of chronic graft dysfunction (chronic rejection or IF/TA) will be 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 retransplantation following graft loss through rejection (acute or chronic).		60 weeks
Avoidance of drug-related complications by immunosuppressant reduction will be assessed by the incidence of reported adverse drug reactions.		60 weeks

Collaborators and Investigators

• Sponsor: Prof. Dr. Petra Reinke

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.
• Roemhild A, Otto NM, Moll G, Abou-El-Enein M, Kaiser D, Bold G, Schachtner T, Choi M, Oellinger R, Landwehr-Kenzel S, Juerchott K, Sawitzki B, Giesler C, Sefrin A, Beier C, Wagner DL, Schlickeiser S, Streitz M, Schmueck-Henneresse M, Amini L, Stervbo U, Babel N, Volk HD, Reinke P. Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial. BMJ. 2020 Oct 21;371:m3734. doi: 10.1136/bmj.m3734.

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): November 1, 2017

Study Registration Dates

• First Submitted: February 18, 2015
• First Submitted That Met QC Criteria: February 19, 2015
• First Posted (Estimate): February 25, 2015

Study Record Updates

• Last Update Posted (Actual): February 5, 2020
• Last Update Submitted That Met QC Criteria: February 3, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Other Study ID Numbers: ONEnTreg13