ONEmreg12

University Hospital Regensburg

Franz-Josef-Strauss-Allee 11, Regensburg, Germany, 93053

Clinical Study Centre Surgery, University Hospital Regensburg, +49 9419444895, theonestudy@klinik.uni-regensburg.de

Clinical Study Centre Surgery, University Hospital Regensburg, +49 9419444895, theonestudy@klinik.uni-regensburg.de

No

No

No

Final

03 Dec 2018

Yes

13 Jun 2017

Yes

13 Jun 2017

Yes

To collect further evidence of the safety of administering donor-derived M reg preparations to living-donor renal transplant recipients. In addition, to determine whether pre-transplant M reg infusion allows some degree of tapering of conventional maintenance immunosuppression within 60 weeks after transplantation. The objective of this study was to evaluate whether the cell-based medicinal product "Mreg_UKR" constitutes a safe and sufficiently promising therapeutic strategy to warrant more extensive development.

The Mreg_UKR cell product was released by the manufacturing facility only when all relevant quality control criteria had been met and authorisation was given by the Qualified Person. Mreg_UKR was infused on the surgical intensive care unit at the trial centre, so that patients could be closely monitored and receive emergency medical treatment, if necessary. Patients received prophylactic doses of paracetamol and anti-histamine, and were fully anti-coagulated using a standard sliding-scale heparin infusion to minimise potential adverse reactions to the cell infusion. Low-dose MMF (500 mg/day) was administered from the day of cell infusion until the day prior to organ transplantation (Day -1) as another precautionary measure, intended to minimise the risk of sensitising the recipient to donor alloantigen. Furthermore, patients were tested for donor-specific antibody (DSA) prior to cell infusion and again on Day -1. A negative DSA test result on Day -1 was confirmed before proceeding with organ transplantation. Graft rejection is a potentially life-threatening condition. Therefore, no patient was denied anti-rejection therapy or any other concomitant treatment that was deemed necessary by the local Investigator. Optimal clinical care for all patients enrolled in the study was paramount. Investigators acted in the patients' best interests at all times by protecting allograft function, even if this resulted in a protocol deviation. Investigators reserved the right to alter the specified regimen in response to intolerable adverse drug reactions or sub-optimal immunosuppression. Dose tapering was not undertaken if there were signs of graft rejection, evidence of declining renal function or any other clinical contraindication.

24 Jul 2014

No

Yes

Germany: 8

8

8

0

0

0

0

0

0

7

1

0

Overall trial (overall period)

Not applicable

Mreg_UKR

Suspension for injection

Intravenous use

Day -7: Single dose of 2.5 - 7.5 x 10^6 cells / kg body weight administered via slow central venous infusion over 10 - 50 minutes.

Prednisolone IV

Powder and solvent for solution for infusion

Intravenous use

Day 0: 500 mg IV (250 mg pre-op, 250 mg intra-op); Day 1: 125 mg IV

Prednisolone oral

Tablet

Oral use

Day 2 to 14: 20 mg/day; Week 3 to 4: 15 mg/day; Week 5 to 8: 10 mg/day; Week 9 to 12: 5 mg/day; Week 13 to 14: 2.5 mg/day; Week 15 to Study End: Cessation.

Tacrolimus

Capsule, hard

Oral use

Tacrolimus was initiated within 48 hours prior to transplantation surgery and doses were adjusted as necessary to achieve whole blood drug trough levels within the following concentration ranges during the specified time frames: ≤ 48 hrs pre-op to Day 14: 3-12 ng/ml; Week 3 to 12: 3-10 ng/ml; Week 13 to 36: 3-8 ng/ml; Week 37 to Study End: 3-6 ng/ml.

Mycophenolate mofetil

Capsule, hard, Film-coated tablet

Oral use

Low-dose MMF was commenced 7 days prior to transplantation to cover the pre-operative infusion of Mreg_UKR. There was the option to gradually taper doses starting from Week 36, depending on the clinical condition of the patient. Day -7 to Day -2: 500 mg/day (250 mg twice daily); Day -1 to 14: 2000 mg/day; Week 3 to 36: 1000 mg/day; Week 37 to 40: 750 mg/day; Week 41 to 44: 500 mg/day; Week 45 to 48: 250 mg/day; Week 49 to Study End: Cessation.

Mycophenolic acid

Gastro-resistant tablet

Oral use

Doses that are biologically equivalent to those specified for mycophenolate mofetil (MMF), if used instead of MMF.

Overall trial

Cell-treated population

All patients who signed informed consent, received an infusion of Mreg_UKR and underwent living-donor kidney transplantation.

Mreg_UKR

Cell-treated population

All patients who signed informed consent, received an infusion of Mreg_UKR and underwent living-donor kidney transplantation.

Kidney graft biopsies were assessed by a nominated Central Pathologist. A patient was deemed to have reached the primary endpoint only if the Central Pathologist issued a histological confirmation of rejection. Therefore, BCAR required a clinical diagnosis from the local Investigator plus a histopathological confirmation from a for-cause biopsy evaluated by the Central Pathologist. A biopsy was considered to be 'for-cause' if there were overt clinical signs of rejection at the time of sampling, even if this coincided with a scheduled protocol biopsy time point. Evidence of subclinical rejection detected in a protocol biopsy did not qualify as a primary endpoint. A clinical diagnosis of acute rejection by the local Investigator, without histopathological confirmation from the Central Pathologist, was also insufficient for a primary endpoint.

Primary

Within 60 weeks following renal transplantation.

For each patient who registered a primary endpoint, the time interval between the date of transplantation (“Day 0”) and the date of first BCAR was calculated. The date of first BCAR was defined as the earliest date when both criteria for the primary endpoint (clinical diagnosis and biopsy confirmation from the Central Pathologist) were fulfilled.

Secondary

Within 60 weeks following renal transplantation.

The severity of BCAR was assessed according to clinical criteria. Investigators were asked to grade rejection severity according to the response of the patient to anti-rejection therapy. In the eCRF, severity was classified as: “Spontaneously resolving”, “Glucocorticoid-responsive”, “Responsive to depleting antibody treatment”, “Unresponsive to rescue therapy” or “Not applicable”. The option “Not applicable” was available in case no additional anti-rejection treatment was initiated and the patient could be treated by modulating the doses of the study drugs.

Secondary

Within 60 weeks following renal transplantation.

Rejections leading to graft loss were defined as episodes of rejection that were reported in the eCRF as "unresponsive to rescue therapy" (severity) and/or "not resolved after 2 weeks" (outcome), if the question "Is this patient dialysis-dependent as a result of this rejection episode?" was answered "Yes".

Secondary

Within 60 weeks following renal transplantation.

For analysis, the observation period for AEs was defined as the date of administration of the first dose of study-specific medication until 28 days after the date of final trial visit or date of withdrawal. Only these treatment-emergent AEs were included.

Information on AEs was collected systematically by the study team at regular trial follow-up visits. It was the responsibility of the Investigator to assess the seriousness and causality of every AE. All reported terms (verbatim terms) were monitored by source data verification and then coded using MedDRA version 20.1.

20.1

Cell-treated patients