ONErgt11

Free State of Bavaria, represented by the University of Regensburg, represented by Prof. Edward K. Geissler

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

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

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

No

No

No

Final

07 Dec 2016

Yes

29 Dec 2015

Yes

29 Dec 2015

No

To confirm the rate of acute kidney graft rejection in the study population under standard immunosuppressive therapy in order to corroborate historical renal transplantation statistics and generate reference ranges for future clinical research within The ONE Study. The Reference Group Trial is the first clinical trial planned within the context of The ONE Study, an international, non-commercial research project that ultimately aims in subsequent trials to test several alternative GMP cell products as adjunct immunosuppressive treatments in kidney transplantation. Future trials will assess whether immunoregulatory cell infusion could allow for a reduction in the use of pharmacological maintenance therapy in transplant recipients and alleviate the drawbacks associated with traditional immunosuppressive agents.

Patients in the Reference Group Trial were treated with a standard immunosuppressive regimen that represented current best practice in preventing renal allograft rejection. Nevertheless, graft rejection is a potentially life-threatening condition. Therefore, no patient was denied anti-rejection therapy 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 and dose tapering was not mandatory if graft rejection had occurred or if renal dysfunction was observed. Upon completion of the trial protocol for individual patients, immunosuppressive treatment proceeded at the discretion of the local clinical team.

11 Dec 2012

No

No

France: 9

Germany: 21

Italy: 4

United Kingdom: 22

United States: 14

70

56

0

0

0

0

0

0

61

9

0

Overall trial (overall period)

Not applicable

Simulect

Powder and solvent for solution for injection/infusion

Intravenous use

Day 0: 20mg IV ≤ 2h prior to surgery; Day 4: 20mg IV

Prednisolone IV

Powder and solvent for solution for injection/infusion

Intravenous use

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

Prednisolone oral

Tablet

Oral use

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

Tacrolimus

Capsule, hard

Oral use

Doses were adjusted as necessary to achieve whole blood drug trough levels within the following concentration ranges during the specified time frames: Day -4 – 14: 3-12ng/ml; Week 3 – 12: 3-10ng/ml; Week 13 – 36: 3-8ng/ml; Week 37 – Study End: 3-6ng/ml

Mycophenolate mofetil

Capsule, hard, Coated tablet

Oral use

Day -1 – 14: 2g/day oral; Day 15 – Study End: 1.5g/day oral (750mg twice daily)

Mycophenolic acid

Tablet

Oral use

Doses that are biologically equivalent to those specified for mycophenolate mofetil.

Overall trial

Safety population

All patients who signed informed consent and received at least one dose of study-specific medication.

Intention-to-treat population

All patients included in the safety population who underwent kidney transplantation.

Per-protocol population

All patients included in the safety population who were treated according to protocol specifications (acceptable limits defined in the PP criteria).

Standard immunosuppressive regimen

Safety population

All patients who signed informed consent and received at least one dose of study-specific medication.

Intention-to-treat population

All patients included in the safety population who underwent kidney transplantation.

Per-protocol population

All patients included in the safety population who were treated according to protocol specifications (acceptable limits defined in the PP criteria).

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. Patients with subclinical rejection detected by a protocol biopsy did not register a primary endpoint. Patients who were diagnosed with acute rejection by the local Investigator, but whose for-cause biopsy did not reveal histopathological evidence of rejection according to the Central Pathologist, also did not register 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. Therefore, in case the timings of clinical diagnosis and biopsy confirmation did not coincide, the later date was used to measure the time interval. For patients who experienced more than one BCAR, episodes subsequent to the first diagnosis were disregarded. Considering only those patients who registered a primary endpoint, the median and full range are presented here. Time to first BCAR was also analysed by Kaplan-Meier method (results not shown here).

Secondary

Within 60 weeks following renal transplantation.

The severity of BCAR was assessed according to clinical criteria. Investigators were asked to grade the severity of a clinically-diagnosed rejection episode 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. For each patient who registered a primary endpoint, severity grades from the first BCAR episode were collected for analysis. For patients who experienced more than one episode of BCAR, episodes subsequent to the first diagnosis were disregarded.

Secondary

Within 60 weeks following renal transplantation.

The severity of BCAR was evaluated according to the histopathological grading provided by the Central Pathologist. In the eCRF, the options for grading acute rejection pathology were: “Antibody-mediated changes (ABMR)”, “Acute T cell-mediated rejection (TCMR) IA”, “Acute TCMR IB”, “Acute TCMR IIA”, Acute TCMR IIB”, “Acute TCMR III” and “Borderline changes”. These options were not necessarily mutually exclusive. It was possible for the pathologist to select “Mixed ABMR + TCMR” and specify both ABMR and TCMR sub-classifications. For each patient who registered a primary endpoint, severity grades from the first BCAR episode were collected for analysis. For patients who experienced more than one episode of BCAR, episodes subsequent to the first diagnosis were disregarded.

Secondary

Within 60 weeks following renal transplantation.

An ADR was defined as any AE with a reasonable possibility of a causal relationship to any of the study-specific drugs (basiliximab, IV prednisolone, oral prednisolone, MMF/MPA, tacrolimus), as judged by the reporting Investigator. Investigator-reported terms (verbatim) were coded using MedDRA version 19.0. To calculate the prevalence of ADRs, multiple occurrences of the same event (Preferred Term) in one individual were counted only once. For the purposes of this study, graft rejection was exempt from AE reporting.

Secondary

The observation period was from 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. Events starting before this period of observation were excluded.

Infections were assessed by systematically collecting information on Serious Adverse Events (SAEs) and Adverse Events (AEs) at the regular trial follow-up visits. Viral loads of CMV, EBV and BKV were measured at Visits 4, 5 and 6 or at 4 week intervals after anti-viral chemoprophylaxis had been completed. The patients were also screened for clinical evidence of bacterial, viral and fungal infections at these three time points. Investigator-reported terms (verbatim) were coded using MedDRA version 19.0. The number of patients who experienced at least one AE belonging to the MedDRA SOC: "Infections and infestations" is reported here.

Secondary

The observation period was from 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. Events starting before this period of observation were excluded.

Neoplasms were assessed by systematically collecting information on Serious Adverse Events (SAEs) and Adverse Events (AEs) at the regular trial follow-up visits. The trial protocol recommended a formal dermatological assessment at Visit 10 (final visit) to screen for signs of skin malignancy. Investigator-reported terms (verbatim) were coded using MedDRA version 19.0. The number of patients who experienced at least one AE belonging to the MedDRA SOC: "Neoplasms benign, malignant and unspecified" is reported here.

Secondary

The observation period was from 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. Events starting before this period of observation were excluded.

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 teams 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) were monitored by source data verification and then coded using MedDRA version 19.0.

19.0

Standard immunosuppressive regimen