I4BiS: 3-month Screening Biopsy to Optimize the Immunosuppression in Renal Transplantation

Sponsor

Hospices Civils de Lyon (Other)

Overall Status

Recruiting

CT.gov ID

NCT02444429

Collaborator

(none)

346

Enrollment

Locations

Arms

Anticipated Duration (Months)

31.5

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Renal transplantation represents currently the best therapeutic alternative for end-stage renal failure, not only in terms of patient outcomes (better quality of life and longer survival), but also in terms of costs for the society.

Progress achieved in the last 20 years has resulted in a drastic reduction of the incidence of "classic" (i.e. clinically patent) acute cellular rejection episodes.

Unfortunately, and rather unexpectedly, this progress has had hardly any effect on the frequency of the loss of kidney transplants beyond the first year, as shown by the stagnation of grafts' half lives.

Furthermore, the use of immunosuppressant combinations that are more and more powerful has an impact on adverse effects in recipients, including an increased incidence of infections, cancers, but also metabolic complications (diabetes, osteoporosis, dyslipidemia, etc.), which are cause of significant morbi-mortality.

In an attempt to improve on these disappointing outcomes, some teams have offered to perform screening biopsies: i.e. routine biopsies at specific time points during the follow up, irrespective of graft function. Their primary interest is to allow a pathological analysis of the graft at an early stage, i.e. when potential histological lesions allow for a diagnosis but before these lesions impact on graft's function. Indeed, it has been clearly demonstrated that therapeutic adjustments intended to protect the grafts are most effective when introduced early. There is a fairly broad consensus to perform these biopsies three months and one year after the transplantation. Performing screening biopsies has led to the identification of "subclinical" forms of rejection, i.e. graft infiltration by recipient immune effectors meeting the Banff histological criteria, but without increase in creatininemia.

Assuming that about 10% of screening biopsies performed at 3 months reveal a subclinical rejection, which needs to be treated, the management strategy for the remaining 90% of patients, whose biopsies show either i) a mild inflammatory infiltrates: i.e. "borderline changes", or ii) the complete absence of immune effectors in the graft is, poorly standardized.

The investigators therefore propose to conduct a prospective randomized trial to answer these questions simultaneously by evaluating a strategy to optimize the immunosuppression of renal graft recipients based on the presence or absence of subclinical intragraft inflammatory infiltrates in the screening biopsy performed at 3 months post transplantation. Patients with borderline changes (sub-study A) will be randomized to receive a treatment for rejection (corticosteroid boluses). Patients without inflammation in their graft (sub-study B) will be randomized for corticosteroid withdrawal. Impact on graft function, progression of histological lesions and incidence of morbidity will be evaluated.

Condition or Disease	Intervention/Treatment	Phase
Renal Transplantation	Drug: Corticosteroid boluses Methylprednisolone Other: No therapeutic modification Other: Stop maintenance corticotherapy	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

346 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Supportive Care

Official Title:

Evaluation of a Strategy Based on the 3-month Screening Biopsy to Optimize the Immunosuppression in Renal Transplantation: the I4BiS Study

Actual Study Start Date :

Sep 1, 2015

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sub-study A experimental arm This experimental arm corresponds to patients with "borderline" infiltrates at 3 months, who will be randomized to receive a treatment for rejection (intensification of the corticotherapy with corticosteroid boluses = Corticosteroid boluses Methylprednisolone )	Drug: Corticosteroid boluses Methylprednisolone Intensification of the corticotherapy in accordance with the validated protocol for the treatment of "classic" and subclinical acute rejections: 3 bolus Methylprednisolone 500 mg IV at D1, D2 and D3 then decreasing during 10-15 days at 1mg/kg/d and down to the maintenance dose. An anti-pneumocystis and anti-CMV prophylaxis will be systemically introduced for 3 months. The rest of maintenance immunosuppressive regimen (mycophenolate mofetil and anti-calcineurin) will remain unaltered
Active Comparator: Sub-study A control arm This control arm corresponds to patients with "borderline" infiltrates at 3 months, who will be randomized to not change their immunosuppressive treatment (No therapeutic modification)	Other: No therapeutic modification No therapeutic modification: continuation of the corticotherapy at the maintenance dose and maintaining unaltered the rest of immunosuppressive treatment (mycophenolate mofetil and anti-calcineurin).
Experimental: Sub-study B experimental arm This experimental arm corresponds to patients without significant infiltrates 3 months, who will be randomized to stop maintenance corticotherapy (Stop maintenance corticotherapy )	Other: Stop maintenance corticotherapy Immediate withdrawal of maintenance corticotherapy. Maintaining unaltered the rest of immunosuppressive treatment (mycophenolate mofetil and anti-calcineurin).
Active Comparator: Sub-study B control arm This control arm corresponds to patients without significant infiltrates 3 months, who will be randomized to not change their immunosuppressive treatment (No therapeutic modification)	Other: No therapeutic modification No therapeutic modification: continuation of the corticotherapy at the maintenance dose and maintaining unaltered the rest of immunosuppressive treatment (mycophenolate mofetil and anti-calcineurin).

Outcome Measures

Primary Outcome Measures

Evolution of graft inflammatory lesions [9 months]
Interstitial infiltrate (i) and tubulitis (t) will be scored at 3 months and 1 year post transplantation using Banff classification (patients will be recruted 3 months after transplantation) A) Patient with "borderline" infiltrates at 3 months will be randomized to receive a treatment for rejection (sub-study A), with the aim of demonstrating the superiority of this strategy in terms of infiltrates involution (superiority study). B) Patient without significant infiltrates at 3 months will be randomized for maintenance corticotherapy withdrawal (sub-study B), with the aim of showing that this strategy does not cause an increase in the percentage of "borderline" infiltrates compared to the strategy that maintains the corticotherapy (non-inferiority study).

Secondary Outcome Measures

Graft function at 1 year post-transplantation [9 months]
Measurement of the glomerular filtration rate by iohexol clearance at 1 year post transplantation (unit: ml/min:1.73m2)
Graft function at 1 year post-transplantation [9 months]
Evolution of proteinuria between 3 months and 1 year (unit: g/24h).
Evolution of chronic histological lesions [9 months]
Interstitial fibrosis will be quantified at 3 months and 1 year using a computerized color image analysis technique (unit = % fibrosis = 100*(green interstitial pixels / total interstitial pixels))
Evolution of chronic histological lesions [9 months]
The 4 basic chronic lesions (unit = chronic glomerular damage [cg]; interstitial fibrosis [ci]; tubular fibrosis [ct]; vascular intimal thickening [cv]) will be scored at 3 months and 1 year using Banff classification)
Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation [9 months]
Percentage of patients showing the appearance of donor specific anti-HLA antibodies using the Luminex method® between the randomization (3 months) and the end of follow-up (1 year). (unit = % of patient)
Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation [9 months]
Proportion of patients showing an increase in humoral lesions (Banff score g+ptc) ≥ 2 on the screening biopsy at 1-year between the randomization (3 months) and the end of follow-up (1 year). (unit = % of patient)
Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation [9 months]
Proportion of patients showing ≥ 1 acute rejection episodes (cellular or humoral) proven by biopsy between the randomization (3 months) and the end of follow-up (1 year). (unit = % of patient)
Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation [9 months]
Comparison of the data from the Holter monitor taken between 3 months and 1 year post-transplantation. (unit = mm of Hg)
Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation [9 months]
Comparison of the data from the orally induced hyperglycemia test taken between 3 months and 1 year post-transplantation. (unit = mmol/l)
Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation [9 months]
Comparison of the data from the lipid profile taken between 3 months and 1 year post-transplantation. (unit = mmol/l)
Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation [9 months]
Comparison of the data from the bone mineral density, taken between 3 months and 1 year post-transplantation. (unit = g/cm2)
Evaluation of the infectious tolerance profile associated with the different strategies of corticosteroid treatment adaptation [9 months]
Number of infectious episodes requiring treatment during the follow-up period between the randomization (3 months) and the end of follow-up (1 year). (unit = nb of episode)
Evaluation of the impact of the different strategies for corticosteroid use on quality of life. [9 months]
Evolution of the patients' quality of life using self-questionnaires, adapted and validated for the French language (SF36), between the randomization (3 months) and the end of follow-up (1 year). (unit = SF 36 score)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Common to both sub-studies (A and B)

Renal transplant patient aged between 18 and 75.
Patient who received a first or second renal graft
Immunosuppressive treatment consisting of an anti-calcineurin [cyclosporine (trough levels: 150<T0<300)], or tacrolimus (trough levels: 8<T0<12), mycophenolate mofetil and corticosteroids.
Patient who benefited from a screening renal biopsy 3 months after the graft
Patient who gave their informed consent
Patient affiliated to a social security scheme or being a beneficiary of such a scheme

Specific to sub-study A

Presence of "borderline" inflammatory infiltrates on the screening biopsy at 3 months as defined by the Banff classification 2013:
Absence of vascular lesions (v0) and:
tubulitis regardless of its significance (t1-3) with minimum interstitial infiltrate (i0-i1) OR
interstitial infiltrates (i2-3) without significant tubulitis (≤ t1)

Specific to sub-study B Absence of significant inflammatory infiltrates (i0-1 and t0) on the screening biopsy at 3 months

Exclusion Criteria:

Common to both sub-studies (A and B)

Histological subclinical rejection criteria on the screening biopsy at 3 months (Banff 2009: > i2+t2)
Donor specific antibodies in historical serum or de novo appearance during the first 3 months
Humoral lesions on the 3-month biopsy (Banff score g+ptc>2)
"Classic" acute rejection episode proven by biopsy during the first 3 months
Multiorgan transplantation
3rd (or subsequent) renal transplantation
BK virus-associated nephropathy on the screening biopsy
Contraindication to the 1-year screening biopsy

Specific to sub-study B Initial nephropathy with a high risk of recurrence on corticosteroid withdrawal: segmental and focal and segmental glomerulosclerosis, lupus nephritis, vasculitis, or membranous glomerulonephritis

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Service de Néphrologie,Transplantation, Dialyse I - Hôpital Pellegrin - CHU Bordeaux	Bordeaux	France	33000
2	Service de Néphrologie, Hémodialyse, Transplantations Rénales - Hôpital de la Cavale Blanche - CHU de Brest	BREST Cedex	France	29609
3	Service de Néphrologie - Hôpital Claude Huriez - CHU de Lille	Lille	France	59037
4	Service de Néphrologie, Transplantation et Immunologie Clinique - Hôpital Edouard Herriot - Hospices Civils de Lyon	LYON Cedex 03	France	69437
5	Institut de Transplantation, Urologie et Néphrologie (ITUN) - CHU de Nantes	NANTES cedex 01	France	44093
6	Unité de Transplantation Rénale - Hôpital Pasteur - CHU de Nice	Nice	France	06202
7	Service de Néphrologie et Transplantation - Hôpital Saint-Louis	PARIS Cedex 10	France	75475
8	Service de Transplantation - Hôpital Universitaire Necker	Paris	France	75015
9	Service Urgences Néphrologiques et Transplantation Rénale - Hôpital Tenon	Paris	France	75020
10	Service de Néphrologie et Transplantation - Nouvel Hôpital Civil - CHRU Strasbourg	Strasbourg	France	67091
11	Département de Néphrologie et Transplantation d'Organes - Hôpital Rangueil - CHU de Toulouse	TOULOUSE Cedex 9	France	31059