Clinical trial NCT02444429: 3-month Screening Biopsy to Optimize the Immunosuppression in Renal Transplantation
Official title: Evaluation of a Strategy Based on the 3-month Screening Biopsy to Optimize the Immunosuppression in Renal Transplantation: the I4BiS Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Renal Transplantation
Keywords: Screening renal biopsy
Immunosuppression
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2015-05-14
Enrollment: 346
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.


Eligibility criteria: Inclusion Criteria:

1. 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
2. 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)
3. Specific to sub-study B Absence of significant inflammatory infiltrates (i0-1 and t0) on the screening biopsy at 3 months

Exclusion Criteria:

1. 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
2. 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

Primary outcomes:
measure: Evolution of graft inflammatory lesions
timeFrame: 9 months
Secondary outcomes:
measure: Graft function at 1 year post-transplantation
timeFrame: 9 months
measure: Graft function at 1 year post-transplantation
timeFrame: 9 months
measure: Evolution of chronic histological lesions
timeFrame: 9 months
measure: Evolution of chronic histological lesions
timeFrame: 9 months
measure: Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation
timeFrame: 9 months
measure: Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation
timeFrame: 9 months
measure: Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation
timeFrame: 9 months
measure: Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation
timeFrame: 9 months
measure: Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation
timeFrame: 9 months
measure: Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation
timeFrame: 9 months
measure: Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation
timeFrame: 9 months
measure: Evaluation of the infectious tolerance profile associated with the different strategies of corticosteroid treatment adaptation
timeFrame: 9 months
measure: Evaluation of the impact of the different strategies for corticosteroid use on quality of life.
timeFrame: 9 months
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Service de Néphrologie,Transplantation, Dialyse I - Hôpital Pellegrin - CHU Bordeaux
city: BREST Cedex
country: France
facility: Service de Néphrologie, Hémodialyse, Transplantations Rénales - Hôpital de la Cavale Blanche - CHU de Brest
city: Lille
country: France
facility: Service de Néphrologie - Hôpital Claude Huriez - CHU de Lille
city: LYON Cedex 03
country: France
facility: Service de Néphrologie, Transplantation et Immunologie Clinique - Hôpital Edouard Herriot - Hospices Civils de Lyon
city: NANTES cedex 01
country: France
facility: Institut de Transplantation, Urologie et Néphrologie (ITUN) - CHU de Nantes
city: Paris
country: France
facility: Service de Transplantation - Hôpital Universitaire Necker
city: Strasbourg
country: France
facility: Service de Néphrologie et Transplantation - Nouvel Hôpital Civil - CHRU Strasbourg
city: TOULOUSE Cedex 9
country: France
facility: Département de Néphrologie et Transplantation d'Organes - Hôpital Rangueil - CHU de Toulouse
Study officials:
affiliation: Hospices Civils de Lyon
name: Olivier THAUNAT, MD
role: PRINCIPAL_INVESTIGATOR
References: