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

Renal Transplantation Clinical Trial

— I4BiS  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02444429
• Other study ID #: 2014.848
• Secondary ID: 2014-005425-13
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 2015
• Est. completion date: December 2024

Study information

• Verified date: May 2024
• Source: Hospices Civils de Lyon
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 346
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Renal Transplantation

Intervention

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

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).
• Stop maintenance corticotherapy
Immediate withdrawal of maintenance corticotherapy. Maintaining unaltered the rest of immunosuppressive treatment (mycophenolate mofetil and anti-calcineurin).

Locations

Country	Name	City	State
France	Service de Néphrologie,Transplantation, Dialyse I - Hôpital Pellegrin - CHU Bordeaux	Bordeaux
France	Service de Néphrologie, Hémodialyse, Transplantations Rénales - Hôpital de la Cavale Blanche - CHU de Brest	BREST Cedex
France	Service de Néphrologie - Hôpital Claude Huriez - CHU de Lille	Lille
France	Service de Néphrologie, Transplantation et Immunologie Clinique - Hôpital Edouard Herriot - Hospices Civils de Lyon	LYON Cedex 03
France	Institut de Transplantation, Urologie et Néphrologie (ITUN) - CHU de Nantes	NANTES cedex 01
France	Service de Transplantation - Hôpital Universitaire Necker	Paris
France	Service de Néphrologie et Transplantation - Nouvel Hôpital Civil - CHRU Strasbourg	Strasbourg
France	Département de Néphrologie et Transplantation d'Organes - Hôpital Rangueil - CHU de Toulouse	TOULOUSE Cedex 9

Sponsors (1)

Lead Sponsor	Collaborator
Hospices Civils de Lyon

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evolution of graft inflammatory lesions	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).	9 months
Secondary	Graft function at 1 year post-transplantation	Measurement of the glomerular filtration rate by iohexol clearance at 1 year post transplantation (unit: ml/min:1.73m2)	9 months
Secondary	Graft function at 1 year post-transplantation	Evolution of proteinuria between 3 months and 1 year (unit: g/24h).	9 months
Secondary	Evolution of chronic histological lesions	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))	9 months
Secondary	Evolution of chronic histological lesions	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)	9 months
Secondary	Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation	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)	9 months
Secondary	Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation	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)	9 months
Secondary	Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation	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)	9 months
Secondary	Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation	Comparison of the data from the Holter monitor taken between 3 months and 1 year post-transplantation. (unit = mm of Hg)	9 months
Secondary	Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation	Comparison of the data from the orally induced hyperglycemia test taken between 3 months and 1 year post-transplantation. (unit = mmol/l)	9 months
Secondary	Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation	Comparison of the data from the lipid profile taken between 3 months and 1 year post-transplantation. (unit = mmol/l)	9 months
Secondary	Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation	Comparison of the data from the bone mineral density, taken between 3 months and 1 year post-transplantation. (unit = g/cm2)	9 months
Secondary	Evaluation of the infectious tolerance profile associated with the different strategies of corticosteroid treatment adaptation	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)	9 months
Secondary	Evaluation of the impact of the different strategies for corticosteroid use on quality of life.	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)	9 months