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

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ClinicalTrials.gov Identifier: NCT02444429
Recruitment Status : Recruiting
First Posted : May 14, 2015
Last Update Posted : April 19, 2023
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
Estimated 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 : September 2015
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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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
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Primary Outcome Measures :
  1. Evolution of graft inflammatory lesions [ Time Frame: 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 :
  1. Graft function at 1 year post-transplantation [ Time Frame: 9 months ]
    Measurement of the glomerular filtration rate by iohexol clearance at 1 year post transplantation (unit: ml/min:1.73m2)

  2. Graft function at 1 year post-transplantation [ Time Frame: 9 months ]
    Evolution of proteinuria between 3 months and 1 year (unit: g/24h).

  3. Evolution of chronic histological lesions [ Time Frame: 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))

  4. Evolution of chronic histological lesions [ Time Frame: 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)

  5. Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation [ Time Frame: 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)

  6. Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation [ Time Frame: 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)

  7. Evaluation of the immunological risk associated with the different strategies of corticosteroid treatment adaptation [ Time Frame: 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)

  8. Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation [ Time Frame: 9 months ]
    Comparison of the data from the Holter monitor taken between 3 months and 1 year post-transplantation. (unit = mm of Hg)

  9. Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation [ Time Frame: 9 months ]
    Comparison of the data from the orally induced hyperglycemia test taken between 3 months and 1 year post-transplantation. (unit = mmol/l)

  10. Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation [ Time Frame: 9 months ]
    Comparison of the data from the lipid profile taken between 3 months and 1 year post-transplantation. (unit = mmol/l)

  11. Evaluation of the metabolic tolerance profile associated with the different strategies of corticosteroid treatment adaptation [ Time Frame: 9 months ]
    Comparison of the data from the bone mineral density, taken between 3 months and 1 year post-transplantation. (unit = g/cm2)

  12. Evaluation of the infectious tolerance profile associated with the different strategies of corticosteroid treatment adaptation [ Time Frame: 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)

  13. Evaluation of the impact of the different strategies for corticosteroid use on quality of life. [ Time Frame: 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
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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02444429


Contacts
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Contact: Olivier THAUNAT, MD 472 110 150 ext +33 olivier.thaunat@chu-lyon.fr

Locations
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France
Service de Néphrologie,Transplantation, Dialyse I - Hôpital Pellegrin - CHU Bordeaux Recruiting
Bordeaux, France, 33000
Contact: Pierre MERVILLE, MD    556 795 538 ext +33    pierre.merville@chu-bordeaux.fr   
Principal Investigator: Pierre MERVILLE, MD         
Service de Néphrologie, Hémodialyse, Transplantations Rénales - Hôpital de la Cavale Blanche - CHU de Brest Recruiting
BREST Cedex, France, 29609
Contact: Yannick LE MEUR, MD    298 347 074 ext +33    yannick.lemeur@chu-brest.fr   
Principal Investigator: Yannick LE MEUR, MD         
Service de Néphrologie - Hôpital Claude Huriez - CHU de Lille Recruiting
Lille, France, 59037
Contact: Marc HAZZAN, MD    320 446 770 ext +33    marc.hazzan-2@univ-lille2.fr   
Principal Investigator: Marc HAZZAN, MD         
Service de Néphrologie, Transplantation et Immunologie Clinique - Hôpital Edouard Herriot - Hospices Civils de Lyon Recruiting
LYON Cedex 03, France, 69437
Contact: Olivier THAUNAT, MD    472 110 150 ext +33    olivier.thaunat@chu-lyon.fr   
Principal Investigator: Olivier THAUNAT, MD         
Sub-Investigator: Emmanuel MORELON, MD         
Sub-Investigator: Valérie HERVIEU, MD         
Institut de Transplantation, Urologie et Néphrologie (ITUN) - CHU de Nantes Recruiting
NANTES cedex 01, France, 44093
Contact: Gilles BLANCHO, MD    240 087 410 ext +33    gilles.blancho@chu-nantes.fr   
Principal Investigator: Gilles BLANCHO, MD         
Unité de Transplantation Rénale - Hôpital Pasteur - CHU de Nice Withdrawn
Nice, France, 06202
Service de Néphrologie et Transplantation - Hôpital Saint-Louis Withdrawn
PARIS Cedex 10, France, 75475
Service de Transplantation - Hôpital Universitaire Necker Recruiting
Paris, France, 75015
Contact: Dany ANGLICHEAU, MD    144 495 355 ext +33    dany.anglicheau@nck.aphp.fr   
Principal Investigator: Dany ANGLICHEAU, MD         
Service Urgences Néphrologiques et Transplantation Rénale - Hôpital Tenon Withdrawn
Paris, France, 75020
Service de Néphrologie et Transplantation - Nouvel Hôpital Civil - CHRU Strasbourg Recruiting
Strasbourg, France, 67091
Contact: Sophie CAILLARD OHLMANN, MD         
Principal Investigator: Sophie CAILLARD OHLMANN, MD         
Département de Néphrologie et Transplantation d'Organes - Hôpital Rangueil - CHU de Toulouse Recruiting
TOULOUSE Cedex 9, France, 31059
Contact: Nassim KAMAR, MD    561 322 335 ext +33    kamar.n@chu-toulouse.fr   
Principal Investigator: Nassim KAMAR, MD         
Sponsors and Collaborators
Hospices Civils de Lyon
Investigators
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Principal Investigator: Olivier THAUNAT, MD Hospices Civils de Lyon
More Information
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Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT02444429    
Other Study ID Numbers: 2014.848
2014-005425-13 ( EudraCT Number )
First Posted: May 14, 2015    Key Record Dates
Last Update Posted: April 19, 2023
Last Verified: April 2023
Keywords provided by Hospices Civils de Lyon:
Screening renal biopsy
Immunosuppression
Additional relevant MeSH terms:
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Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
 Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents