Clinical trial NCT02328963: Proportion of CMV Seropositive Kidney Transplant Recipients Who Will Develop a CMV Infection When Treated With an Immunosuppressive Regimen Including Everolimus and Reduced Dose of Cyclosporine Versus an Immunosuppressive Regimen With Mycophenolic Acid and Standard Dose of Cyclosporine A
Official title: A Multicenter, Two Arms, Randomized, Open Label Clinical Phase IV Study Investigating the Proportion of CMV Seropositive Kidney Transplant Recipients Who Will Develop a CMV Infection Within the First 6 Months Post-transplantation When Treated With an Immunosuppressive Regimen Including Everolimus (Certican®) and Reduced Dose of Cyclosporine A (Neoral®) Versus an Immunosuppressive Regimen With Mycophenolic Acid (Myfortic®) and Standard Dose of Cyclosporine A (Neoral®).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Transplantation Infection
Cytomegalovirus Infection
Keywords: Cytomegalovirus infection and disease
CMV-seropositive recipients
Everolimus
preemptive strategy
mTOR inhibitor
Lead sponsor: University Hospital, Bordeaux
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2014-12-31
Enrollment: 186
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Cytomegalovirus (CMV) infection is the most frequent opportunistic viral infection after transplantation. It is associated with an increased incidence of acute rejection and lower graft and patient survivals. The goal of this study is to demonstrate that an immunosuppressive regimen associating everolimus and reduced dose of cyclosporine A can prevent acute rejection episodes as efficiently as standard regimen but also efficiently reduce the incidence of CMV infection at 6 months post-transplantation.

Detailed description: Cytomegalovirus (CMV) infection is the most frequent opportunistic viral infection after kidney transplantation. Therefore most of the patients receive an universal prophylaxis. On the contrary to CMV naïve patients, seropositive recipients (R+) have already mounted a specific immunologic response directed against the virus, which is not completely abrogated by immunosuppressive drugs. Although CMV infection management guidelines offer little guidance on immunosuppressive therapy for preventing CMV infection and disease, recent data plead for reappraising the place of mTOR inhibitors in this situation. The potential anti-CMV action of these molecules could be added to their potential antitumor effect and their equivalent immunosuppressive efficacy in kidney transplant recipients at low immunological risk. By the way, it could represent an alternative of a systematic universal prophylaxis in R+ kidney transplant recipients. However, the proof of this anti-CMV action must be confirmed in vivo in a study, which could have a close monitoring of CMV infection.

We therefore designed a prospective multicentric randomized controlled trial comparing an immunosuppressive regimen based on everolimus and reduced dose of cyclosporine A to a regimen based on mycophenolic acid and standard dose of cyclosporine A, in order to demonstrate the superiority of the first one in the prevention of CMV infection.

Subjects will be randomized to one of the two treatment arms and will be followed for a period of 12 months. Whole blood CMV real time PCR will be performed every week during the first three months, then every two weeks from Month 3 to Month 6, then at Months 8, 10 and 12. Incidence of CMV infection will be compared between the two arms at 6 and 12 months post-transplantation.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years.
* End stage kidney disease and a suitable candidate for primary renal transplantation or re-transplantation.
* Patient seropositive for CMV (confirmed within two weeks post-transplant) and having received an allograft from a CMV seropositive or seronegative donor.
* Receiving a kidney transplant from a deceased or living donor with compatible ABO blood type.
* Female subject of childbearing potential must have a negative serum pregnancy test at enrollment and must agree to maintain effective birth control during the study and two months later the discontinuation of the test drug.
* Total ischemia time below 36 hours.
* Capable of understanding the purpose and risks of the study.
* Fully informed and having given written informed consent (signed Informed Consent has been obtained).
* Affiliation to the social security regimen

Exclusion Criteria:

* CMV seronegative patient.
* Historical or current TGI (French equivalence of calculated PRA) \> 85 %
* Presence of historical or current anti-HLA donor specific antibodies
* Patient who received anti-CMV therapy within the past 30 days prior to screening.
* Receiving or having previously received an organ transplant other than a kidney.
* Receiving a graft from a non-heart-beating donor.
* Patient known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B (HBV; HBs Ag positive) or Hepatitis C (HCV; anti-HCV Ab positive).elevated SGPT/ALT and/or SGOT/AST and/or total bilirubin levels ≥ 2 times the upper value of the normal range of the investigational site or receiving a graft from a hepatitis C or B positive donor.
* Significant, uncontrolled concomitant infections and/or severe diarrhea, vomiting, active upper gastro-intestinal tract malabsorption or active peptic ulcer.
* Known allergy or intolerance to everolimus, valganciclovir, ganciclovir, mycophenolic acid, basiliximab, corticosteroids, or cyclosporine A or any of the product excipients.
* Severe hyperlipidemia defined by: total cholestérol ≥ 9,1 mmol/L (≥ 350 mg/dL) et/ou triglycérides ≥ 8,5 mmol/l (≥ 750 mg/dL) in spite an adequate medication.
* Patient has adequate hematological post-transplant defined as:

  1. Absolute neutrophil count (ANC) \> 1000 cells/μL.
  2. Platelet count \> 50,000 cells/μL.
  3. Hemoglobin \> 8.0 g/dL.
* Requiring initial therapy with induction immunosuppressive antibody preparations, such as anti-thymocyte globulins or rituximab or IVIG.
* Currently participating in another clinical trial investigating drugs. Observational studies are not considered as an exclusion criteria
* Any form of substance abuse, psychiatric disorder or condition which, in the opinion of the investigator, may complicate communication with the investigator.
* Unlikely to comply with the visits scheduled in the protocol.

Primary outcomes:
measure: Number of participants without CMV infection and without graft loss in CMV seropositive kidney transplant recipients.
timeFrame: 6 months post-transplantation
Secondary outcomes:
measure: Proportion of patients who will develop CMV disease
timeFrame: 6 and 12 months post-transplantation
measure: Proportion of patient with graft loss, death and loss of follow-up
timeFrame: 12 months post-transplantation
measure: Proportion of patient with acute rejection, graft loss, death and loss of follow-u
timeFrame: 12 months
measure: Level to the first CMV DNAemia
timeFrame: Throughout the study
measure: Time to the first CMV disease
timeFrame: Throughout the study
measure: Proportion of patients treated for CMV infection in both groups
timeFrame: 6 months
measure: Half-life of decreasing of DNAemia
timeFrame: after initiation of anti-CMV therapy
measure: Occurrence of treatment failure, defined as the absence of viral eradication.
timeFrame: Day 49 (or 8 weeks) after the initiation of anti-CMV therapy
measure: Occurrence of CMV mutation (UL97 ou UL54) associated with a resistance to an anti-CMV therapy.
timeFrame: Throughout the study
measure: Graft function
timeFrame: 6 and 12 months post-transplantation
measure: Proportion of patients with biopsy-proven acute rejection (BPAR)
timeFrame: 6 and 12 months post-transplantation
measure: Degree of interstitial fibrosis/tubular atrophy
timeFrame: 12 months on protocol biopsies
measure: Graft and patient survival
timeFrame: 6 and 12 months post-transplantation
measure: Proportion of BK virus viremia
timeFrame: month 1, 3, 6 and 12
measure: Proportion of patients with adverse events (AE) and/or serious adverse events (SAE) including opportunistic infections and neoplasias.
timeFrame: 12 months
measure: Proportion of patients with haematological disorders
timeFrame: 12 months
measure: Proportion of patients with diarrhea
timeFrame: 12 months
measure: Proportion of dyslipidemia
timeFrame: 12 months
measure: Proportion of patients with occurrence of New Onset Diabetes Mellitus as defined by American Diabetic Association (ADA) criteria.
timeFrame: 12 months
measure: Proportion of patients who will discontinue the immunosuppressive treatment and the reasons why.
timeFrame: 12 months
measure: Proportion of patients with delayed graft function
timeFrame: 12 months
measure: Proportion of lymphocele
timeFrame: 12 months
measure: Time to the first CMV DNAemia
timeFrame: Throughout the study
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU de Bordeaux
city: Brest
country: France
facility: CHU La Cavale Blanche
city: Caen
country: France
facility: CHRU Caen - Hôpital de Caen
city: Limoges
country: France
facility: CHU de Limoges - Hôpital Dupuytren
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Paris
country: France
facility: APHP - Hôpital Necker
city: Paris
country: France
facility: APHP - Kremlin Bicetre
city: Strasbourg
country: France
facility: CHRU Strasbourg
city: Toulouse
country: France
facility: CHU de Toulouse - Hôpital Rangueil
Study officials:
affiliation: University Hospital, Bordeaux
name: Lionel COUZI, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Bordeaux
name: Rodolphe THIEBAUT, MD, PhD
role: STUDY_CHAIR
References:
citation: Kaminski H, Marseres G, Yared N, Nokin MJ, Pitard V, Zouine A, Garrigue I, Loizon S, Capone M, Gauthereau X, Mamani-Matsuda M, Coueron R, Duran RV, Pinson B, Pellegrin I, Thiebaut R, Couzi L, Merville P, Dechanet-Merville J. mTOR Inhibitors Prevent CMV Infection through the Restoration of Functional alphabeta and gammadelta T cells in Kidney Transplantation. J Am Soc Nephrol. 2022 Jan;33(1):121-137. doi: 10.1681/ASN.2020121753. Epub 2021 Nov 1.