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Trial record 7 of 36 for:    "Viral Infectious Disease" | "Everolimus"

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 (EVERCMV)

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ClinicalTrials.gov Identifier: NCT02328963
Recruitment Status : Completed
First Posted : December 31, 2014
Last Update Posted : November 14, 2018
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
University Hospital, Bordeaux

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.

Condition or disease Intervention/treatment Phase
Transplantation Infection Cytomegalovirus Infection Drug: Everolimus Drug: mycophenolic acid Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 186 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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®).
Actual Study Start Date : May 2, 2014
Actual Primary Completion Date : October 10, 2018
Actual Study Completion Date : October 10, 2018


Arm Intervention/treatment
Experimental: Everolimus
Everolimus + reduced dose of cyclosporine A
Drug: Everolimus

Everolimus : 0.75 bid, targeted to 3-8 ng/ml

Cyclosporin A :

CsA target ranges for Arm 1 will be 100-200 ng/mL from Day 3 to Month 2, decreasing to 75-150 ng/mL from Month 2 to Month 4 and 25-50 ng/mL from Months 6 to 12.

Corticosteroids :

Méthylprednisolone: 500 mg at Day 0, 120 mg à Day 1. Prednisone or equivalent: 20 mg/d from Day 3. Corticosteroid dosing will be tapered according to center standard practice but to not less than 5 mg per day for the duration of the 12-month study

Basiliximab :Day 0: 20 mg ; Day 4: 20 mg


Active Comparator: mycophenolic acid
mycophenolic acid + standard dose of cyclosporin A
Drug: mycophenolic acid

Mycophenolic acid :

1080 mg bid for one month, then 720 mg bid

Cyclosporin A :

CsA target ranges for Arm 1 will be 100-200 ng/mL from Day 3 to Month 2, decreasing to 75-150 ng/mL from Month 2 to Month 4 and 25-50 ng/mL from Months 6 to 12.

Corticosteroids :

Méthylprednisolone: 500 mg at Day 0, 120 mg à Day 1. Prednisone or equivalent: 20 mg/d from Day 3. Corticosteroid dosing will be tapered according to center standard practice but to not less than 5 mg per day for the duration of the 12-month study

Basiliximab :Day 0: 20 mg ; Day 4: 20 mg





Primary Outcome Measures :
  1. Number of participants without CMV infection and without graft loss in CMV seropositive kidney transplant recipients. [ Time Frame: 6 months post-transplantation ]
    The primary objective of this study is to compare the survival without CMV infection and without graft loss in CMV seropositive kidney transplant recipients, within the first 6 months post-transplantation when treated with an immunosuppressive regimen including everolimus (Certican®) and reduced dose (RD) of cyclosporine A (Néoral®) versus an immunosuppressive regimen with mycophenolic acid (Myfortic®) and standard dose (SD) of cyclosporine A (Néoral®).


Secondary Outcome Measures :
  1. Proportion of patients who will develop CMV disease [ Time Frame: 6 and 12 months post-transplantation ]
    The proportion of patients who will develop CMV disease during the first 6 and 12 months post-transplantation (CMV disease includes both CMV syndrome and CMV tissue-invasive disease).

  2. Proportion of patient with graft loss, death and loss of follow-up [ Time Frame: 12 months post-transplantation ]
  3. Proportion of patient with acute rejection, graft loss, death and loss of follow-u [ Time Frame: 12 months ]
  4. Level to the first CMV DNAemia [ Time Frame: Throughout the study ]
  5. Time to the first CMV disease [ Time Frame: Throughout the study ]
  6. Proportion of patients treated for CMV infection in both groups [ Time Frame: 6 months ]
  7. Half-life of decreasing of DNAemia [ Time Frame: after initiation of anti-CMV therapy ]
  8. Occurrence of treatment failure, defined as the absence of viral eradication. [ Time Frame: Day 49 (or 8 weeks) after the initiation of anti-CMV therapy ]
  9. Occurrence of CMV mutation (UL97 ou UL54) associated with a resistance to an anti-CMV therapy. [ Time Frame: Throughout the study ]
  10. Graft function [ Time Frame: 6 and 12 months post-transplantation ]
    Graft function defined as glomerular filtration rate (GFR) estimated by simplified MDRD formula and proteinuria/creatininuria ratio.

  11. Proportion of patients with biopsy-proven acute rejection (BPAR) [ Time Frame: 6 and 12 months post-transplantation ]
  12. Degree of interstitial fibrosis/tubular atrophy [ Time Frame: 12 months on protocol biopsies ]
  13. Graft and patient survival [ Time Frame: 6 and 12 months post-transplantation ]
  14. Proportion of BK virus viremia [ Time Frame: month 1, 3, 6 and 12 ]
  15. Proportion of patients with adverse events (AE) and/or serious adverse events (SAE) including opportunistic infections and neoplasias. [ Time Frame: 12 months ]
  16. Proportion of patients with haematological disorders [ Time Frame: 12 months ]
    The proportion of patients with haematological disorders (neutropenia, anaemia, thrombopenia)

  17. Proportion of patients with diarrhea [ Time Frame: 12 months ]
  18. Proportion of dyslipidemia [ Time Frame: 12 months ]
  19. Proportion of patients with occurrence of New Onset Diabetes Mellitus as defined by American Diabetic Association (ADA) criteria. [ Time Frame: 12 months ]
  20. Proportion of patients who will discontinue the immunosuppressive treatment and the reasons why. [ Time Frame: 12 months ]
  21. Proportion of patients with delayed graft function [ Time Frame: 12 months ]
  22. Proportion of lymphocele [ Time Frame: 12 months ]
  23. Time to the first CMV DNAemia [ Time Frame: Throughout the study ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT02328963


Locations
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France
CHU de Bordeaux
Bordeaux, France, 33000
CHU La Cavale Blanche
Brest, France, 29609
CHRU Caen - Hôpital de Caen
Caen, France, 14033
CHU de Limoges - Hôpital Dupuytren
Limoges, France
Hôpital Edouard Herriot
Lyon, France, 69003
APHP - Hôpital Necker
Paris, France, 75015
APHP - Kremlin Bicetre
Paris, France, 94275
CHRU Strasbourg
Strasbourg, France
CHU de Toulouse - Hôpital Rangueil
Toulouse, France, 31000
Sponsors and Collaborators
University Hospital, Bordeaux
Novartis
Investigators
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Principal Investigator: Lionel COUZI, MD University Hospital, Bordeaux
Study Chair: Rodolphe THIEBAUT, MD, PhD University Hospital, Bordeaux

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Responsible Party: University Hospital, Bordeaux
ClinicalTrials.gov Identifier: NCT02328963     History of Changes
Other Study ID Numbers: CHUBX2012/29
First Posted: December 31, 2014    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: November 2018
Keywords provided by University Hospital, Bordeaux:
Cytomegalovirus infection and disease
CMV-seropositive recipients
Everolimus
preemptive strategy
mTOR inhibitor
Additional relevant MeSH terms:
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DNA Virus Infections
Virus Diseases
Everolimus
Infection
Communicable Diseases
Cytomegalovirus Infections
Herpesviridae Infections
Sirolimus
Mycophenolic Acid
Cyclosporine
Cyclosporins
Immunosuppressive Agents
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Dermatologic Agents
Antirheumatic Agents
Calcineurin Inhibitors
Antibiotics, Antitubercular
Antitubercular Agents