Certican® (Everolimus) Against Cytomegalovirus Disease in Renal Transplant Patients (Certi-CMV)

A prospective, randomized safety and efficacy study of Certican® as add-on therapy against CMV disease in renal transplant recipients

OBJECTIVES:

Primary Objective:

To demonstrate efficacy of Certican® as add-on therapy against CMV disease in comparison to either valcyte® (valganciclovir) or cymevene® (ganciclovir) alone, evaluated by quantitative measurement of CMV-DNA with PCR from the blood (qCMV-PCR)

Secondary Objectives:

To assess safety and tolerability of Certican® in patients with CMV- disease To study the effects of Certican® treatment on quality of life

Study Overview

• Status: Unknown
• Conditions: Cytomegalovirus Disease
• Intervention / Treatment: Drug: Certican (everolimus) + valganciclovir; Drug: Valganciclovir

Detailed Description

DESIGN / PHASE Prospective, single-center, randomized, parallel group, controlled, phase II study.

PATIENTS / GROUPS 40 patients in 2 groups 20 patients per group Randomization ratio 1:1, no stratification

INVESTIGATIONAL DRUG Oral MED 1: Certican® initial dose: 1,5-3 mg day target trough level: 3-8 ng/mL (first levels will be performed after 3 days and then adjusted until - according to the judgment of the clinical investigator - a stable degree of immunosuppression is reached; thereafter Certican® trough levels will be performed at the scheduled appointments)

COMPARATIVE DRUG No therapy (add-on design

CONCOMITANT MEDICATION Allowed The concomitant immunosuppressive medication will be adjusted to the additional administration of Certican®. For example, if the patient already receives cyclosporine A or tacrolimus, this will be adjusted, according to the current recommendations4 at the judgment of the clinical investigator

TOLERABILITY / SAFETY ENDPOINTS:

Rejection Hematocrit Platelet count WBC count Wound healing disorders Blood lipids (cholesterol, triglycerides) Infections (other than CMV)

PHARMACOKINETIC / PHARMACODYNAMIC ENDPOINTS Certican® (everolimus) trough levels

STATISTICAL METHODOLOGY Primary Endpoint: CMV-load (copies/mL)

Null and alternative hypotheses:

H0 Treatment with Certican® (everolimus) in combination with valcyte® (valganciclovir) or cymevene® (ganciclovir) is equal to valcyte® (valganciclovir) or cymevene® (ganciclovir) alone in reducing the CMV-load in renal transplant patients with CMV-disease H1: Treatment with Certican® (everolimus) in combination with valcyte® (valganciclovir) or cymevene® (ganciclovir) is superior to valcyte® (valganciclovir) or cymevene® (ganciclovir) in reducing CMV load (copies/mL) in renal transplant patients with CMV-disease Type-I and -II errors - power. α=0.05 ß=0.2 (power 0.8) Statistical methodology ANOVA of repeated measures (CMV-copies/mL), one-sided t-test of CMV load at distinct time-points, one-sided t-test of the time (in weeks) until CMV-load reaches ≤600 copies/mL Sample size calculation Based on a one-sided testing and a σ of 0.2 in relative changes of CMV-copies, an α=0.05 And a ß=0.2 a sample size of 20 patients per group was determined. Main analysis set Per-protocol (efficacy) and intention to treat (ITT) for safety Other endpoints Bonferroni corrected t-tests will be performed for CMV-copies/mL at each time point of the follow-up period. The time to copies ≤ 600 will also be analyzed by a t-test. All other secondary endpoints and subgroup analysis will be performed in explorative intention (descriptive statistics).

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Marcus D Säemann, MD; Phone Number: +431404005593; Email: marcus.saemann@meduniwien.ac.at
• Study Contact Backup: Name: Manfred Hecking, MD; Phone Number: +431404005593; Email: manfred.hecking@meduniwien.ac.at

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Recruiting
    • Medical University of Vienna
    • Sub-Investigator: Manfred Hecking, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• CMV-disease after renal transplantation, i.e.,(1.) CMV present in the blood, and (2.) one of the following symptoms (for viral syndrome, from the American Society of Transplantation recommendations for use in clinical trials1):

  • body temperature ≥ 38°C
  • new or increased significant malaise
  • leucopenia (< 3500/mL)
  • atypical lymphocytosis ≥ 5%
  • thrombocytopenia (platelets < 100.000/mL)
• no other cause of symptoms/signs identified
• informed consent of the patient

Exclusion Criteria:

• patients with a known hypersensitivity to everolimus, sirolimus or any of the excipients
• administration of strong CYP3A4 Inhibitors (e.g. ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin) and inducers (rifampicin), unless the benefit outweighs the risk, according to the judgment of the clinical investigator
• acute rejection episodes in the first 3 months after renal transplantation
• active hepatitis in the previous month
• Significant proteinuria (> 0.8g/24h Urine)
• hepatic impairment, according to the criteria defined by Bénichou et al.2: a singular elevation of GPT or conjugated bilirubin to a value twice above the normal level, or a combined elevation of GOT, AP, and total bilirubin, given that at least one parameter is twice above the normal level
• hematocrit < 25%
• any significant wound healing disorder (anamnestic)
• blood white blood cell (WBC) count < 3000/mL
• platelets < 50.000/mL
• severe dyslipidemia (cholesterol >300mg/dL, triglycerides > 350mg/dL)
• uncontrolled hypertension (continuous episodes of hypertension above 140/90 (WHO classification and American Society of Transplantation recommendations 3) despite adequate hypertensive therapy)
• uncontrolled hyperuricemia (uric acid > 8mg/dL)
• pregnancy
• any immunosuppressive protocol which does not allow the addition of Certican®, according to the judgment of the clinical investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 1 Certican + Valganciclovir; Valganciclovir will be administered and Certican (everolimus) will be added as immunosuppression	Drug: Certican (everolimus) + valganciclovir; Oral MED 1: Certican® initial dose: 1,5-3 mg day target trough level: 3-8 ng/mL (first levels will be performed after 3 days and then adjusted until - according to the judgement of the clinical investigator - a stable degree of immunosuppression is reached; thereafter Certican® trough levels will be performed at the scheduled appointments) MED 2: Valganciclovir (or ganciclovir) will be administered in addition to Certican (valganciclovir: 450 mg twice daily, ganciclovir 5 mg/kg i.v. twice daily)
ACTIVE_COMPARATOR: 2 Valganciclovir alone; Valganciclovir will be added alone.	Drug: Valganciclovir; Valganciclovir (or ganciclovir) will be administered alone (valganciclovir: 450 mg twice daily, ganciclovir 5 mg/kg i.v. twice daily)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
relative changes in CMV-load (copies/mL), as determined by qCMV-PCR from whole blood throughout the observational period	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
CMV-load (copies/mL) after 1-8 weeks, in months 3, 4, 6 and 12; Time (in weeks) until the CMV-load reaches ≤600 copies/mL	2 years

Collaborators and Investigators

• Sponsor: Marcus Saemann
• Investigators: Study Chair: Sabine Schmaldienst, MD, Medical University of Vienna

Publications and helpful links

General Publications

• Humar A, Michaels M; AST ID Working Group on Infectious Disease Monitoring. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant. 2006 Feb;6(2):262-74. doi: 10.1111/j.1600-6143.2005.01207.x.
• Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990 Sep;11(2):272-6. doi: 10.1016/0168-8278(90)90124-a.
• Kasiske BL, Vazquez MA, Harmon WE, Brown RS, Danovitch GM, Gaston RS, Roth D, Scandling JD, Singer GG. Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol. 2000 Oct;11 Suppl 15:S1-86.

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (ANTICIPATED): December 1, 2013
• Study Completion (ANTICIPATED): June 1, 2014

Study Registration Dates

• First Submitted: January 23, 2009
• First Submitted That Met QC Criteria: January 23, 2009
• First Posted (ESTIMATE): January 26, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): September 3, 2012
• Last Update Submitted That Met QC Criteria: August 30, 2012
• Last Verified: August 1, 2012

More Information

Terms related to this study

• Keywords: renal transplant; Certi-CMV; immunosuppressive switch (to Certican)
• Additional Relevant MeSH Terms: Virus Diseases; Infections; DNA Virus Infections; Herpesviridae Infections; Cytomegalovirus Infections; Physiological Effects of Drugs; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus; Valganciclovir
• Other Study ID Numbers: EudraCT: 2008-004745-28