Cytomegalovirus Control in Critical Care
Information source: University Hospital Birmingham NHS Foundation Trust
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Critical Illness
Intervention: Valaciclovir/Aciclovir (Drug); Valganciclovir/Ganciclovir (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: University Hospital Birmingham NHS Foundation Trust Official(s) and/or principal investigator(s): Julian F Bion, MD FRCP FRCA, Principal Investigator, Affiliation: University Hospital Birmingham NHS Foundation Trust Nicholas J Cowley, MBChB MRCP FRCA, Study Director, Affiliation: University Hospital Birmingham NHS Foundation Trust Paul AH Moss, PhD MRCP MRCPath, Study Director, Affiliation: University Hospital Birmingham NHS Foundation Trust
Summary
The purpose of this study is to determine whether reactivation of latent cytomegalovirus
infection in critically ill patients looked after in the intensive care unit can be
successfully and safely prevented using antiviral agents. Comparison is made between
standard care, and treatment with one of two different antiviral regimens:
valaciclovir/aciclovir, which has a favourable side effect profile but requires high dosage
to be effective, and valganciclovir/ganciclovir, which has more side effects, but has been
demonstrated to be effective in low dosage.
The primary hypothesis is that cytomegalovirus reactivation can be effectively suppressed
with antiviral prophylaxis.
Clinical Details
Official title: Anti-viral Prophylaxis for Prevention of Cytomegalovirus (CMV) Reactivation in Immunocompetent Patients in Critical Care
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention
Primary outcome: Time to reactivation of cytomegalovirus (CMV) polymerase chain reaction (PCR) (defined as above the lower limit of sample assay).
Secondary outcome: Time to reactivation above the lower limit of assay detection of CMV PCR in urine, throat swab and non-directed bronchiolar lavage (NDBL). NDBL whilst trachea is intubated only.Time to >1000 CMV copies in blood, urine, throat swab and NDBL (NDBL whilst intubated) Time to >10000 CMV copies in blood, urine, throat swab and NDBL (NDBL whilst intubated) CMV PCR in blood, urine, throat swab and NDBL (NDBL whilst intubated) Markers of inflammation Clinical Outcomes Clinical Outcomes Clinical Outcomes Clinical Outcomes Number of Serious Adverse events Time to neutropenia (count <1.0x10-9/L) Time to thrombocytopenia (platelet <50x10-9/L) Use of G-CSF or termination of study drug Number of platelet transfusions received Time to renal insufficiency (CrCl <60ml/min, <30ml/min, need for renal support)
Detailed description:
Background:
* Cytomegalovirus (CMV) is a common virus which infects around half the UK population.
Infection is usually mild, but after infection the virus is never completely eradicated, and
may reactivate in ill health. Reactivation is most commonly seen in those with compromised
immune systems, such as people with advanced HIV infection, or whilst on immunosuppression
following organ transplantation. CMV reactivation in these patients can be life threatening.
There is evidence to support the use of antiviral medication in these groups of
immunosuppressed patients to prevent CMV reactivation, and their use is part of standard
therapy. There is increasing evidence demonstrating that a third of critically ill patients
will reactivate CMV, and these patients have as much as a doubled mortality.
Aims:
* This study is a proof of concept study designed to assess whether antiviral prophylaxis
can effectively and safely suppress CMV reactivation in CMV seropositive high risk
critically ill patients. Antiviral prophylaxis is currently not standard practice in
critical care units, and no previous trials of prophylaxis have been undertaken in this
setting. All commonly used antiviral agents have side effects, and it is important to
demonstrate their efficacy and safety in the critical care setting before undertaking a
large multicentre trial powered to identify mortality or morbidity differences with
prophylaxis. Intravenous ganciclovir, and its oral prodrug valganciclovir have been
effectively used as prophylaxis at low doses in immunosuppressed patients. Intravenous
aciclovir and its oral prodrug valaciclovir in high dosage have also been demonstrated to be
effective as prophylaxis in immunosuppressed patients. This study sets out to determine
whether their use in critically ill patients are both effective and safe.
Plan of Investigation:
* This is a prospective, randomised, open-label single centre study. Patients admitted to
the Queen Elizabeth Hospital Birmingham critical care unit, and identified by study criteria
to be at high risk of CMV reactivation will be assessed for inclusion into the study. Blood
will be analysed for CMV antibodies to establish eligibility. Recruited patients will be
randomised to receive high dose aciclovir/valaciclovir, or low dose
ganciclovir/valganciclovir for the duration of their critical care stay, for a maximum of 28
days, or to enter the control group receiving standard care. CMV viral load by polymerase
chain reaction (PCR) will be measured in blood, throat swab, urine, and sputum via
non-directed bronchiolar lavage (NDBL) twice weekly.
Potential Impact:
* Latent CMV infection is common, affecting around half of all adults in the UK. Evidence
demonstrates that a third of these patients will reactivate leading to CMV viraemia when
critically ill. Epidemiological data from multiple independent groups have identified a
doubling in mortality in this group, although a causal link between CMV reactivation and
mortality without a trial of antiviral drugs can not be assumed. From these figures, it is
estimated that 16. 5% of critically ill patients (current mortality rates of around 40%) may
benefit from antiviral prophylaxis. Almost no patients are receiving prophylaxis or
screening for reactivation worldwide in this group. Demonstration of mortality or morbidity
improvements could potentially change worldwide intensive care practice.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Total hospital stay of less than 7 days
- CMV seropositive
- Critical care stay of >24 hours
- Mechanically ventilated, anticipated to continue for > 48 hours
Exclusion Criteria:
- Known Pregnancy or breast feeding
- Expected to survive less than 48 hours
- Confirmed immunosuppression
- Known or suspected Human Immunodeficiency Virus infection
- Known or suspected underlying immunodeficiency (organ transplantation including
stem cell transplantation on immunosuppression, congenital immunodeficiency, in
receipt of immunosuppressive medication e. g. azathioprine, methotrexate,
tacrolimus, cyclosporine, sirolimus, cyclophosphamide within 30 days)
- Corticosteroids: Prednisolone chronic administration may be used up to a dose of
10mg/day on average over the preceding 30 days, stress dose hydrocortisone (up
to 400mg/day) may be used, topical steroids may be used, short duration of
higher dose steroids for exacerbations of chronic obstructive pulmonary disease
(COPD) up to 1mg/kg prednisolone or equivalent are permitted for up to 14 days
- Receipt of chemotherapeutic agent within the last 6 months
- Use of systemic antiviral medication other than oseltamivir within the last 7 days.
- Intubated and mechanically ventilated secondary to brain injury alone.
Locations and Contacts
University Hospitals Birmingham NHS Foundation Trust, Birmingham, West Midlands B15 2WB, United Kingdom
Additional Information
Starting date: January 2012
Last updated: January 9, 2015
|